Autacoids and Related Drugs


The word autacoids come from the Greek “autos” (self) and “Ecos” (relief; i.e., drug). Autacoids or “autocoids” are biological factors (molecules) that act as local hormones, have a brief duration, and act near their site of synthesis. Vasodilator autacoids are released during periods of exercise.

The effects of autacoids are primarily local, though large quantities can be produced and moved into circulation. Autacoids may thus have systemic effects by being transported via circulation. These regulating molecules are also metabolized locally. In sum, these compounds typically are produced locally, act locally, and are metabolized locally. Autacoids can have a variety of different biological actions, including modulating the activities of smooth muscles, glands, nerves, platelets, and other tissues.

Some autacoids are chiefly characterized by the effect they have on specific tissues, such as smooth muscle. For vascular smooth muscle, there exist both vasoconstrictor and vasodilator autacoids. Vasodilator autacoids are released during periods of exercise. Their main effect is seen in the skin, where they facilitate heat loss.

These are local hormones; they, therefore, have a paracrine effect. Some notable autacoids are eicosanoids, angiotensin, neurotensin, NO (nitric oxide), kinins, histamine, serotonin, endothelins, and palmitoylethanolamide.

Recently, research on autacoids has given rise to the nascent field of “Autacoid Medicine” particularly since new lipid autacoids are of utility in the treatment of chronic disorders, where inflammation plays a role. In 2015, a new definition of autacoids was proposed, which helps to more specifically describe Autacoid Medicine.

Autacoids and Related Drugs


These are heterogeneous substances produced by a wide variety of cells having widely different structures and intense biological activity but generally act locally at the site of its synthesis and release.

“Autacoids are locally produced modulating factors, influencing locally the function of cells and/or tissues, which are produced on demand and which subsequently are metabolized in the same cells and/or tissues”.

Classification of Autacoids:

  1. Amine Autacoids (Decarboxylated autacoids amines): Histamine, 5-hydroxy tryptamine (Serotonin).
  2. Peptide autacoids (Polypeptide): Bradykinin, Kallidin, Vasoactive intestinal peptides.
  3. Lipid-derived autacoids (Eicosonoids): Prostaglandins, Thromboxane, Leucotrines, Platelets activating factors (PAF).


Different autacoids are:

  • Histamine
  • 5 Hydroxytryptamine (5HT)
  • Bradykinin and Kallidin
  • Cytokines
  • Autacoids derived from membrane phospholipid
  1. Eicosanoids – arachidonic acid
  2. (PG, PGI, TXA2, LT)
  3. Modified phospholipids – PAF



Histamine is a basic amine formed from histidine by histidine decarboxylase.

Storage: It is found in most tissues but is present in high concentrations in the lungs and the skin, and particularly high concentrations in the gastrointestinal tract. At the cellular level, it is found largely in mast cells but non-mast cell histamine occurs in ‘Histaminocytes’ in the stomach and histaminergic neurons in the brain.

In mast cells and basophils, histamine is complexed in intracellular granules with an acidic protein and high-molecular-weight heparin termed Macroheparin. Stored in granules of mast cells, basophils and secreted when complement interact with cell membranes or antigen with cell IgE.

Others – GIT, lungs, skin, heart, liver, neural tissue, reproductive mucosa, rapidly growing tissues, and body fluids.

Produces effects by acting on H1, H2, H3 receptors.

Histamine Release

Histamine is released from mast cells by exocytosis during inflammatory or allergic reactions. Stimuli include C3a and C5a that interact with specific surface receptors and the combination of antigen with cell-fixed IgE antibodies. In common with many secretory processes, histamine release is initiated by a rise in cytosolic Ca2+. Various basic drugs, such as morphine and tubocurarine, release histamine through a non-receptor action. Agents that increase cAMP formation (e.g. β-adrenoceptor agonists;) inhibit histamine secretion. Replenishment of secreted histamine by mast cells or basophils is a slow process, which may take days or weeks, whereas turnover of histamine in the gastric Histaminocyte is very rapid. Histamine is metabolized by histaminase and/or by the methylating enzyme imidazole N-methyltransferase.

Histamine-Synthesis and Metabolism

Synthesis and Metabolism of histamines
Fig.1: Synthesis and Metabolism of histamines


  • Histamine act on the H1 (Gq, protein-coupled) receptor causes activation of IP3 and DAG and protein kinase, and releases NO.
  • Histamine acts on the H2 (GS protein-coupled) receptor and causes activation of cAMP and release of Ca2+. Activation of H/K+ ATPase pumps and increases HCL secretion.
  • Histamine acts on H3 (Gi protein-coupled) receptor and inactivates cAMP and decreased the influx of calcium and opening of K+ channels.
Autacoids and Related Drugs

Table.1: Selected Actions of Histamine in Humans:

H1 – Located in the postsynaptic membrane:
Smooth muscles – Contraction
Blood vessels – Vasodilation
Sensory nerve endings – Pain, itching.
H2 – Located in the postsynaptic membrane:
Gastric glands – Acid secretion
Blood vessels – Vasodilation
Heart – Increased FOC and HR.
Brain presynaptic – Decreases histamine, NE, Ach release.
Lung, Spleen, Gastric mucosaDecreases histamine release
CD4 T cells.
H1, H2 – Located in the postsynaptic membrane.
H3 – Presynaptic.
H1 – Predominant in endotracheal and smooth muscle.
H2 – Facial veins, carotid a, pulm. a heart gastric mucosa, heart, smooth muscle, and some immune cells.
H3 – Several areas in CNS.
Triple response – Wheal, flare, and redness.

Pharmacological Action:

1. CVS: H1 mediated response

Blood vessels:

  • Contraction of major blood vessels like arteries and veins.
  • Dilation of minor blood vessels like capillaries, venules, and cranial blood vessels.
  • Net effects – vasodilatation.

Blood pressure:

  • Moderate dose – Hypotension.
  • High dose – prolonged hypotension.


  • Increase forced and frequency of ventricular contraction.
  • Increased coronary blood flow.
  • Large dose – Ventricular arrhythmias.
2. Allergic Reaction: H1 mediated response.

Itching occurs if histamine is injected into the skin or applied to a blister base because it stimulates sensory nerve endings by an H1-dependent mechanism. Injected intradermally, histamine causes the ‘triple response’:

  • Reddening /Flush (local vasodilatation),
  • Flare (bright flare, irregular outline extended up to 1-5 mm beyond flush, it is developed from an ‘axon’ reflex in sensory nerves releasing a peptide mediator) and
  • Weal (direct action on blood vessels, developments of localized edema due to escape of fluid from localized capillaries )
3. Smooth muscle: H1 mediated response.
  • Moderate dose – Contraction of smooth muscles of GIT urethral.
  • High dose – Abdominal cramps, colic and increase intestinal contraction.
4. Exocrine glands: H2 mediated response.

