Effects of BRL 34915 (cromakalim) on renal hemodynamics and function in anesthetized dogs

K Hayashi, Y Matsumura, Y Yoshida, T Ohyama, K Hisaki, Y Suzuki and S Morimoto

Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Japan.

The effects of BRL 34915, a newly developed potassium channel opener, on renal hemodynamics and function were investigated in anesthetized dogs. An i.v. injection of BRL 34915 (4, 20 and 100 micrograms/kg) caused a dose-related reduction of mean arterial pressure but there were no significant changes in renal blood flow. The agent at lower doses (4 and 20 micrograms/kg) produced a slight increasing action on urine formation. When BRL 34915 was infused intrarenally at nonhypotensive doses (0.04 and 0.2 micrograms/kg/min), there were no significant increases in renal blood flow and glomerular filtration rate. At 1.0 micrograms/kg/min, a dose which produced a slight reduction in mean arterial pressure, significant decreases in calculated renal vascular resistance were observed, thereby indicating that BRL 34915 has vasodilator action on the renal vasculature. In cases of infusion at higher doses (0.2 and 1.0 micrograms/kg/min), the levels of urine flow, urinary excretion of sodium and fractional excretion of sodium were elevated significantly and these events were accompanied by decreases in urine osmolality. Although the intrarenal administration of BRL 34915 at higher doses produced no alterations in the fractional excretion of lithium (index of sodium excretion at the proximal tubules), the agent did increase the calculated value of the fractional distal excretion of sodium. These effects seen when BRL 34915 was infused intrarenally were suppressed markedly by glibenclamide (6 mg/kg i.v.), a putative inhibitor of the ATP-sensitive potassium channel. Our results suggest that BRL 34915 has renal vasodilating and diuretic effects as a result of opening the potassium channels within the kidney. The agent-induced diuresis may be due partly to an inhibitory effect on sodium reabsorption at the distal portion of the tubules beyond the proximal tubules.

Volume 252, Issue 3, pp. 1240-1246, 03/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics