15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and monatepil

Graft spasm may develop during coronary artery bypass grafting and reversal of spasm is still challenging. The purpose of this study was to investigate the in vitro vascular relaxant properties of AJ-2615 in human internal mammary artery (IMA).. We studied 264 IMA rings taken from 65 patients undergoing coronary artery bypass grafting surgery with organ bath technique. The interaction between AJ-2615 and various vasoconstrictors was investigated in two ways.. AJ-2615 caused complete relaxation in methoxamine-contracted IMA rings (100.0+/-0.0%; n = 8) and nearly full relaxation in potassium chloride-contracted IMA rings (91.4+/-5.7%; n = 8) or noradrenaline-contracted IMA rings (89.3+/-2.8%; n = 8). AJ-2615 also induced remarkable relaxation in IMA rings contracted by other vasoconstrictors. In comparison with the alpha1-adrenoceptor antagonist prazosin, AJ 2615 showed similar maximal relaxation in IMA rings contracted by methoxamine or norepinephrine. On the other hand, incubation with AJ-2615 (0.1-1 microM) significantly inhibited all the vasoconstrictor-mediated vasoconstriction except endothelin-1 in a concentration-dependent manner.. The results suggested that in human IMA, AJ-2615 has an inhibitory effect on vasoconstriction mediated by a variety of vasoconstrictors and the mechanism of relaxation may be related to its calcium antagonism and alpha1-adrenergic receptor blocking activity. AJ-2615 may have important clinical implications for patients undergoing coronary artery bypass surgery for reversing and preventing graft spasm.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Aged; Calcium Channel Blockers; Coronary Artery Bypass; Dibenzothiepins; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; In Vitro Techniques; Male; Mammary Arteries; Methoxamine; Middle Aged; Norepinephrine; Piperazines; Potassium Chloride; Prazosin; Serotonin; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Antianginal effects of monatepil ([(+-)-N-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-(4-fluor ophenyl)-1-piperazinebutanamide]monomaleate, AJ-2615, CAS 10337-41-9), a new calcium antagonist, were evaluated in experimentally induced myocardial ischemia in anesthetized rats and compared with those of diltiazem. Ischemic electrocardiogram change (ST elevation) and reduction of myocardial tissue oxygen tension were induced by intracoronary arterial administration of U-46619 ((5Z,9a,11a,13E,15(S))-9,11-(methano-epoxy)prosta-5,13-di en-1-oic acid) (10 micrograms/kg), a stable thromboxane A2 agonist. The ST elevation induced by U-46619 was significantly prevented by monatepil pretreatment (0.1 mg/kg i.v.), and to a lesser extent by diltiazem (0.3 mg/kg i.v.). Moreover, the decrease in myocardial tissue oxygen tension at the time of ST elevation after U-46619 was inhibited by monatepil pretreatment (0.3 mg/kg i.v.). These results indicate that monatepil exerts a more potent preventive effect against U-46619-induced myocardial ischemic changes than diltiazem and suggest that monatepil has potential for treating vasospastic angina.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Calcium Channel Blockers; Dibenzothiepins; Diltiazem; Electrocardiography; Heart Rate; Male; Myocardial Ischemia; Myocardium; Oxygen Consumption; Piperazines; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents