P. Eyre

Classification and biological distribution of histamine receptor sub-types

The distribution and classification of histamine receptors in mammalian and avian tissues have been summarized in Tables 1–4. It is evident that histamine receptors are present on a number of morphologically distinct cell types and the proportion of cells bearing H1- and H2-receptors varies not only with the species but also with the cell source. The pharmacological receptors mediating mepyramine-sensitive histamine responses have been defined as H1-receptors. Receptors mediating mepyramine-resistant, but burimamide or metiamide-sensitive histamine responses have been classified as H2-receptors. Histamine responses mediated via H2-receptors seem to involve the adenylcyclase system resulting in elevation of intracellular cyclic-AMP level, which is susceptible to burimamide blockade but insensitive to β-adrenergic blocking agents. This mode of action of histamine involving H2-receptors and the adenyl cyclase system has been shown to stimulate the mammalian heart; promote gastric acid secretion; inhibit antigen-induced histamine release from leucocytes and inhibit lymphocyte-mediated cytotoxicity. It can further be concluded that both H1- and H2-receptors are widely distributed throughout the animal body in the gastro-intestinal, reproductive, respiratory and cardiovascular systems, nervous system and on mast cells and blood leucocytes. In these tissues, histamine receptors play an important role in physiological, immunological and immunopathological processes. Interaction of histamine with both H1- and H2-receptors in varying proportions modulates the overall manifestation of cardiovascular and respiratory syndromes during certain immunopathological conditions (e.g. inflammation, allergy and anaphylaxis). Histamine receptors also appear to play an important role in the development of immuno-competence and immunity.

Acute systemic anaphylaxis in the calf.

1 Acute systemic anaphylaxis in calves was characterized by marked systemic hypotension hypertension in the pulmonary arteries and abdominal vena cava, and transient apnoea. Calves responded with a second reaction to antigen, but a third anaphylactic response could not be evoked. 2 Suppression of systemic anaphylaxis could not be effected with mepyramine, whereas methysergide or diethylcarbamazine each suppressed anaphylaxis by 50%. Disodium cromoglycate alone did not inhibit anaphylaxis: however, when disodium cromoglycate was combined with diethylcarbamazine almost total suppression (85%) was achieved. Sodium meclofenamate also was a powerful inhibitor of anaphylaxis (80%). It is tentatively suggested that slow reacting substance (SRS‐A) may be an important mediator of bovine anaphylaxis. 3 Bilateral vagotomy did not modify the circulatory responses to injected histamine, 5‐hydroxytryptamine (5‐HT) or antigen, whereas the effects of these agents on ventilation (apnoea) were abolished by vagotomy. 4 Plasma histamine concentration was increased during anaphylaxis, whereas plasma 5‐HT was not. Whole blood histamine concentration fell sharply and remained depressed during 20 min of anaphylactic shock. Reduced whole blood histamine levels probably reflect the severe leucopoenia in the calves. 5 Histamine concentrations in six tissues taken from calves subjected to anaphylaxis were not different from those in control calves mast cells were of similar numbers to controls, but showed some swelling, granular spilling and metachromasia. 6 Histamine, 5‐HT, bradykinin and antigen caused increased pulmonary artery perfusion pressure and ventilation resistance in isolated lungs from sensitized calves. However, there was no difference in histamine and 5‐HT concentration in perfusates obtained during antigen infusion of sensitized and control lungs. 7 Systemic anaphylaxis of calves may result from the interaction of histamine, 5‐HT and SRS‐A. The present data implicate (by indirect measurement) SRS‐A as an important mediator of anaphylaxis in this species.

The Schultz-Dale reaction: A review

Vascular (pulmonary and hepatic blood vessels) and nonvascular (gastro-intestinal, reproductive and respiratory systems) smooth muscle preparations obtained from specifically sensitized animals of numeroius species including man contract toi specific antigen in vitro (Schultz-Dale phenomenon). This immunopharmacological technique is a useful tool to demonstrate immediate-type hypersesnsitivity in actively or passively sensitized tissues and may be used to investigate the nature of the principal pharmacological mediators involved in a particular tissue as well as toi screen mains toi be investigated on the complex mechanisms of action of antigen, desensitization and resensitization (recovery) of anaphylactic responsiveness.