Powerful stimulation of gastric acid and pepsin secretion. Histamine acts on the H2 (Gs protein-coupled) receptor and causes activation of cAMP and release of Ca2+. Activation of H/K+ ATPase pumps and increases HCl secretion.

Exocrine glands - Autacoids
5. CNS: H3 mediated response.

Histamine does not cross BBB its synthesized locally from histidine. The central physiological role is not clear, intracerebral and intravertebral injection may cause hypothermia and vomiting.

6. Autonomic ganglion and adrenal medulla:

Histamine at high concentration stimulates both and causes the release of Adrenaline.

  • Major pathways: Histamine is metabolized by histaminase and/or by the methylating enzyme imidazole N-methyltransferase, and converts to N-methyl histamine, which is an act by MAO, after oxidation excreted in urine as methyl imidazole acetic acid.
  • Deamination: Small intestine, liver, kidney, and monocytes. Methylation – small intestine, liver, skin, kidney, thymus, and leukocytes. N-methylimidazole acetic acid − principal urinary metabolite
Metabolism of Histamine - Autacoids
Fig.2: Metabolism of Histamine

1. Role in allergic responses – Ag + IgE (bound to mast cells and basophils).

2. Preformed mediators.

3. Most important mechanism of release/controlled by H2 esp. in skin and blood.

4. Release of other autacoids.

5. Release by drugs (morphine, urase, amines), peptides, venoms, and other agents.

6. Release by urticarias.

7. Gastric secretagogue.

8. Neurotransmitter → increased wakefulness, thermoregulation.

  • Hypotension, Flushing, Headache, Visuals distribution, Allergic reaction like-Flush, flare and weal, Anaphylaxis shock.



These are the drugs that antagonized various actions of histamine that liberate in the body or are exogenously administered.

These drugs are used mainly for symptomatic relief of allergic disorders and peptic ulcers.

These acts in 3 Ways:

  • Physiological Antagonist: Adrenaline
  • By inhibiting the release of histamine from the sensitive mast cells following:
  1. Antigen-Antibody reaction – Disodium cromoglycate, Nedocromil Sodium, Calcium channels blockers, Loratidine, Cetirizine
  • Receptor antagonists – This prevents histamine to reach the site of actions.

Competitively inhibits the action of Histamine at Histamine Receptor:

  • These are the competitive Antagonists at all the H receptors.
  • H1 antagonists: Triprolidine, Chlorpheniramine.
  • H2 antagonists: Ranitidine, Famotidine.
  • H3 antagonists: Iodophenprofit, Chlobenpropit.
  • H4 antagonists: Thioperamide.

Classifications of H1 Antagonists:

1. Potent and Sedative: Diphenhydramine, Promethazine, Dimenhydramine.

2. Potent and non-Sedative: Tripalanamine, Chlorcyclizine, Chlorpheniramine.

3. Less Potent and Less sedative: Pheniramine, Phenindone, Mepyramine.

4. Non-sedative:

  • First-generation: Loratidine, Cetrizine, hydroxyzine.
  • Second generation: Astimazole, Acrivastine, Terfenamide, Desloratidine, Fexofenatidine.
  • First-generation ones are short/ intermediate-acting; more sedating; more antimuscarinic effects.
  • The second generation has a longer duration of action, poor permeability to BBB, so less sedating.

Histamine H2 receptor blocker: Cimetidine, Ranitidine, Famotidine.


Antihistamine blocks histamine receptors and antagonizes the action produce by histamine.

Pharmacological Action:
H1 Receptor Blocking Action:

It produced CNS depression that may lead to sedation, hypnosis, drowsiness, and sleep. These drugs also may be used in motion sickness due to various degrees of CNS depression.

Smooth Muscles:

It antagonizes the contraction of bronchial smooth muscles produced by histamine and relaxes bronchial smooth muscles.

The relaxation of smooth muscles of the intestine, uterus, and gall bladder is lesser extent compared to bronchial smooth muscles.

These all action mediated through H1 receptor blocking action.


It produces membrane-stabilizing action which leads to anti-arrhythmic effects. It also produced relaxation of vascular smooth muscles.

Anti-Parkinsonism effects:

It produced anticholinergic effects which may lead to decreased acetylcholine and caused relief from Parkinsonism.

Local anesthetics action:

Due to its membrane-stabilizing action, it produces local anesthesia.

General action: It blocks histamine receptors and causes relief from all allergic reactions including the triple response.

H2 Receptor Blocking Action:
H2 Receptor Blocking Action - Autacoids

ADME: Well absorbed by oral and parenteral routes of administration, 50-60% binds to plasma proteins, metabolized in the liver by hydroxylation, and followed by glucuronide conjugation and excreted in the urine.

Therapeutic uses: H1 Blocker:
  • Prevents or treats symptoms of allergic rhinitis and urticaria.
  • First-generation ones cause sedation and are better for itching so used in atopic dermatitis.
  • Second-generation ones are non-sedative, preferred for hay fever.
  • Most of them show antimuscarinic effects, though as a side effect.
  • So used in motion sickness( cyclizine, meclizine).
  • Used as anti-emetics( hydroxyzine, promethazine).
  • Suppressing Parkinsonism Symptoms( Diphenhydramine, promethazine).
ADR: H1 Blocker:
  • Sedation and anticholinergic actions like dry mouth, urinary retention, constipation.
  • Drug allergy with topical agents.
  • Tolerance after prolonged use.
  • Teratogenic effects by hydroxyzine, cyclizine.
  • Toxic doses lead to excitement, hallucinations, convulsions, and coma.
  • Drowsiness, Euphoria, diplopia, tinnitus, weakness.
  • High Dose- Anticholinergic effects- Gastric distress, Dryness of mouth and throat, Blurred vision, Lightness of chest, Hypotension.
Therapeutic uses: H2 Blocker:
  • In peptic ulcer.
  • Duodenal ulcer.
  • Zollinger Ellison syndrome.
  • Gastro-esophageal reflux.
  • Heartburn.
ADR: H2 Blocker:
  • Headache, fatigue, myalgia, constipation.
  • Mental status change occurs with cimetidine.
  • Endocrinal effects with Cimetidine.
  • Male impotence.
  • Skin rashes, headache, dizziness, gynecomastia, Impotence, Mental confusion, Hepatotoxicity.
Histamine Release Inhibitors
  • Examples are Cromolyn Sodium and Nedocromil Sodium.
  • They prevent degranulation of mast cells hence inhibit histamine release.
  • Used as pulmonary inhalants in the treatment of bronchial asthma.
  • Nasal and ophthalmic formulations are used to reduce symptoms of allergic rhinitis and conjunctivitis.


