RWJ-26629, A NEW POTASSIUM CHANNEL OPENER AND VASCULAR SMOOTH-MUSCLE RELAXANT - A POTENTIAL ANTIHYPERTENSIVE AND ANTIANGINAL AGENT

The effects of 6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin-1 -yl) -7H-thieno[3,2-b]pyran (RWJ 26629) were compared with those of the sta ndard potassium channel opener cromakalim and several standard calcium channel blockers. RWJ 26629 lowered the mean arterial blood pressure in conscious spontaneously hypertensive (ED30 = 10 ug/kg p.o. or 8 ug/ kg i.v.) and renal hypertensive (1 5 mug/kg p.o.) rats, conscious rena l hypertensive (ED20 = 4)mug/kg p.o.) and normotensive (ED20 = 5 mug/k g p.o. or 2 mug/kg i.v.) dogs and anesthetized rhesus monkeys (ED20 = 6 ug/kg i.v.). RWJ 26629 was more potent than cromakalim and had a max imal activity greater than the calcium channel blockers. At antihypert ensive doses, RWJ 26629 had no significant effect on cardiac force, ca rdiac output, stroke volume or stroke work in dogs and had little or n o effect on renal, carotid or femoral blood flow or vascular resistanc e. RWJ 26629 was also selective for antihypertensive activity in rats compared with its ability to inhibit intestinal motility. However, RWJ 26629 did relax contracted pulmonary smooth muscle in vivo at antihyp ertensive doses. All compounds tested caused reflex tachycardia in con scious dogs, although this effect was lowest for RWJ 26629. Most impor tantly, RWJ 26629 potently and selectively increased coronary blood fl ow with a potency and duration of action greater than that of cromakal im or nifedipine without affecting contractile force. In vitro, RWJ 26 629 selectively relaxed precontracted coronary arteries compared with its effect on femoral arteries. Finally, several studies in ferret iso lated papillary muscle and using Rb-86 efflux and prestimulation proto cols in rabbit aortic rings suggested that RWJ 26629 exerts its relaxa nt effects by opening ATP-dependent potassium channels.