RWJ 26629, a new potassium channel opener and vascular smooth muscle relaxant: a potential antihypertensive and antianginal agent.

The effects of trans-5,6-dihydro-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 standard potassium channel opener cromakalim and several standard calcium channel blockers. RWJ 26629 lowered the mean arterial blood pressure in conscious spontaneously hypertensive (ED30 = 10 micrograms/kg p.o. or 8 micrograms/kg i.v.) and renal hypertensive (15 micrograms/kg p.o.) rats, conscious renal hypertensive (ED20 = 4 micrograms/kg p.o.) and normotensive (ED20 = 5 micrograms/kg p.o. or 2 micrograms/kg i.v.) dogs and anesthetized rhesus monkeys (ED20 = 6 micrograms/kg i.v.). RWJ 26629 was more potent than cromakalim and had a maximal activity greater than the calcium channel blockers. At antihypertensive doses, RWJ 26629 had no significant effect on cardiac force, cardiac output, stroke volume or stroke work in dogs and had little or no effect on renal, carotid or femoral blood flow or vascular resistance. 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 antihypertensive doses. All compounds tested caused reflex tachycardia in conscious dogs, although this effect was lowest for RWJ 26629. Most importantly, RWJ 26629 potently and selectively increased coronary blood flow with a potency and duration of action greater than that of cromakalim or nifedipine without affecting contractile force. In vitro, RWJ 26629 selectively relaxed precontracted coronary arteries compared with its effect on femoral arteries.(ABSTRACT TRUNCATED AT 250 WORDS)