  • In humans, present in GI enterochromaffin cells (90%), platelets, and the brain.
  • Synthesized from tryptophan (in diet) in two steps.
  • Platelets do not synthesize but take up from blood (active uptake process in platelets and nerve terminals).


Widely distributed amine (animals + plants). In humans, present in the Small intestine-(90%, found in enterochromaffin cells) platelets, mast cells, lungs, bone marrow, pineal gland, and CNS

Sources: Tunicates, mollusks, anthropods, coelenterates, fruits, nuts, wasps, and scorpions, Cell storage in granules similar to catecholamines.

Synthesis and metabolism of 5-HT

  • Competition at the level of brain and neuronal uptake
  • Rate limiting enzyme not saturated usually
  • No end-product negative feedback
  • 5-OHTr decarboxylase same as DOPA decarboxylase
  • 5-OHIAA actively extruded from CNS (probenecid-sensitive) and excreted in the urine.
 Tryptophan hydroxylase
 5- hydroxytryptophan
 L-amino acid decarboxylase
 5 hydroxytryptamine (Serotonin)
 5-hydroxy indole acetaldehyde
 Aldehyde dehydrogenase
 5-hydroxy indole acetic acid 
5HT1 – Subtypes:
  • Located in CNS.
  • Inhibitory pre-synaptic receptor.
  • Behavioral effects, Sleep, anxiety, thermoregulation, Decreased CAMP.
  • Located in CNS, Vascular smooth muscle.
  • Pulmonary contraction, Behavioural effects, Inhibitory pre-synaptic receptor decreased CAMP.
  • Act by decreasing IP3 – DAG system.
  • Most parts of the brain, cranial blood vessels.
  • Cerebral vasoconstriction.
  • Behavioral effects decreased CAMP.
  • Act by decreasing IP3 – DAG system.
  • Located mainly CNS, Smooth Muscles, and Platelets.
  • CNS, PNS, Smooth Muscles, and Platelets.
  • Excitements, Platelet aggregation.
  • Behavioral effects, GIT, and bronchial smooth muscle contraction.
  • Act by Increasing IP3 – DAG system.
  • Located in the gastric fundus.
  • Contraction.
  • Act by Increasing IP3 – DAG system.
  • Located in CNS, Choroid plexus, and hippocampus.
  • CSF secretion.
  • Act by Increasing IP3 – DAG system.
  • Located in PNS and CNS.
  • Neuronal excitation, emesis, anxiety, and behavioral effects.
  • Act by increasing IP3 – DAG system.
  • Located in PNS and CNS.
  • Neuronal motility and excitation.
  • Act by increasing IP3 – DAG system.
  • Located in CNS, hippocampus
  • Decrease CAMP
  • Act by Decreasing IP3 – DAG system
  • CNS, Stratum
  • Increased cAMP
  • Act by Increasing IP3 – DAG system
  • CNS, Hippocampus
  • GIT, Blood vessels
  • Increased cAMP
  • Act by Increasing IP3 – DAG system
Endogenous Function:
  • Central neurotransmitter
  • Precursor of melatonin
  • GI tract: uncertain; motility?
  • In carcinoid tumors: large amounts released leading to diarrhea, bronchoconstriction, and edema
  • Platelets: 5-HT2 receptors → aggregation and vasoconstriction
Pharmacological actions of 5HT:
  • Serotonin-mediated actions through a large number of receptors that possess diverse characteristics.
  • Among these many subtypes, receptors lack any specific physiological roles, So common actions are:
  • It is a very important neurotransmitter in CNS – in the brain, brain stem, hypothalamus, raphae nuclei, limbic system, pituitary glands.
  • 5HT causes regulation of mood, behavior, sleep, depression, pain, sexual activity, thermoregulation, pain perception, and Sleep/Wakefulness.
  • Various behaviors normal/abnormal: depression, schizophrenia, obsessive-compulsive behavior, etc.
  • Neuroendocrine regulation – controls hypothalamic cells involved in the release of several anterior pituitary hormones.
  • Hypothalamic controls release pituitary hormones.
  • 5HT in the pineal gland is a precursor for the synthesis of melatonin, a melanocyte-stimulating hormone, which controls/ influences sleep.
  • 5HT acts on 5HT2 receptors to dilate blood vessels of the skin, heart, smooth muscles, and skeletal muscles.
  • It also produces bradycardia, decreased COP – Overall result is decreased BP/Hypotension, though there is minor peripheral vasoconstriction.
Platelets Aggregation:
  • It causes released of more 5HT by acting on 5HT2A receptor and also cause the release of platelets, resulting in forms clot and decreased blood shade out of the damaged organ.
  • The small intestine is very sensitive to serotonin → intense rhythmic contractions due to direct and indirect (ganglia in a wall) effects.
  • Increased GI peristalsis partly by acting on 5HT2 and partly by acting on 5HT3 and 5HT4.
  • Increased gastric acid secretion results in GIT irritation and nausea, vomiting.
Respiratory system:
  • Broncho constriction if asthmatic; stimulation of aortic and carotid chemoreceptors → ↑ RR and minute vol.
  • Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally).
  • 5HT causes contraction of Bronchial smooth muscles.
  • It produces anorexia.
  • It increased pain perception and itching.

ADME: Well absorbed and rapidly degraded

5 hydroxytryptamine (Serotonin)
 5-hydroxy-indole acetaldehyde
 Aldehyde dehydrogenase
 5-hydroxy-indole acetic acid
 It is excreted through urine. 
Therapeutic use:
  • Useful in various inflammatory responses.

ADR: GIT irritation, vertigo, insomnia, hypotension, edema, nausea, and vomiting.

