松本 鉄也

Dopamine is widely used for the treatment of cardiogenic and hypovolemic shock. This study was undertaken to compare the response to dopamine in epicardial conduit coronary arteries of humans, Japanese monkeys, and dogs, and to determine the mechanism of vasoconstriction and vasodilatation. In helical strips of coronary arteries from humans and monkeys partially contracted with prostaglandin F2alpha, dopamine produced a concentration-related contraction; the human artery contraction was greater. The contractions were reversed to a relaxation by treatment with phentolamine. Relaxation of monkey arteries treated with the a adrenoceptor antagonist was not influenced by metoprolol, a beta1 antagonist, or endothelium denudation, but was reversed to contraction by SCH23390, a dopamine1, receptor antagonist. On the other hand, dog coronary arteries responded to dopamine with a relaxation that was abolished by metoprolol, but not influenced by SCH23390 or butoxamine, a beta2 antagonist. We conclude that dopamine in clinical doses elicits significant contractions, mediated possibly by alpha adrenoceptors, in human and monkey coronary arteries; thus, care has to be taken when the amine is used in patients with variant angina pectoris. Relaxation of monkey coronary arteries appears to be associated with activation of dopamine, receptors, whereas those of the dog arteries are mediated mainly by beta1 receptors.

In isolated porcine coronary arteries, acetylcholine elicited contractions that were potentiated by endothelium denudation. In endothelium-intact strips, the contraction deteriorated by repeated trials and was reversed to a relaxation. N(G)-nitro-L-arginine (L-NA), a nitric oxide (NO) synthesis inhibitor, abolished the relaxation or reversed it to a contraction. Endothelium-dependent relaxations caused by serotonin were also reversed to a contraction by treatment with L-NA, Relaxations caused by substance P were dependent on the endothelium and were abolished by oxyhemoglobin; however, L-NA did not completely abolish the relaxation. It may be concluded that porcine coronary arteries respond to acetylcholine with contractions by a direct action on smooth muscle that are minimized by stimulated release of NO from the endothelium. It appears that the relaxation caused by serotonin is due to NO released from the endothelium, whereas the substance P-induced relaxation is associated mainly with endothelium-derived NO produced by NO synthase sensitive to L-NA and also with NO produced via a L-NA-resistant process or via a pathway distinct from that through NO synthase.

1 Endothelin-3 (ET-3) elicited relaxations at low concentrations (up to 10(-8) M) and contractions at higher concentrations in dog isolated coronary arteries precontracted with prostaglandin F2alpha (PGF2alpha). The relaxation by ET-3 was not affected by endothelium denudation nor treatment with N(G)-nitro-L-arginine, but was abolished or reversed to a contraction by treatment with indomethacin and markedly suppressed by tranylcypromine, a PGI2 synthetase inhibitor, or diphloretin phosphate, a prostaglandin receptor antagonist. ET-1 produced only concentration-dependent contractions. 2 BQ-123, a new selective ET(A) receptor antagonist, caused relaxation of the strips contracted with ET-3 in a dose-dependent manner and prevented the ET-3-induced contraction but did not affect the contraction produced by PGF2alpha. The relaxation caused by ET-3 was enhanced by treatment with BQ-123. 3 It is concluded that the relaxations elicited by ET-3 in dog coronary arteries are mediated via liberation of PGI2 by activation of non-ET(A) receptors, located in subendothelial tissues, possibly smooth muscle cells, whereas the peptide-induced contractions are mediated via ET(A) receptors.