Histamine-mediated adenylate cyclase stimulation in human myocardium

We evaluated the mechanisms of histamine-mediated adenylate cyclase stimulation in 18 human hearts obtained from cardiac transplant recipients or prospective donors. Mg2+ and guanyl nucleotide were required for histamine stimulation. In the presence of 10-5 M GTP, histamine produced a maximal stimulation of 1.54 +/- 0.06 times basal activity in left ventricle (39% of the isoproterenol maximum), which rose to 1.75 +/- 0.14 times basal activity (68% of the isoproterenol maximum) in the presence of a 10-5M concentration of the synthetic guanyl nucleotide 5'-guanylyl imidodiphosphate. Histamine stimulation of adenylate cyclase was antagonized by cimetidine (KB = 1.58 X 10-6 M) but not by H1-blocking doses of mepyramine or pyrrobutamine. The selective H2 agonist dimaprit stimulated adenylate cyclase to approximately the same extent as histamine, whereas a selective H1 agonist produced only minimal stimulation that was H2-mediated. The selective H2 agonist impromidine was a partial agonist and produced approximately 20-40% of maximal histamine stimulation at lower concentrations (10-7 and 10-6 M) and inhibition of histamine stimulation at higher concentrations (10-5 and 10-4 M). Histamine stimulated adenylate cyclase activity over the same dose range as that which produced a positive inotropic response in isolated papillary muscles. Under one set of assay conditions, contractile response and adenylate cyclase does-response curves were essentially super-imposable. We conclude that human myocardial adenylate cyclase is coupled to the H2 receptor and linked to the contractile response, whereas the H1 receptor does not mediate a biochemical or mechanical effect.