CHARACTERIZATION OF HISTAMINE-RECEPTORS MODULATING INOTROPIC AND BIOCHEMICAL ACTIVITIES IN RABBIT LEFT ATRIA

The experiments were performed to identify histamine H-1- and H-2-receptors in rabbit left atrium and to characterize the pharmacological properties mediated by the respective subtypes of histamine recptors. High-affinity saturable binding to the left atrial membranes was obtained for [H-3]mepyramine, yielding a maximum binding capacity (B(max)) of 96 fmol/mg of protein and an equilibrium dissociation constant (K(D)) of 3.8 nM and also for [H-3]tiotidine, yielding a B(max) of 126 fmol/mg of protein and a K(D) of 14.7 nM. In isolated left atrium, histamine produced a concentration-dependent positive inotropic effect, an effect which was competitively antagonized by cimetidine but not altered by chlorpheniramine. Schild analysis showed that the pA2 value for cimetidine was 6.55 and the slope was not significantly different from unity. An excellent correlation was found between the increase in force of contraction and cyclic AMP in the presence of histamine, suggesting that the positive inotropic effect of histamine in rabbit left atrium is dependent on an increased level of intracellular cyclic AMP through stimulation of histamine H-2-receptors. Histamine also produced concentration-dependent stimulation of phosphoinositide hydrolysis as measured by [H-3]inositol monophosphate accumulation. The phosphoinositide response to histamine was blocked by chlorpheniramine and mepyramine but not by cimetidine. The data indicate that histamine H-1-receptors, in addition to histamine H-2-receptors, are present in the rabbit left atrium. Although this tissue lacks an inotropic response to histamine H-1-receptor stimulation, the histamine H-1-receptors interact with histamine to mediate the stimulation of phosphoinositide hydrolysis.