CARDIOVASCULAR EFFECTS OF THE NOVEL POTASSIUM CHANNEL OPENER UR-8225

We compared the hemodynamic and electrophysiological effects of UR-822 5, a new potassium channel opener with those of levcromakalim. UR-8225 and levcromakalim (0.03-1 mg/kg) dose-dependently decreased mean arte rial pressure (MAP) in conscious spontaneously hypertensive rats (SHR) and deoxycorticosterone-salt (DOCA) hypertensive rats and in consciou s and anesthetized normotensive rats. The decrease in MAP was accompan ied by a dose-dependent increase in heart rate (HR). Levcromakalim was about twice as potent as an antihypertensive agent, and its hypotensi ve and tachycardic effects were of longer duration than those of UR-82 25. In conscious normotensive rats, the hypotensive response to UR-822 5 (1 mg/kg) did not diminish with repeated dosing for 16 days. In cons cious SHR, propranolol antagonized the tachycardic response of UR-8225 without affecting its hypotensive response. In anesthetized rats, gli benclamide (3, 10, and 20 mg/kg) dose-dependently reduced the hypotens ive effect of the drug. In anesthetized dogs, UR-8225 and levcromakali m (0.01-30 mu g/kg) dose-dependently decreased MAP and total periphera l resistance (TPR): UR-8225 was similar to 10 times less potent than p otent than levcromakalim. UR-8225 had no effect on HR, left ventricula r end-diastolic pressure (LVEDP), stroke volume (SV), or cardiac outpu t (GO) but decreased rate-pressure product (RPP) and cardiac work (CW) . In contrast, levcromakalim decreased HR, RPP, and CW and increased S V and LVEDP, whereas CO remained unaltered. UR-8225 and levcromakalim (0.1-10 mu M) had no effect on the ventricular action potentials (APs) , whereas at higher concentrations they shortened the AP duration (APD ), an effect that was antagonized by glibenclamide. UR-8225 and levcro makalim decreased the V-max and shortened the APD of the slow ventricu lar APs elicited by isoprenaline in K+-depolarized ventricular muscle fibers. These results indicated that UR-S225 decreases blood pressure (BP) by reducing TPR. Its electrophysiological and hemodynamic effects were blocked by glibenclamide, which suggests that they may be mediat ed largely through the activation of ATP-sensitive K+ channels.