Drugs acting on 5HT Receptors:
Serotonin Agonists:
  • Sumatriptan: 5-HT1D agonist; contraindicated in patients with angina.
  • Fluoxetine: Selective serotonin uptake inhibitors for depression and other indications.
  • Buspirone: 5-HT1A agonist for anxiety.
  • Cisapride: 5-HT4 agonist to ↑ GI motility and decrease G-E reflux (Removed from US market due to fatal arrhythmias).
  • LSD: 5HT1A – hallucinogen.
  • Ergot alkaloids: 5-HT1 and 2 and other receptors.
Serotonin Antagonists:
  • Methysergide and Cyproheptadine: 5HT2 antagonists. In carcinoid, migraine.
  • Ketanserin: 5HT2 and Alpha antagonist – used as antihypertensive.
  • Ondansetron: 5HT3 antagonist for chemotherapy-induced nausea and vomiting
  • Clozapine: 5HT2A/2C antagonist: for schizophrenia.
5HT Receptor Agonists
  • Newer anti-anxiety drugs, Non-Benzodiazepine group.
  • Partial agonist of 5HT1 receptor in CNS.
  • Selective agonist at 5HT1B and 5HT1D.
  • Cerebral vasoconstrictor agents regularly use in a migraine attack.
Cisapride and Renzapride:
  • 5HT4 receptor agonists, Increased GI motility use to treat gastroesophageal reflux.
5HT Receptor Antagonists:
  • 5HT2A receptor antagonists also block 5HT2C Receptors.
  • Effective antihypertensive agents with mild effects-Dizziness, Lethargy, nausea, and dry mouth.
  • More selective 5HT2A antagonists than Ketanserin.
  • Significant α1 blocking action. It inhibits thromboxane formation and platelet aggregation and increased bleeding time.
Ondansetron, Granisetron, Dolasetron:
  • 5HT3 antagonists
  • Use in chemotherapy-induced emesis.
  • Potent 5HT2A and D2 receptor antagonists. Use as antipsychotic agents
  • Ergot group of alkaloids
  • Potent 5HT2A-2C antagonists.
  • Prophylaxis of Migraine and post gastrectomy.
  • Potent 5HT2 receptor antagonists.
  • Also having antihistaminic and anticholinergic action.
  • Possesses significant CNS depression action.
  • Reduced allergic reactions.
  • Stimulate appetite probably by acting on hypothalamus, increased weight gain from the first week of therapy and decreased once its stops.
  • It decreases Aldosterone production.
  • It also controls the secretion of ACTH secretion by the hypothalamus.
Therapeutic uses:
  • Relief from pruritis, urticaria, dermatitis, itching, skin disease, rashes, patches.
  • Treatment of Gastrectomy.
  • Dryness of mouth, Ataxia, Mental confusion, Headache, Visual hallucination.


Clinical Presentations:
  • Often accompanied by a brief aura (visual scotomas, hemianopia).
  • Severe, throbbing, usually unilateral headache (few hours to a few days in duration).
Migraine Pathophysiology:
  • The vasomotor mechanism — inferred from:
  1. increased temporal artery pulsation magnitude.
  2. pain relief (by ergotamine) occurs with decreased artery pulsations.
  • Migraine attack associated with (based on histological studies):
  1. sterile neurogenic perivascular edema.
  2. inflammation (clinically effective antimigraine medication reduces perivascular inflammation).
Migraine: Drug Treatment:

Ergotamine: best results when drug administered before the attack (prodromal phase) −less effective as the attack progresses.

  • Combined with caffeine: better absorption
  • Potentially severe long-lasting Vasoconstriction.

Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine.

Nonsteroidal Antiinflammatory Drugs (NSAIDs):

Sumatriptan: Alternative to ergotamine for acute migraine treatment; not recommended for patients with coronary vascular disease risk.

  • Formulations: subcutaneous injection, oral, nasal spray.
  • Selective serotonin-receptor agonist (short duration of action).
  • Probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray).
Migraine: Prophylaxis:
  • Effective in about 60% of patients.
  • NOT effective in treating an active migraine attack or even preventing an impending attack.
  • Methysergide toxicity: retroperitoneal fibroplasia, subendocardial fibrosis. Recommend 3-4 week drug holiday every six months.
  • Most common for continuous prophylaxis
  • Best established drug for migraine attack prevention.
Amitriptyline (TCA):
  • Most frequently used among the tricyclic antidepressants.
Valproic acid (Antiepileptic)
  • Effective in decreasing migraine frequency.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Used for attack prevention and aborting acute attack.

Platelet-activating factor (PAF)

  • Platelet-activating factor, also known as PAF, is a potent phospholipid activator and mediator of many leukocyte functions, platelet aggregation, degranulation, inflammation, and anaphylaxis. It is also involved in changes to vascular permeability, the oxidative burst, chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism in phagocytes.
  • PAF is produced by a variety of cells, but especially those involved in host defense, such as platelets, endothelial cells, neutrophils, monocytes, and macrophages. PAF is continuously produced by these cells but in low quantities and production is controlled by the activity of PAF acetyl-hydrolases. It is produced in larger quantities by inflammatory cells in response to specific stimuli.
  • Platelets are involved primarily in coagulation and thrombotic phenomena but also play a part in inflammation. They have low-affinity receptors for IgE and are believed to contribute to the first phase of asthma. In addition to generating thromboxane (TX) A2 and PAF, they can generate free radicals and proinflammatory cationic proteins. Platelet-derived growth factor contributes to the repair processes that follow inflammatory responses or damage to blood vessels.


Membrane acyl-PAF
 Phospholipase A2
 Lyso PAF
 Acetyl CoA

PAF is biosynthesized from acyl-PAF in a two-step process. The action of PLA2 on acyl-PAF produces lyso-PAF, which is then acetylated to give PAF. PAF, in turn, can be deacetylated to the inactive lyso-PAF.

Sources of platelet-activating factor:

Platelets stimulated with thrombin and most inflammatory cells can release PAF under the right circumstances.

Pharmacological action:
  • PAF receptor is a G-protein coupled receptor. Activate IP3-DAG system

Increased Ca2++ release

  • By acting on specific receptors, PAF is capable of producing many of the signs and symptoms of inflammation.
  • Chemotactic to neutrophils and eosinophils.
  • Activate leucocytes.
  • Activate platelet aggregation.
  • It produces vasodilatation (and thus erythema), increased vascular permeability, and weal formation.
  • Higher doses produce hyperalgesia. It is potent chemotaxis for neutrophils and monocytes and recruits eosinophils into the bronchial mucosa in the late phase of asthma.
  • It can activate PLA2 and initiates eicosanoid synthesis.
  • On platelets, PAF triggers arachidonate turnover and TXA2 generation, producing shape change and the release of the granule contents. This is important in hemostasis and thrombosis.
  • PAF has spasmogenic effects on both bronchial and ileal smooth muscle.
  • The anti-inflammatory actions of the glucocorticoids may be caused, at least in part, by inhibition of PAF synthesis.
  • Competitive antagonists of PAF and/or specific inhibitors of lyso-PAF acetyltransferase could well be useful anti-inflammatory drugs and/or antiasthmatic agents.
  • The PAF antagonist lexipafant is in a clinical trial in the treatment of acute pancreatitis.


