Cardiovascular effects of the novel potassium channel opener UR-8225.

We compared the hemodynamic and electrophysiological effects of UR-8225, a new potassium channel opener with those of levcromakalim. UR-8225 and levcromakalim (0.03-1 mg/kg) dose-dependently decreased mean arterial pressure (MAP) in conscious spontaneously hypertensive rats (SHR) and deoxycorticosterone-salt (DOCA) hypertensive rats and in conscious and anesthetized normotensive rats. The decrease in MAP was accompanied by a dose-dependent increase in heart rate (HR). Levcromakalim was about twice as potent as an antihypertensive agent, and its hypotensive and tachycardic effects were of longer duration than those of UR-8225. In conscious normotensive rats, the hypotensive response to UR-8225 (1 mg/kg) did not diminish with repeated dosing for 16 days. In conscious SHR, propranolol antagonized the tachycardic response of UR-8225 without affecting its hypotensive response. In anesthetized rats, glibenclamide (3, 10, and 20 mg/kg) dose-dependently reduced the hypotensive effect of the drug. In anesthetized dogs, UR-8225 and levcromakalim (0.01-30 micrograms/kg) dose-dependently decreased MAP and total peripheral resistance (TPR): UR-8225 was approximately 10 times less potent than potent than levcromakalim. UR-8225 had no effect on HR, left ventricular end-diastolic pressure (LVEDP), stroke volume (SV), or cardiac output (CO) but decreased rate-pressure product (RPP) and cardiac work (CW). In contrast, levcromakalim decreased HR, RPP, and CW and increased SV and LVEDP, whereas CO remained unaltered. UR-8225 and levcromakalim (0.1-10 microM) 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 levcromakalim decreased the Vmax and shortened the APD of the slow ventricular APs elicited by isoprenaline in K(+)-depolarized ventricular muscle fibers. These results indicated that UR-8225 decreases blood pressure (BP) by reducing TPR. Its electrophysiological and hemodynamic effects were blocked by glibenclamide, which suggests that they may be mediated largely through the activation of ATP-sensitive K+ channels.