GLYBURIDE BLOCKS THE RELAXATION RESPONSE TO BRL-34915 (CROMAKALIM), MINOXIDIL SULFATE AND DIAZOXIDE IN VASCULAR SMOOTH-MUSCLE

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  • 1 January 1989
    • journal article
    • research article
    • Vol. 248  (1) , 149-156
Abstract
BRL 34915 [6-cyano3,4-dihydro-2,2-dimethyl-trans-4(2-oxo-1-pyrrolidyl) 2H-benzo(b) pyran-3-ol], minoxidl sulfate and diazoxide may relax vasuclar smooth muscle via hyperpolarization due to an opening of membrane potassium channels. We therefore examined the effects of several potassium channel antagonists on the relaxation response to these vasodilators in ioslated rat portal venous strips which were mounted in vitro for detecting changes in isometric force. BRL 34915 (IC50 = 4.7 .times. 10-8 M), minoxidil sulfate (IC50 = 1.4 .times. 10-7 M) and diazoxide (IC50 = 5 .times. 10-6 M) elicited concentration-dependent relaxations of the spontaneous, myogenic contractions in venous strips. The relatively nonselective potassium channel antagonists tetraethylammonium ion (0.3-10 .times. 10-3 M) and 4-aminopyridine (1-10 .times. 10-3 M) caused concentration-dependent shifts (5- to 50-fold) in the relaxation responses to each vasodilator. Charybdotoxin (up to 10-7 M) and apamin (up to 10-7 M), known to be antagonists of high and low conductance calcium-activated potassium channels, respectively, had no inhibitory effect on the relaxation-response curves to BRL 34915, minoxidil sulfate or diazoxide. Glyburide (10-7 to 3 .times. 10-5 M), a sulfonylurea which has been shown to block the ATP-modulated potassium channel in insulin-secreting cells, caused concentration-dependent shifts to the right (up to 100-fold) of the IC50 value for BRL 34915 an ddiazoxide, and at 10-6 M, abolished the relaxation response to minoxidil sulfate. These concentrations of glyburide had modest potentiating effects (approximately 80% increse) on the spontaneous contractile activity but failed to alter the relaxation responses to either papaverine or diltiazem. Glyburide was also found to be effective in antagonizing the relaxation response to BRL 34915 in methoxamine-contracted rabbit aortic rings. This efficacy and selectivity of glyburide suggests that the vasorelaxation to BRL 34915, minoxidil sulfate and diazoxide may be associated with an opening of the ATP-modulated potassium channels in vascular smooth muscle. Minoxidil sulfate appears to be especially sensitive to pharmacological blockage of these channels. ATP-modulated potassium channels may exert an important influence on tone in vascular smooth muscle.