  • Any of a group of biologically active compounds, originally isolated from leucocytes.
  • Leuko – because they are made by white cells, and trienes because they contain conjugated a triene system of double bonds.
  • Synthesized from arachidonic acid by lipoxygenase catalyzed pathways.
  • Mainly found in lung, platelets, mast cells, and white blood cells.
  • Leukotrienes together with prostaglandins and other related compounds are derived from 20 carbon fatty acids that contain double carbon. Hence this group is called Eicosanoids.
  • It is produced along with histamine, unlike histamine, they are more potent and has a longer duration, and is called Slow Reacting Substances (SRS).
  • The main enzyme in this group is 5-lipoxygenase.
  • On cell activation, this enzyme translocates to the nuclear membrane, where it associates with a crucial accessory protein, affectionately termed FLAP (five-lipoxygenase activating protein.
  • The 5-lipoxygenase incorporates a hydroperoxy group at C5 in arachidonic to form 5-hydroperoxytetraenoic acid (5-HPETE) leading to the production of unstable acid leukotriene(LTA4) which is enzymatically converted to LTB4.
  • LTB4, utilizing a separate the glutathione, to with conjugation involving pathway cysteinyl-containing leukotrienes LTC4, LTD4, LTE4 and LTF4 (Sulfidopeptide leukotrienes by mainly )which are produced eosinophils, mast cells, basophils macrophages.
  • LTB4 is produced mainly by neutrophils.
  • Lipoxins and other active products, some of which have anti-inflammatory properties, are also produced from arachidonate.
Receptors and Actions:
  • Receptors are termed BLT if the ligand is LTB4, CysLT for the cysteinyl leukotrienes.
  • Receptors coupled with Gq protein and function through the IP3/DAG transducer mechanism.
  • BLT receptors are chemotactic and primarily expressed in leucocytes and the spleen. BLT1 receptor has high, while BLT2 receptor has lower affinity for LTB4.
Leukotrienes B4 Receptors (BLT):


1. BLTR1

2. BLTR2

  • G Protein-coupled receptors associated with Gq, activated upon binding of cells.
  • Gq stimulates the membrane-bound phospholipase C which then cleaves PIP2 into two-second messengers IP3 and DAG.
  • DAG remains bound to the membrane and IP3 is released.
  • IP3 binds to IP3 receptors within cells particularly Calcium channels in the endoplasmic reticulum and causes an increase in the release of Ca.
Cysteinyl Leukotrienes:

They include

1. LTC4

2. LTD4

3. LTE4

  • The signaling pathway is similar to LTB receptors.
  • Mainly expressed in bronchial and intestinal muscle and has a higher affinity for LTD4 than for LTC4.
  • The primary location of the cysLT2 receptor is leucocytes and spleen, and it shows no preference for LTD4 over LTC4.
  • Cysteinyl leukotrienes may mediate the cardiovascular changes of acute anaphylaxis.
  • Agents that inhibit 5-lipoxygenase are therefore obvious candidates for anti-asthmatic and anti-inflammatory agents.
  • All Leukotrienes acts through the IP3 DAG system.
Pharmacological Action:
The respiratory system:
  • Cysteinyl leukotrienes are potent spasmogens contraction of human, causing the dose-related muscle in vitro bronchiolar
  • LTE4 is less potent than LTC4 and LTD4, mucus secretion is lasting. All-cause and increase but its effect is much longer.
The cardiovascular system:
  • Small amounts of LTC4 or LTD4 given pressure, and rapid, short-lived fall in blood intravenously cause a constriction of small coronary resistance vessels.
The role in inflammation:
  • LTB4 is a potent chemotactic agent for neutrophils and macrophages.
  • Regulates membrane adhesion molecule expression on neutrophils, and increases the production of toxic oxygen products and the release of granule enzymes.
On macrophages and lymphocytes:
  • Its release and stimulates proliferation and cytokine control and regulation.
Membrane Phospholipids:
  • Control and regulation are dependent on factors like availability and the amount of integral fatty acids.
  • Alpha linoleic acid present in the plasma membrane.
  • Fatty acids are broken down to arachidonic by lipoxygenase for leukotriene synthesis.
  • LTB4 is metabolized by a unique membrane-bound cytochrome P450 enzyme in neutrophils and then further oxidized to 20-carboxy-LTB4
  • LTC4 and LTD4 are metabolized to LTE4, which is excreted in the urine
Therapeutic Uses:
  • Abortion
  • Induction of labor
  • Postpartum hemorrhage
  • Cervical ripening
  • Peptic ulcer
  • Glaucoma
  • To avoid platelet damage
  • Nausea
  • Vomiting
  • Diarrhea
  • Uterine cramps
  • Forceful uterine contractions
  • Flushing
  • Shivering
  • Fever
  • Fall in BP
  • Tachycardia
  • Chest pain.


Bradykinin and lysyl bradykinin (kallidin) are active peptides formed by proteolytic cleavage of circulating proteins termed kininogens through a protease cascade pathway.

Source and Formation of Bradykinin

  • An outline of the formation of bradykinin from high-molecular-weight kininogen in plasma by the serine protease kallikrein.
  • Kininogen is a plasma α-globulin that exists in both high and low molecular weight forms. Kallikrein is derived from the inactive precursor prekallikrein by the action of the Hageman factor (factor XII).
  • Hageman factor is activated by contact with negatively charged surfaces such as collagen, basement membrane, bacterial lipopolysaccharides, urate crystals, and so on.
  • Hageman factor, prekallikrein, and the kininogens leak out of the vessels during inflammation because of increased vascular permeability, and exposure to negatively charged surfaces promotes the interaction of Hageman factor with prekallikrein.
  • The activated enzyme then ‘clips’ bradykinin from its kininogen precursor.
  • Kallikrein can also activate the complement system and can convert plasminogen to plasmin.
  • In addition to plasma kallikrein, there are other kinin-generating isoenzymes found in the pancreas, salivary glands, colon, and skin. These tissue kallikreins act on both high and low-molecular-weight kininogens and generate mainly kallidin, a peptide with actions similar to those of bradykinin.

Metabolism and Inactivation of Bradykinin

  • Specific enzymes that inactivate bradykinin and related kinins are called kininases.
  • One of these, kininase II, is a peptidyl dipeptidase that inactivates kinins by removing the two C-terminal amino acids.
  • This enzyme, which is bound to the luminal surface of endothelial cells, is identical to an angiotensin-converting enzyme which cleaves the two C-terminal residues from the inactive peptide angiotensin I, converting it to the active vasoconstrictor peptide angiotensin II.
  • Thus kininase II inactivates a vasodilator and activates a vasoconstrictor.
  • Potentiation of bradykinin actions by ACE inhibitors may contribute to some side effects of these drugs (e.g. cough).
  • Kinins are also metabolized by various less specific peptidases, including a serum carboxypeptidase that removes the C-terminal arginine, generating des-Arg9- bradykinin, a specific agonist at one of the two main classes of bradykinin receptor.

