Acetylcholine and bradykinin produced potent relaxation of isolated canine intrapulmonary arteries contracted by serotonin, norepinephrine, or phenylephrine-provided the endothelium was left intact. Selective mechanical destruction of the endothelium transformed the activity of these substances from vasodilatation to vasoconstriction. Acetylcholine-induced relaxations, in the presence of intact endothelium, could be selectively inhibited competitively by atropine, but could not be inhibited by cyclooxygenase inhibitors, a lipoxygenase inhibitor, adrenergic blocking drugs, or histaminergic antagonists. RElaxations produced by prostacyclin, prostaglandin E1, isoproterenol, papaverine, or histamine H2-receptor agonists were not modified, or attenuated, by selective destruction of pulmonary endothelial cells. These observations might provide insight into the etiology of the increased pulmonary resistance observed in pulmonary hypertension and shock lung.
Vascular (pulmonary and hepatic blood vessels) and nonvascular (gastro-intestinal, reproductive and respiratory systems) smooth muscle preparations obtained from specifically sensitized animals of numerous species including man contract to specific antigen in vitro (Schultz-Dale phenomenon). This immunopharmacological technique is a useful tool to demonstrate immediate-type hypersensitivity 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 to screen anti-anaphylactic (anti-allergic) drugs. However, much remains to be investigated on the complex mechanisms of action of antigen, desensitization and resensitization (recovery) of anaphylactic responsiveness.
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 beta-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 and important role in the development of immuno-competence and immunity.
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.
When most arteries are removed from mammals and man, the in vitro response to kinins, particularly of helically-cut vascular strips, is usually one of contraction; and often no response is observed. This is in sharp contrast to the in situ arterial vasodilator action of kinins. The reason(s) for this transformation is not known. The present in vitro experiments demonstrate that bradykinin can produce potent relaxation of canine isolated intrapulmonary arteries (threshold concentration = 7.5 ± 2.7 x 10 10M) and renal arteries (threshold concentration = 3.2 ± 1.6 x 10 10M) contracted by phenylephrine, provided the endothelium is left intact. Selective, mechanical destruction of the endothelium transforms the vasodilator activity of bradykinin to either contraction or to no response at all.Our results probably explaiii why previous investigators have found that bradykinin usually induced contraction, rather than relaxation, of excised peripheral arteries.
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