Depressor and natriuretic effects of M&B 22,948, a guanosine cyclic 3',5'-monophosphate-selective phosphodiesterase inhibitor.

We examined the effects of an acute infusion of M&B 22,948 (2-o-propoxyphenyl-8-azapurin-6-one), a (cGMP)-selective phosphodiesterase inhibitor, on mean arterial pressure (MAP) and urinary sodium excretion in anesthetized rats. M&B 22,948 (at doses of 0.34-2.72 mg/kg/min for 30 min) lowered MAP in a dose-dependent manner, with a 60 mm Hg fall in pressure produced at the highest dose. Despite large decreases in MAP, a profound natriuresis was observed at all doses. Plasma concentrations of cGMP increased in parallel with the depressor action of M&B 22,948, whereas increases in the urinary excretion of cGMP temporally correlated with the natriuresis. The concentration of cyclic AMP in plasma increased transiently in rats treated with M&B 22,948 but the urinary excretion of cyclic AMP was not elevated in these animals. Because changes in cGMP correlated with the physiological effects of M&B 22,948, and the increase in cyclic AMP did not, it is likely that the depressor and natriuretic actions of M&B 22,948 are mediated by increases in cGMP. M&B 22,948 administered chronically at an oral dose of 200 mg/kg/day normalized MAP in spontaneously hypertensive rats; whereas MAP in vehicle-treated spontaneously hypertensive rats remained at hypertensive levels. cGMP-selective phosphodiesterase inhibitors (like M&B 22,948) could be more effective antihypertensive drugs than currently available vasodilators because, when administered acutely, M&B 22,948 simultaneously lowers blood pressure and promotes sodium excretion in the anesthetized rat.