Bradykinin Receptors

  • There are two bradykinin receptors, designated B1 and B2.
  • Both are G-protein-coupled receptors and mediate very similar effects.
  • B1 receptors are normally expressed at very low levels but are strongly induced in inflamed or damaged tissues by cytokines such as IL-1.
  • B1 receptors respond to des-Arg9- bradykinin but not to bradykinin itself. Several selective peptide antagonists are known.
  • B1 receptors likely play a significant role in inflammation and hyperalgesia, and there is recent interest in developing antagonists for use in cough and neurological disorders.
  • B2 receptors are constitutively present in many normal cells and are activated by bradykinin and kallidin, but not by des-Arg9 -bradykinin.
  • Peptide and non-peptide antagonists have been developed, the best known being icatibant. None are yet available for clinical use.

Actions and Role of Bradykinin in Inflammation

  • Bradykinin causes vasodilatation and increased vascular permeability.
  • Its vasodilator action is partly a result of the generation of PGI2 and the release of NO.
  • It is a potent pain-producing agent, and its action is potentiated by prostaglandins. It stimulates pain nerve endings.
  • Bradykinin also has spasmogenic actions on intestinal, uterine, and bronchial smooth muscle (in some species).
  • The contraction is slow and sustained in comparison with that produced by histamine (hence Brady, which means ‘slow’).
  • Although bradykinin reproduces many inflammatory signs and symptoms, its role in inflammation and allergy has not been clearly defined, partly because its effects are often part of a complex cascade of events triggered by other mediators.
  • However, excessive bradykinin production contributes to the diarrhea of gastrointestinal disorders, and in allergic rhinitis, it stimulates nasopharyngeal secretion.
  • Bradykinin also contributes to the clinical picture in pancreatitis.
  • Physiologically, the release of bradykinin by tissue kallikrein may regulate blood flow to certain exocrine glands and influence secretions.
  • It also stimulates ion transport and fluid secretion by some epithelia, including the intestine, airways, and gall bladder.


  • Unlike histamine, eicosanoids are not performed in cells but are generated from phospholipid precursors on demand.
  • They are implicated in the control of many physiological processes and are among the most important mediators and modulators of the inflammatory reaction.
  • Interest in eicosanoids arose in the 1930s after reports that semen contained a lipid substance that contracted uterine smooth muscle.
  • The substance was believed to originate in the prostate and was saddled with the misnomer prostaglandin.
  • Later, it became clear that prostaglandin was not a single substance but a whole family of compounds that could be generated from 20-carbon unsaturated fatty acids by virtually all cells.
Structure and biosynthesis
  • In mammals, the main eicosanoid precursor is arachidonic acid (5,8,11,14- eicosatetraenoic acid), a 20-carbon unsaturated fatty acid-containing four double bonds (hence eicosa, referring to the 20 carbon atoms, and tetradic, referring to the four double bonds).
  • In most cell types, arachidonic acid is esterified in the phospholipid pool, and the concentration of the free acid is low.
  • The principal eicosanoids are the prostaglandins, the thromboxanes, and the leukotrienes, although other derivatives of arachidonate, for example, the lipoxins, are also produced.
  • (The term prostanoid will be used here to encompass both prostaglandins and thromboxanes.)
  • In most instances, the initial and rate-limiting step in eicosanoid synthesis is the liberation of arachidonate, either in a one-step process or a two-step process from phospholipids by the enzyme phospholipase A2 (PLA2).
  • Several species exist, but the most important is probably the highly regulated cytosolic PLA2. This enzyme generates not only arachidonic acid (and thus eicosanoids) but also lysoglyceryl-phosphorylcholine (lyso-PAF), the precursor of platelet-activating factor, another inflammatory mediator.
  • Cytosolic PLA2 is activated (and hence arachidonic acid liberated) by phosphorylation.
  • This occurs in response to signal transduction events triggered by many stimuli, such as thrombin action on platelets, C5a on neutrophils, bradykinin on fibroblasts, and antigen-antibody reactions on mast cells.
  • General cell damage also triggers the activation process. The free arachidonic acid is metabolized by several pathways, including the following.
  • Fatty acid cyclo-oxygenase (COX). Two main isoform forms, COX-1 and COX-2, transform arachidonic acid to prostaglandins and thromboxanes.
  • Lipoxygenases: Several subtypes synthesize leukotrienes, lipoxins, or other compounds.


  • The term prostanoids encompass prostaglandins and thromboxanes.
  • Cyclo-oxygenases (Coxs) oxidize arachidonate, producing the unstable intermediates prostaglandin (PG) G2 and PGH2.
  • There are two main COX isoforms: COX-1, a constitutive enzyme, and COX-2, which is often induced by inflammatory stimuli.
  • Cyclo-oxygenase-1 is present in most cells as a constitutive enzyme that produces prostanoids that act as homeostatic regulators (e.g. modulating vascular responses), whereas COX-2 is not normally present but is strongly induced by inflammatory stimuli and therefore believed to be more relevant to inflammation therapy (see next chapter for a full discussion of this point).
  • Both enzymes catalyze the incorporation of two molecules of oxygen into every arachidonate molecule, forming the highly unstable endoperoxides PGG2 and PGH2.
  • These are rapidly transformed by isomerase or synthase enzymes to PGE2, PGI2, PGD2, PGF2α, and TXA2, which are the principal bioactive end products of this reaction.
  • The mix of eicosanoids thus produced varies between cell types depending on the particular endoperoxide isomerases or synthases present. In platelets, for example, TXA2 predominates, whereas in vascular endothelium PGI2 is the main product.
  • Macrophages, neutrophils, and mast cells synthesize a mixture of products. If eicosatrienoic acid (three double bonds) rather than arachidonic acid is the substrate, the resulting prostanoids have only a single double bond, for example, PGE1, while eicosapentaenoic acid, which contains five double bonds, yields PGE3.
  • The latter substrate is significant because it is present in abundance in some fish oils and may, if present in sufficient amounts in the diet, come to represent a significant fraction of cellular fatty acids.
  • When this occurs, the production of the proinflammatory PGE2 is diminished and, more significantly, the generation of TXA2 as well.
  • This may underlie the beneficial anti-inflammatory and cardiovascular actions that are ascribed to diets rich in this type of marine product.
Catabolism of the prostanoids
  • This is a multistep process. After carrier-mediated uptake, most prostaglandins are rapidly inactivated by ‘prostaglandin-specific’ enzymes, and the inactive products are further degraded by general fatty acid-oxidizing enzymes.
  • The prostaglandin-specific enzymes are present in high concentrations in the lung, and 95% of infused PGE2, PGE1, or PGF2α is inactivated on the first passage. The half-life of most prostaglandins in the circulation is less than 1 minute.
  • Prostaglandin I2 and TXA2 are slightly different. Both are inherently unstable and decay rapidly (5 minutes and 30 seconds, respectively) in biological fluids into inactive 6-keto-PGF1α and TXB2.
Prostanoid receptors
  • There are five main classes of prostanoid receptors, all of which are typical G-protein-coupled receptors.
  • They are termed DP, FP, IP, EP, and TP receptors, respectively, depending on whether their ligands are PGD2, PGF2α, PGI2, PGE2, or TXA2.
  • Some have further subtypes; for example, the EP receptors are subdivided into three subgroups.
  • Act by IP3/DAG system.
Pharmacological Actions of the prostanoids

The prostanoids affect most tissues and exert a variety of effects.

