Johnson C L, Mizoguchi H
J Pharmacol Exp Ther. 1977 Jan;200(1):174-86.
Histamine stimulates adenylate cyclase activity in a washed membrane preparation from guinea-pig ventricle. Marked synergistic effects are observed with histamine and GTP. In the absence of GTP, the degree of stimulation of the enzyme by histamine is slight and occurs only in the presence of relatively high concentrations of ATP suggesting that ATP, or contaminating GTP in commercial preparations of ATP, may partially satisfy the guanylnucleotide requirement. The GTP analog, GppNHp, strongly and irreversibly activates the cardiac enzyme. Preincubation studies, in which the membranes are treated with GppNHp alone or in combination with histamine followed by estensive washing, indicate that histamine markedly increases the rate of activation of the enzyme by the guanylnucleotide. It is suggested that the mechanism of action of histamine on adenylate cyclase involves a facilitation of the interaction of guanylnucleotides with the regulatory site of the enzyme. The relative activities for stimulation of adenylate cyclase of a series of histamine analogs correlate quite well with the activities of these derivatives on four H2-receptor systems, including atrial rate and ventricular contractility and do not correlate with the activities on H1-receptors. The H2-receptor antagonists, burimamide and metiamide, competitively inhibit hitamine-stimulated adenylate cyclase and the dissociation constants for these antagonists on the enzyme agree with the pharmacological data on the H2-receptors in the atria and ventricles. Our results suggest that histamine-stimulated cardiac adenylate cyclase can be classified inotorpic and chronotropic effects of histamine on the intact heart.
组胺可刺激豚鼠心室洗涤膜制剂中的腺苷酸环化酶活性。观察到组胺与GTP有明显的协同作用。在没有GTP的情况下，组胺对该酶的刺激程度轻微，且仅在存在相对高浓度ATP时才会发生，这表明ATP或ATP商业制剂中污染的GTP可能部分满足鸟苷酸的需求。GTP类似物GppNHp可强烈且不可逆地激活心脏酶。预孵育研究中，将膜单独用GppNHp处理或与组胺联合处理，然后进行充分洗涤，结果表明组胺显著增加了鸟苷酸对该酶的激活速率。提示组胺对腺苷酸环化酶的作用机制涉及促进鸟苷酸与该酶调节位点的相互作用。一系列组胺类似物刺激腺苷酸环化酶的相对活性与这些衍生物在包括心房率和心室收缩力在内的四个H2受体系统上的活性相当吻合，而与在H1受体上的活性不相关。H2受体拮抗剂布立马胺和甲硫咪特竞争性抑制组胺刺激的腺苷酸环化酶，这些拮抗剂在该酶上的解离常数与心房和心室中H2受体的药理学数据一致。我们的结果表明，组胺刺激的心脏腺苷酸环化酶可解释组胺对完整心脏的变力性和变时性作用。
