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.
McMahon
E G
EG
Washington University School of Medicine, Department of Pharmacology, St. Louis, Missouri.
Palomo
M A
MA
Mehta
P
P
Olins
G M
GM
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D000242:Cyclic AMP / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D011688:Purinones / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012964:Sodium / Q000652:urine
D011688:Purinones; D012964:Sodium; D000242:Cyclic AMP; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast; D006152:Cyclic GMP