  • PGD2 causes vasodilatation, inhibition of platelet aggregation, relaxation of gastrointestinal and uterine muscle, and modification of release of hypothalamic/pituitary hormones. It has a bronchoconstrictor effect through action on TP receptors.
  • PGF2α causes myometrial contraction in humans, luteolysis in some species (e.g. cattle), and bronchoconstriction in other species (cats and dogs).
  • PGI2 causes vasodilatation, inhibition of platelet aggregation, renin release, and natriuresis through effects on tubular reabsorption of Na+.
  • TXA2 causes vasoconstriction, platelet aggregation, and bronchoconstriction (more marked in guinea pigs than in humans).
  • PGE2 is prominent in inflammatory responses and is a mediator of fever. The main effects are:
  1. EP1 receptors: contraction of bronchial and gastrointestinal tract (GIT) smooth muscle
  2. EP2 receptors: relaxation of bronchial, vascular, and GIT smooth muscle
  3. EP3 receptors: inhibition of gastric acid secretion, increased gastric mucus secretion, contraction of the pregnant uterus and GIT smooth muscle, inhibition of lipolysis, and autonomic neurotransmitter release.
  • PGF2α acts on FP receptors, found in uterine (and other) smooth muscle, and corpus luteum, producing contraction of the uterus and luteolysis (in some species).
  • PGD2 is derived particularly from mast cells and acts on DP receptors, causing vasodilatation and inhibition of platelet aggregation.
  • In their own right, PGE2, PGI2, and PGD2 are powerful vasodilators and synergize with other inflammatory vasodilators such as histamine and bradykinin.
  • It is this combined dilator action on precapillary arterioles that contributes to the redness and increased blood flow in areas of acute inflammation.
  • Prostanoids do not directly increase the permeability of the postcapillary venules but potentiate this effect of histamine and bradykinin.
  • Similarly, they do not themselves produce pain but potentiate the effect of bradykinin by sensitizing afferent C fibers to the effects of other noxious stimuli.
  • The anti-inflammatory effects of the NSAIDs stem largely from their ability to block these actions of the prostaglandins.
  • Prostaglandins of the E series are also pyrogenic (i.e. they induce fever). High concentrations are found in cerebrospinal fluid during infection, and there is evidence that the increase in temperature (attributed to cytokines) is finally mediated by the release of PGE2. NSAIDs exert antipyretic actions by inhibiting PGE2 synthesis in the hypothalamus.
  • However, some prostaglandins have anti-inflammatory effects under some circumstances. For example, PGE2 decreases lysosomal enzyme release and the generation of toxic oxygen metabolites from neutrophils, as well as the release of histamine from mast cells. Several prostanoids are available for clinical use.
The role of the prostanoids in inflammation

Mediators derived from phospholipids:

  • The main phospholipid-derived mediators are the eicosanoids (prostanoids and leukotrienes) and platelet-activating factor (PAF).
  • The eicosanoids are synthesized from arachidonic acid released directly from phospholipids by phospholipase A2, or by a two-step process involving phospholipase C and diacylglycerol lipase.
  • Arachidonate is metabolized by cyclo-oxygenase (COX)-1 or COX-2 to prostanoids, or by 5-lipoxygenase to leukotrienes.
  • PGI2 (prostacyclin), predominantly from vascular endothelium, acts on IP receptors, producing vasodilatation and inhibition of platelet aggregation.
  • Thromboxane (TX) A2, predominantly from platelets, acts on TP receptors, causing platelet aggregation and vasoconstriction.

PAF is derived from phospholipid precursors by phospholipase A2, giving rise to lyso PAF, which is then acetylated to give PAF. The inflammatory response is inevitably accompanied by the release of prostanoids. PGE2 predominates, although PGI2 is also important. In areas of acute inflammation, PGE2 and PGI2 are generated by the local tissues and blood vessels, while mast cells release mainly PGD2. In chronic inflammation, cells of the monocyte/macrophage series also release PGE2 and TXA2. Together, the prostanoids exert a sort of yin-yang effect in inflammation, stimulating some responses and decreasing others. The most striking effects are as follows.

Therapeutic uses of Prostanoids:
1. Gynecological and Obstetric:
  • termination of pregnancy: gemeprost or misoprostol (a metabolically stable prostaglandin (PG) E analog)
  • induction of labor: dinoprostone or misoprostol
  • postpartum hemorrhage: carboprost.
2. Gastrointestinal:
  • to prevent ulcers associated with non-steroidal anti-inflammatory drug use: misoprostol
3. Cardiovascular:
  • to maintain the patency of the ductus arteriosus until surgical correction of the defect in babies with certain congenital heart malformations: alprostadil (PGE1)
  • to inhibit platelet aggregation (e.g. during hemodialysis): epoprostenol (PGI2), especially if heparin is contraindicated
  • primary pulmonary hypertension: epoprostenol
4. Ophthalmic
  • open-angle glaucoma: latanoprost eye drops.


  • The renin-angiotensin system (RAS), or renin-angiotensin-aldosterone system (RAAS), is a hormone system that regulates blood pressure and fluid and electrolyte balance, as well as systemic vascular resistance.
  • When renal blood flow is reduced, juxtaglomerular cells in the kidneys convert the precursor prorenin (already present in the blood) into rennin and secrete it directly into circulation.
  • Plasma renin then carries out the conversion of angiotensinogen, released by the liver, to angiotensin I. Angiotensin I is subsequently converted to angiotensin II by the angiotensin-converting enzyme (ACE) found on the surface of vascular endothelial cells, predominantly those of the lungs.
  • Angiotensin II is a potent vasoconstrictive peptide that causes blood vessels to narrow, resulting in increased blood pressure. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex.
  • Aldosterone causes the renal tubules to increase the reabsorption of sodium and water into the blood, while at the same time causing the excretion of potassium (to maintain electrolyte balance). This increases the volume of extracellular fluid in the body, which also increases blood pressure.
  • If the RAS is abnormally active, blood pressure will be too high. Many drugs interrupt different steps in this system to lower blood pressure.
  • These drugs are one of the primary ways to control high blood pressure, heart failure, kidney failure, and the harmful effects of diabetes.
  • The system can be activated when there is a loss of blood volume or a drop in blood pressure (such as in hemorrhage or dehydration). This loss of pressure is interpreted by baroreceptors in the carotid sinus.
  • It can also be activated by a decrease in the filtrate sodium chloride (NaCl) concentration or a decreased filtrate flow rate that will stimulate the macula densa to signal the juxtaglomerular cells to release renin.

