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

Potassium channel openers (KCOs) are of potential therapeutic value. Little is known about the effect of these drugs on human conduit arteries used as coronary bypass grafts. The purpose of this study was to determine the effect of the KCO aprikalim (RP52891) on human arteries used as coronary bypass grafts with emphasis on the possible difference in the inhibitory effect on depolarizing agent-mediated rather than receptor-mediated contraction.. Human internal mammary artery segments (IMA, n = 88) taken from 28 patients were studied. Concentration-relaxation curves for aprikalim were established in IMA precontracted with three vasoconstrictors (K+, U46619, and phenylephrine). In IMA rings incubated with aprikalim (1 or 30 microM) for 10 min concentration-contraction curves for the three vasoconstrictors were constructed.. Aprikalim-induced relaxation was less in K+ (37.3 +/- 6.4%) than in U46619 (80.2 +/- 7.7%, P=0.002), or phenylephrine (67.5 +/- 7.0%, P=0.038) -precontracted IMA. The EC50 for K+-(-5.40 +/- 0.12 log M) was significantly higher than that for phenylephrine (-6.43 +/- 0.30 log M, P=0.007) but not significant compared with that for U46619 (-5.81 +/- 0.11, P>0.05). Pretreatment with aprikalim depressed the contraction by phenylephrine from 140.6 +/- 27.6% to 49.3 +/- 14.1% (P=0.002) and shifted the EC50 11.0-fold higher in rings treated with 1 microM aprikalim (P=0.007). Treatment of aprikalim did not significantly reduce the K+ and U46619-induced contraction (P>0.05) but shifted the concentration-contraction curves rightward (2.8-fold higher for K+, P<0.05 and 2.2-fold higher for U46619, P<0.05).. This study demonstrates that aprikalim has vasorelaxant effects in human conduit arteries used as coronary artery bypass grafts contracted by a variety of vasoconstrictors and this effect is vasoconstrictor-selective with greater potency for alpha1-adrenoceptor agonists than for depolarizing agent K+. These findings provide information on the possible use of this KCO in various clinical settings.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Coronary Artery Bypass; Female; Humans; In Vitro Techniques; Male; Mammary Arteries; Middle Aged; Phenylephrine; Picolines; Potassium Channels; Pyrans; Vasoconstriction; Vasodilator Agents

Constriction in response to serotonin is enhanced in the coronary arteries of atherosclerotic monkeys. The main objective of the present study was to determine whether abnormal responses to serotonin in atherosclerosis are reversed following removal of dietary cholesterol. In addition, we examined the effect of an atherogenic diet and reduction in dietary cholesterol on vascular responses to activation of ATP-sensitive K+ channels with aprikalim. Diameters of small coronary arteries were measured on the epicardial surface of the left ventricle in vivo by using stroboscopic illumination synchronized to the heart cycle to visually freeze the motion of the heart. Diameters were measured with a microscope-video system during topical application of two vasoconstrictor agonists, serotonin and the thromboxane mimetic U46619, and the vasodilator agonists aprikalim and nitroprusside. Responses were compared in normal (n = 9), atherosclerotic (n = 14; high-cholesterol diet), and regression (n = 8; high-cholesterol diet followed by normal diet) monkeys. Constriction of coronary arteries in response to serotonin was enhanced in monkeys on an atherogenic diet and was normal in regression monkeys. Vasoconstriction in response to U46619 and vasodilation in response to nitroprusside and aprikalim were not altered by atherosclerosis. Thus, abnormal vascular responses to serotonin in small coronary arteries of atherosclerotic monkeys without morphological evidence of disease can be reversed to normal by reducing dietary cholesterol.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Triphosphate; Animals; Cholesterol, Dietary; Coronary Artery Disease; Coronary Vessels; Macaca fascicularis; Male; Nitroprusside; Picolines; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Pyrans; Serotonin; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Pulmonary vasodilator responses to the K+ATP channel opener, RP 52891, were investigated in the intact-chest cat under constant flow conditions. When pulmonary vascular tone was increased with U46619, intralobar injections of RP 52891 caused dose-related decreases in lobar arterial and systemic arterial pressures without altering left atrial pressure. RP 52891 was more potent than pinacidil but less potent than cromakalim in dilating the pulmonary vascular bed. Pulmonary vasodilator responses to RP 52891, cromakalim and pinacidil, but not to acetylcholine, nitroprusside or isoproterenol, were blocked by glibenclamide. These data demonstrate that RP 52891 has potent pulmonary vasodilator activity in the cat and suggest that responses are due to opening of a glibenclamide-sensitive K+ATP channel.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Adenosine Triphosphate; Animals; Benzopyrans; Blood Gas Analysis; Blood Pressure; Cats; Cromakalim; Female; Glyburide; Guanidines; Hydrogen-Ion Concentration; Isoproterenol; Male; Nitroprusside; Picolines; Pinacidil; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pyrans; Pyrroles; Vasodilation; Vasodilator Agents