H1- and H2-receptor mediated responses to histamine on contractility and cyclic AMP of atrial and papillary muscles from guinea-pig hearts

Abstract

On guinea-pig heart we investigated whether cyclic AMP serves as a messenger for H1 - and/or H2-mediated responses to histamine. (1) On papillary muscle histamine elicited positive inotropic responses which were antagonized by burimamide but not by promethazine. The stimulation of H2-receptors was not only associated with an increase in contractility but also with an increase in cAMP. As shown by the time course of effects for 10(-5) M histamine, the maximal increase in cAMP preceded the maximum in contractility. The mechanical and biochemical responses to histamine were potentiated by the phosphodiesterase inhibitor papaverine, but antagonized by burimamide. (2) On the left guinea-pig atrium containing H1-receptors the inotropic response to histamine (10(-5) M) was not accompanied by increases in cAMP at stimulation frequencies of 0.5 and 2 Hz, respectively. In addition, in the presence of papaverine (3 X 10 (-5) M) no change in the cyclic AMP level occurred after application of histamine. Papaverine by itself, however, concomitantly increased contractility and cyclic AMP at a stimulation frequency of 0.5 Hz. In contrast, at 2 Hz papaverine increased only cAMP leaving the contractility unchanged. At this frequency the well-known Ca2+-antagonistic effect comes into prominence, thus masking the positive inotropic effect attributable to the inhibition of the phosphodiesterase. (3) On the right guinea-pig atrium the mediation of the positive chronotropic response to histamine by H2-receptors which is partly involved in the inotropic effect via the frequency-force relationship does not lead to a concomitant increase in cAMP. Also, in the presence of papaverine, histamine had no influence on the cAMP. However, papaverine potentiated the cardioacceleration produced by histamine. Although it is very likely that the cAMP in the sinus node rises, we were not able to detect an increase in cAMP in the whole atrial tissue. From the present results the conclusion can be drawn that the mediation of the inotropic effect due to stimulation of H2-receptors by histamine is associated with an increase of cyclic AMP, whereas that of H1-receptors is not. The view that cAMP may be the second messenger in the chronotropic action of histamine needs further elucidation by experiments on sino-atrial cells.

Histamine Receptors Mediating a Positive Inotropic Effect in Guinea Pig and Rabbit Ventricular Myocardium: Distribution of the Receptors and Their Possible Intracellular Coupling Processes

“…This find ing is in agreement with earlier reports that the positive inotropic effect in guinea pig ventricular myocardium is mediated predominantly or exclusively by H2-receptors (2,4,9). However, the question has remained as to whether H,-receptors are also capable of contributing to the positive inotropic effect of histamine in this tissue.…”

“…A great deal of evidence strongly suggests that the H2-receptor-mediated responses to histamine in the heart are associated with stimulation of adenylate cyclase and with increases in cyclic AMP (2,9,11,23). In accord with this suggestion, the present study demonstrated that hista mine via H2-receptors significantly activated adenylate cyclase in membranes prepared from guinea pig ventricu lar myocardium where the H2-receptor-mediated ino tropism was dominating.…”

“…10 pM), but this noncompetitive antagonism has been inter preted as nonspecific properties of the molecule (6). Fur thermore, Reinhardt et al (9) have reported that prome thazine at the same concentration as used by Verma and McNeill (2) does not have any influence on the positive inotropic response to histamine. In this study, we noticed that the rightward shift of the concentration-response curve for the positive inotropic effect of histamine elicited by cimetidine alone was somewhat nonparallel, especially at the foot of the curve.…”

Analysis of competitive antagonism when this property occurs as part of a pharmacological resultant

“…This possibility was considered to account for the apparently low affinity expressed by amitriptyline for the histamine H2-receptors in tissue bioassays compared with that expressed in adenylate cyclase assays (Kanof & Greengard, 1979). The known, leftward-shifting effect of phosphodiesterase inhibition on histamine concentration-effect curves (Reinhardt et al, 1977: Broadley & Wilson, 1980 would account for this discrepancy and indeed amitriptyline was later found to inhibit this enzyme (Reynolds & Claxton, 1982). In this case, there is no way of eliminating the phosphodiesterase component in tissue assays because inhibition of this enzyme produces full agonism.…”

Suramin Inhibits Glucose-Induced Ca2+ Response in Single Rat Pancreatic β Cells

“…It is known that stimulation of H2-receptors by Hi in duces cyclic AMP formation in the brain, stomach and cardiac muscle in various species (4,5). Also, we have reported that when rat adipocytes were exposed to dibutyryl cyclic AMP or intracellular application of cy clic AMP was carried out, a significant depolarization took place, although the relation between Hi-induced depolarization and the cyclic AMP system is not yet clearly understood (3).…”