CARDIOVASCULAR PROFILE OF RWJ 29009, A NEW POTASSIUM CHANNEL ACTIVATOR, IN ANESTHETIZED AND CONSCIOUS DOGS

RWJ-29009, (6S)-trans(-)-1-(6,7-dihydro-6-hydroxy-5 ,5-dimethyl-2-nitr o-5 H-thieno[3,2-b]pyran-7-yl)-2-piperidinone, is a structurally novel and extremely potent potassium channel activator that may be useful f or treatment of hypertension and ischemic heart disease. We assessed t he cardiovascular profile of RWJ 29009 in anesthetized and conscious d ogs. RWJ 29009 (0.1-2 mu g/kg intravenously, i.v.) dose-relatedly incr eased coronary blood flow (CBF) and decreased arterial pressure in ane sthetized dogs. Total peripheral resistance and coronary vascular resi stance were concurrently reduced without significant changes in heart rate (HR) or cardiac output (CO). Left ventricular (LV) dP/dt(max) and myocardial contractile force were decreased only at the highest dose of 10 mu g/kg, Cromakalim (3-100 mu g/kg), although much less potent, had a qualitatively similar profile. Glyburide pretreatment (5 mg/kg i .v.) shifted the dose response of RWJ 29009 for increasing CBF and dec reasing arterial pressure to the right. The dose responses of cromakal im were similarly shifted to the right, whereas the effects of nifedip ine on CBF and arterial pressure were not affected by glyburide. RWJ 2 9009 (0.3 and 1 mu g/kg) had no effect on myocardial O-2 consumption ( MVO(2)) except for a transient increase immediately after administrati on of 1 mu g/kg. MVO(2) returned to control 15 min after dosing, altho ugh CBF remained significantly increased. In conscious dogs, RWJ 29009 (0.3-10 mu g/kg, i.v. and orally, p.o.) produced dose-related increas es in CBF and decreases in arterial pressure similar to those produced in anesthetized dogs, except that HR was increased concurrently. The i.v. and p.o. potency of RWJ 29009 were comparable, indicating high or al bioavailability. Thus, RWJ 29009 is an extremely potent coronary an d peripheral vasodilator with a cardiovascular profile similar to that of other potassium channel activators. Like those of other potassium channel activators, its mechanism of action appears to involve activat ion of ATP-regulated potassium channels.