1. If the perfusion of the juxtaglomerular apparatus in the kidney’s macula densa decreases, then the juxtaglomerular cells (granular cells, modified pericytes in the glomerular capillary) release the enzyme rennin.

2. Renin cleaves a decapeptide from angiotensinogen, a globular protein. The decapeptide is known as angiotensin I.

3. Angiotensin I is then converted to an octapeptide, angiotensin II by angiotensin-converting enzyme (ACE), which is thought to be found mainly in endothelial cells of the capillaries throughout the body, within the lungs, and the epithelial cells of the kidneys. One study in 1992 found ACE in all blood vessel endothelial cells.

4. Angiotensin II is the major bioactive product of the renin-angiotensin system, binding to receptors on intraglomerular mesangial cells, causing these cells to contract along with the blood vessels surrounding them and causing the release of aldosterone from the zona glomerulosa in the adrenal cortex. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine hormone.

renin angiotensin system

Autacoids and Related Drugs
Cardiovascular Effects:

It is believed that angiotensin I may have some minor activity, but angiotensin II is the major bio-active product. Angiotensin II has a variety of effects on the body:

  • Throughout the body, angiotensin II is a potent vasoconstrictor of arterioles.
  • In the kidneys, angiotensin II constricts glomerular arterioles, having a greater effect on efferent arterioles than afferent.
  • As with most other capillary beds in the body, the constriction of afferent arterioles increases the arteriolar resistance, raising systemic arterial blood pressure and decreasing the blood flow.
  • However, the kidneys must continue to filter enough blood despite this drop in blood flow, necessitating mechanisms to keep glomerular blood pressure up. To do this, angiotensin II constricts efferent arterioles, which forces blood to build up in the glomerulus, increasing glomerular pressure. The glomerular filtration rate (GFR) is thus maintained, and blood filtration can continue despite lowered overall kidney blood flow.
  • Because the filtration fraction has increased, there is less plasma fluid in the downstream peritubular capillaries. This in turn leads to a decreased hydrostatic pressure and increased oncotic pressure (due to unfiltered plasma proteins) in the peritubular capillaries.
  • The effect of decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries will facilitate increased reabsorption of tubular fluid.
  • Angiotensin II decreases medullary blood flow through the vasa recta. This decreases the washout of NaCl and urea in the kidney medullary space.
  • Thus, higher concentrations of NaCl and urea in the medulla facilitate increased absorption of tubular fluid. Furthermore, increased reabsorption of fluid into the medulla will increase passive reabsorption of sodium along the thick ascending limb of the Loop of Henle.
  • Angiotensin II stimulates Na+ /H+ exchangers located on the apical membranes (faces the tubular lumen) of cells in the proximal tubule and thick ascending limb of the loop of Henle in addition to Na+ channels in the collecting ducts. This will ultimately lead to increased sodium reabsorption.
  • Angiotensin II stimulates the hypertrophy of renal tubule cells, leading to further sodium reabsorption.
  • In the adrenal cortex, angiotensin II acts to cause the release of aldosterone. Aldosterone acts on the tubules (e.g., the distal convoluted tubules and the cortical collecting ducts) in the kidneys, causing them to reabsorb more sodium and water from the urine.
  • This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium into blood, potassium is secreted into the tubules, becomes part of urine, and is excreted.
  • Angiotensin II causes the release of anti-diuretic hormone (ADH), also called vasopressin – ADH is made in the hypothalamus and released from the posterior pituitary gland. As its name suggests, it also exhibits vaso-constrictive properties, but its main course of action is to stimulate the reabsorption of water in the kidneys.
  • ADH also acts on the central nervous system to increase an individual’s appetite for salt and to stimulate the sensation of thirst.
  • These effects directly act together to increase blood pressure and are opposed by atrial natriuretic peptide (ANP).
Local Renin-angiotensin Systems:
  • Locally expressed renin-angiotensin systems have been found in several tissues, including the kidneys, adrenal glands, the heart, vasculature, and nervous system, and have a variety of functions, including local cardiovascular regulation, in association or independently of the systemic renin-angiotensin system, as well as non-cardiovascular functions.
  • Outside the kidneys, renin is predominantly picked up from the circulation but may be secreted locally in some tissues; its precursor prorenin is highly expressed in tissues and more than half of circulating prorenin is of extrarenal origin, but its physiological role besides serving as a precursor to renin is still unclear.
  • Outside the liver, angiotensinogen is picked up from the circulation or expressed locally in some tissues; with renin, they form angiotensin I, and locally expressed angiotensin-converting enzyme, chymase, or other enzymes can transform it into angiotensin II. This process can be intracellular or interstitial.
  • In the adrenal glands, it is likely involved in the paracrine regulation of aldosterone secretion; in the heart and vasculature, it may be involved in remodeling or vascular tone; and in the brain, where it is largely independent of the circulatory RAS, it may be involved in local blood pressure regulation. In addition, both the central and peripheral nervous systems can use angiotensin for sympathetic neurotransmission.
  • Other places of expression include the reproductive system, the skin, and digestive organs. Medications aimed at the systemic system may affect the expression of those local systems, beneficially or adversely.
Fetal Renin–angiotensin System:
  • In the fetus, the renin-angiotensin system is predominantly a sodium-losing system, as angiotensin II has little or no effect on aldosterone levels. Renin levels are high in the fetus, while angiotensin II levels are significantly lower; this is due to the limited pulmonary blood flow, preventing ACE (found predominantly in the pulmonary circulation) from having its maximum effect.
Clinical Significance:
  • ACE inhibitors–inhibitors of the angiotensin-converting enzyme are often used to reduce the formation of the more potent angiotensin II. Captopril is an example of an ACE inhibitor. ACE cleaves several other peptides, and in this capacity is an important regulator of the kinin–kallikrein system, as such blocking ACE can lead to side effects.
  • Angiotensin II receptor antagonists, also known as angiotensin receptor blockers, can be used to prevent angiotensin II from acting on its receptors.
  • Direct renin inhibitors can also be used for hypertension. The drugs that inhibit renin are aliskiren and investigational remikiren.
  • Vaccines against angiotensin II, for example, CYT006-AngQb, have been investigated.
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