Effective stimulation of cardiac contractility and myocardial metabolism by impromidine and dimaprit--two new H2-agonistic compounds--in the surviving, catecholamine-insensitive myocardium after coronary occlusion.
Left ventricular infarctions were produced in guinea pigs, and the contractile response to beta-adrenergic and H2-histaminergic stimulation was tested in isolated perfused heart preparations. Adenylate cyclase activity and binding characteristics of sarcolemmal beta 1-, H2-, and muscarinic cholinergic receptors were determined in sarcolemmal membrane preparations of the uninvolved right ventricle of the same hearts. Three days after infarction, the positive inotropic effects of isoproterenol (2.8 X 10(-9) mol/L) and tyramine (5.5 X 10(-5) mol/L) were nearly abolished, while the inotropic effects of impromidine (4.6 X 10(-7) mol/L) and dimaprit (8.5 X 10(-6) mol/L) were not impaired. Stimulation rates of cardiac adenylate cyclase activity by isoproterenol were markedly reduced (-90%) whereas impromidine, dimaprit, and NaF revealed stimulation rates equivalent to the sham-operated control group. beta-Receptor binding studies with [3H]dihydroalprenol revealed 90% loss and nearly 10 times lowered affinity (KD) of the remaining receptors, while specific binding of [3H]tiotidine and [3H]quinuclidinyl-benzylate was unchanged in the same preparations. All of the above alterations could be prevented to a similar extent by treatment with different beta-blocking agents, but differences between the drugs were seen with respect to survival rates and reduction of infarct size. In agreement with previous findings, we conclude that the observed alterations in the nonischemic surviving myocardium are the result of specific damage of sarcolemmal beta-receptors due to excessive exposure to increased catecholamines after infarction. The stimulation of the uninvolved H2-receptors may be of therapeutic value.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000502:physiology; D003331:Coronary Vessels / Q000502:physiology; D017259:Dimaprit; D005260:Female; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D017446:Impromidine; D066298:In Vitro Techniques; D008566:Membranes / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D011968:Receptors, Histamine / Q000187:drug effects*; D011970:Receptors, Histamine H2 / Q000187:drug effects*; D013890:Thiourea / Q000494:pharmacology*
D002395:Catecholamines; D007093:Imidazoles; D011968:Receptors, Histamine; D011970:Receptors, Histamine H2; D017446:Impromidine; D000262:Adenylyl Cyclases; D013890:Thiourea; D017259:Dimaprit