Spasmolytic action of histamine in airway smooth muscle of horse

Histamine, 2-methylhistamine (a specific H1-agonist), 5-HT, PGF2α, SRS-A, bradykinin (BK) and carbachol contract bronchial and tracheal smooth muscles of the horse. Isoprenaline, PGE1, E2, dimaprit and 4-methylhistamine (last two=specific H2-agonists) relaxed airways which were partially contracted to carbachol. Mepyramine (a specific H1-antagonist) selectively antagonized contractions to histamine. In the presence of mepyramine, histamine caused relaxation of airways partially contracted to carbachol. Metiamide and burimamide (specific H2-antagonists) specifically antagonized or reversed histamine-induced bronchorelaxation. However the H2-antagonists, indomethacin and propranolol each failed to block histamine-induced relaxations in trachea. Thus, the results of this study show: (i) preponderence of H1-receptors-mediating contractions in horse airways; (ii) presence of H2-receptors-mediating bronchorelaxation and (iii) the existence of an atypical (relaxant) response (resistance to H2-antagonists; indomethacin and propranolol) in the horse trachea.

ATYPICAL TRYPTAMINE RECEPTORS IN SHEEP PULMONARY VEIN

1 Both the pulmonary artery and vein of the sheep contracted dose‐dependently to histamine, carbamoylcholine, prostaglandin F2α, noradrenaline and bradykinin and relaxed in the presence of isoprenaline or prostaglandin E1. 2 The effect of 5‐hydroxytryptamine (5‐HT) on the artery was consistently to produce dose‐dependent contractions without tachyphylaxis. The effect on the vein was biphasic. 5‐HT 5 × 10−10 to 5 × 10−8 M relaxed the partially constricted vein. 5‐HT 10−7 to 10−6 M caused brief venoconstriction followed by relaxation. 5‐HT > 10−6 M caused dose‐related contraction of the vein. 3 Methysergide effectively blocked the contractile response of the artery to 5‐HT, but only weakly inhibited the contractions of the vein (dose‐ratio <20). 4 Each of ten antagonists tested failed to inhibit the 5‐HT‐induced relaxation of the vein. Sheep pulmonary vein possesses tryptamine receptors which mediate relaxation and which are not of the classical M‐ or D‐type. These receptors appear not to be involved directly or indirectly with responses to acetylcholine, catecholamines, histamine or prostaglandins.

Atypical (relaxant) response to histamine in cat bronchus

Histamine, 2-methylhistamine (a specific H1-receptor agonist), 4-methylhistamine (a specific H2-receptor agonist), isoprenaline, bradykinin, prostaglandin E1, E2 and F2α induce relaxation of carbachol-contracted isolated cat bronchial strips and tracheal chains. Bovine SRS-A contracts bronchus but not trachea. Histamine-induced relaxation of cat bronchus is not blocked by mepyramine, (a specific H1-receptor antagonists); metiamide or burimamide (specific H2-receptor antagonists); propranolol (a β-adrenoceptor blocker) and indomethacin (a PG-synthetase inhibitor) suggesting non-participation of H1, H2-histamine receptors, β-adrenoceptors (catecholamine release) and prostaglandin release in histamine-induced broncho-relaxations in the cat. The existence of an atypical histamine response, resistant to both H1- and H2-receptor antagonists is thus established in cat bronchus.

Histamine H2‐receptors modulate systemic anaphylaxis: a dual cardiovascular action of histamine in calves

Depressor changes in carotid blood pressure caused by histamine or anaphylaxis in calves, were incompletely blocked by the H(1)-receptor antagonist mepyramine. Burimamide, the selective histamine H(2)-receptor antagonist, potentiated the depressor actions of histamine and anaphylaxis. Potentiated depressor responses were inhibited by mepyramine. Observations are consistent with histamine stimulating both H(1)- and H(2)-receptors to cause respectively vasodilatation and vasoconstriction.

