Hemodynamic basis for the depressor activity of zaprinast, a selective cyclic GMP phosphodiesterase inhibitor.
The present investigation was undertaken to define the hemodynamic mechanisms by which the selective cyclic GMP phosphodiesterase inhibitor zaprinast (M&B 22,948; 2-o-propoxy-phenyl-8-azapurin-6-one) lowers mean arterial pressure (MAP). Anesthetized rats were instrumented with electromagnetic or pulsed-Doppler flow probes to measure cardiac output or regional blood flow, respectively, and catheters to record MAP, left ventricular pressure and administer drugs. Zaprinast (0.33-2.0 mg.min-1.kg-1) produced dose-dependent decreases in MAP (maximum = -39 +/- 6 mm Hg) and total peripheral resistance (maximum = -45 +/- 5%) when infused i.v. The greatest reductions in regional vascular resistance were observed in the mesenteric bed, with smaller decreases in the hindquarters and renal beds. Cardiac output increased (maximum = 22 +/- 7%) during the infusion of zaprinast; however, heart rate was only minimally affected. These increases in cardiac output were still evident in animals pretreated with beta adrenergic and muscarinic receptor antagonists. At the lowest dose, zaprinast tended to increase maximal first derivative of left ventricular pressure, whereas, at higher doses maximal first derivative of left ventricular pressure was depressed or unchanged. Additional studies were performed to examine the effect of the cyclic GMP phosphodiesterase inhibitor on the pressor and vasoconstrictor activity of phenylephrine and angiotensin II. The increases in MAP and total peripheral resistance produced by these agents were attenuated markedly during continuous infusion of zaprinast (1 mg.min-1.kg-1). These data suggest that zaprinast lowers MAP by decreasing peripheral vascular resistance and by antagonizing the actions of endogenous neurohumoral vasoconstrictor systems.
Trapani
A J
AJ
Searle Research and Development, G.D. Searle and Company, Chesterfield, Missouri.
Smits
G J
GJ
McGraw
D E
DE
McMahon
E G
EG
Blaine
E H
EH
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000187:drug effects; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D011433:Propranolol / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D011688:Purinones; D000804:Angiotensin II; D001285:Atropine; D011433:Propranolol; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast