Histamine receptors in the coronary circulation of the dog. Effects of mepyramine and metiamide on responses to histamine infusions.

Abstract

SUMMARY The effect of histamine on coronary blood flow (CBF) was studied in anaesthetized greyhounds. CBF and systemic blood pressure were measured using electromagnetic flow transducers and catheters in the aorta during infusions of drugs into the left circumflex coronary artery. Histamine infusions (5, 10, and 20 figjmin) produced dose-related increases in CBF without changing heart rate or blood pressure. Metiamide (100 /ig/min) given simultaneously produced a parallel displacement of the histamine dose-response curve to the right (P < 0.05) with a dose ratio of 2. Mepyramine (100 /ig/min) produced a larger parallel displacement of the dose-response curve (dose ratio = 4). Together, metiamide and mepyramine greatly reduced the histamine response (dose ratio = 16), showing that the metiamide blockade is augmented in the presence of mepyramine. Similarly, mepyramine blockade is augmented in the presence of metiamide. The increase in CBF produced by histamine infusion (20 pig/ min) was similar to the peak flow response of reactive hyperemia following 8-second occlusions. However, mepyramine and metiamide together had no effect on the peak flow response, duration, or total repayment of flow debt in reactive hyperemia. These results show that histamine-induced coronary vasodilation is mediated by both H, and H, receptors. However, the vasodilation of reactive hyperemia after brief coronary artery occlusions does not appear to involve histamine.HISTAMINE acts through at least two specific receptors.'• 2 The development of H, receptor antagonists 3 and more recently of specific H 2 antagonists 2 has made it possible to identify the presence in tissues of these two receptors. Histamine is taken up actively by the heart 4 and its release may be quantified.5 " But the role of histamine in the regulation of the coronary circulation and the nature of coronary histamine receptors are unknown.In the present investigation we have studied the action of histamine in the coronary circulation, using low dose close coronary arterial infusions of histamine and specific H, and H 2 receptor antagonists. By giving drugs in this way we avoided systemic effects. The results show that there are H, and H, receptors in the coronary vasculature with vasodilator effects similar in magnitude to that found during reactive hyperemia following brief coronary artery occlusions. We extended the study to examine the effects on myocardial reactive hyperemia of blocking histamine responses with both H, and H, receptor antagonists. Methods EXPERIMENTAL MODELExperiments were performed on anesthetised. healthy, young grayhounds weighing 19-30 kg. Anesthesia was induced with thiopentone (20 mg/kg. iv) and maintained by ventilation with a Harvard respirator using a 2:1 nitrous oxide-oxygen mixture and sodium pentobarbital. Sodium pentobarbital (20 mg/kg. iv) was given as an initial bolus and further doses were administered as necessary to suppress respiration. The nitrous oxide-oxygen gas mixture was passed through a humidifier to maintain body temperat...

Effects of histamine and the histamine antagonists mepyramine and cimetidine on human coronary arteries in vitro

“…This would seem to indicate some type of interaction between H1-and H2-receptors to produce dilatation that can only be inhibited by a combination of H1-and H2-receptor antagonists. Such an effect has also been reported in dog coronary arteries in vivo (Giles et al, 1977) and in guinea-pig isolated hearts by some (Reinhardt, Wiemann & Schumann, 1976) but not all observers (Ecran, Bokesoy & Turker, 1974;Levi & Kuye, 1974;Broadley, 1976).…”

Membrane electrical effects of histamine on vascular smooth muscle of canine coronary artery.

“…In beating guinea-pig (Broadley, 1975) and dog (Giles et al, 1977) heart, histamine produces a vasodilation, whereas it produces vasoconstriction in isolated canine coronary arteries (Smith et al, 1951;Carrier, 1965). The results of this study shed little light on such divergent data except that the differences may be dependent upon the type of or concentration of histamine receptors, or a histamine-mediated release of vasodilating substances in the beating heart.…”

“…The hyperpolarization induced by histamine may be due to an increased K + conductance that is mediated by an increased Ca 2+ influx, since inhibition of Ca THE effects of histamine on vascular smooth muscle (VSM) are highly variable and range from excitation to inhibition to no effect (Broadley, 1975;Carrier, 1965;Reite, 1972;Altura and Altura, 1974;Hudgins and Weiss, 1968). When injected into the beating dog heart, histamine causes a marked in-crease in coronary blood flow (Giles et al, 1977) suggesting a vasodilation. However, when added to the bathing solution of isolated coronary arteries of dog (Carrier, 1965), swine, and man (Smith et al, 1951), histamine causes a vasoconstriction.…”

Effects of histamine on atrial and ventricular contractility in the canine isovolumic heart

“…In view of the known dependence of changes in contractility on changes in rate [20], interpretation of the above results is not unequivocal. The use of intact anesthetized dogs to determine the inotropic effects of histamine by measuring changes in left ventricular dP/dt has yielded conflicting results ranging from negative [12,13] to positive [11,13] responses, including a lack of effect [14]. In addition to the confounding influence of chronotropic changes already alluded to, the results obtained in this type of preparation were undoubtedly affected by extracardiac actions of histamine, notably hypotension.…”

“…Thus, a dose of the amine eliciting marked peripheral dilator and constrictor responses had minimal influence on cardiac function [6,7]. In this species, either positive [8][9][10][11], negative [12,13], or lack of [14] inotropic effects have been reported. Such conflicting results are apparently due to the varying degrees of reliability of the methods used to measure changes in cardiac contractility, as well as to the confounding influence of the reflex and general hemodynamic actions of histamine in intact preparations.…”