Autacoid and anaphylactic reactivity of pulmonary and hepatic smooth musculature of the cat

Histamine, 2-methylhistamine (2-MeH: a relatively specific H1 receptor agonist), 5-HT, carbachol, bradykinin (BK) and PGF2alpha contract isolated cat pulmonary vein, artery and hepatic vein. PGE1, PGF2alpha and 4-methylhistamine (4-MeH: a relatively specific H2-receptor agonist) contract pulmonary arterial strips but further increase in the dose of PGE1 produces relaxation. Isoproterenol relaxes partially contracted blood vessels at low doses, but contracts at high doses. Cat trachea contracts to 5-HT, acetylcholine and carbachol but is insensitive to histamine, its analogues, BK and PGF2alpha. However, partially contracted trachea relaxes to histamine, 4-MeH, 2-MeH, isoprenaline, BK, PGE1, E2 and F2alpha. PGF2alpha and SRS-A contract cat bronchus. Isoprenaline, PGE1 and E2 relax cat bronchus contracted to carbachol, 5-HT, PGF2alpha, SRS-A and antigen. The in vitro anaphylactic contraction (Schultz-Dale reaction) of isolated pulmonary and hepatic veins, bronchus and trachea from horse plasma sensitized cat suggested the involvement of lung and liver in anaphylaxis of the cat.

THE PHARMACOLOGY OF ANAPHYLAXIS IN THE CHICKEN INTESTINE

1 The Schultz‐Dale phenomenon has been demonstrated in several circular smooth muscle strips of oesophagus, crop, duodenum, jejunum and ileum taken from young and adult domestic fowl sensitized actively to crystalline bovine albumin or horse plasma. 2 The ileal strips contract to acetylcholine, histamine, 5‐hydroxytryptamine (5‐HT), prostaglandins E1, E2, F2α, bradykinin and bovine slow reacting substance of anaphylaxis (SRS‐A). Marked seasonal and individual variations in the responsiveness of gut tissues to these exogenous agonists were noted. 3 Antagonism of contractions to histamine by mepyramine suggests the existence of H1‐histamine receptors in chicken ileum. Blockade of 5‐HT‐induced contractions by methysergide shows the preponderance of ‘D’‐musculotropic tryptamine receptors. 4 Failure of selective receptor antagonists of acetylcholine, histamine and 5‐HT to modify the Schultz‐Dale reaction suggests the nonparticipation of aminergic mechanisms in this reaction. 5 Partial to complete blockade of the Schultz‐Dale reaction by a prostaglandin receptor antagonist (polyphloretin phosphate, PPP); prostaglandin synthetase inhibitors (sodium meclofenamate and phenylbutazone); inhibitors of synthesis and release of histamine and SRS‐A (PR‐D‐92‐EA, M&B 22948, diethylcarbamazine citrate, and PPP) and an inhibitor of proteinases (aprotinin) strongly suggests the involvement of vasoactive lipids and polypeptides in the anaphylactic response of chicken ileum to specific antigen.

Preliminary pharmacological characterization of the bovine isolated bronchial artery strip: a new preparation.

1 This paper describes a preliminary pharmacological study of the isolated helical strip of bovine bronchial artery under isotonic conditions in Krebs‐Henseleit solution. 2 The tissue contracted to histamine and 5‐hydroxytryptamine (5‐HT), actions which were selectively antagonized by mepyramine and methysergide respectively. Histamine was not inhibited by metiamide and 5‐HT was not affected by morphine. 3 Slow reacting substance of anaphylaxis (SRS‐A), prostaglandin F2α (PGF2α) and PGE2 were spasmogenic, whereas PGE1 caused relaxation. No potential antagonists of these agents were tested. 4 Carbachol, at all concentrations, caused contractions of the bronchial artery which were completely, irreversibly blocked by atropine. 5 The spasmogenic action of phenylephrine was selectively blocked by dibenamine. Vessel strips which were partially contracted to histamine, relaxed to isoprenaline and salbutamol. The action of isoprenaline was inhibited similarly by either propranolol or practolol. The evidence therefore suggests the presence of functional α, β1 and β2‐adrenoceptors.