Influence of Zaprinast on vascular tone and vasodilator responses in the cat pulmonary vascular bed.
The influence of Zaprinast (M&B 22948), a guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, was investigated in the pulmonary vascular bed of the cat under conditions of controlled blood flow and constant left atrial pressure. Under baseline conditions, injections of Zaprinast into the perfused lobar artery produced small decreases in lobar arterial pressure without altering systemic arterial or left atrial pressure. When tone was increased with U-46619, Zaprinast caused larger dose-dependent decreases in lobar arterial pressure without altering left atrial pressure. The decreases in lobar arterial pressure were reduced significantly by treatment with the nitric oxide (NO) synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the guanylate cyclase inhibitor methylene blue. Under elevated tone conditions, efferent vagal stimulation and intralobar injections of acetylcholine, substance P, NO solution, and the S-nitrosothiols [S-nitroso-N-acetylpenicillamine (SNAP) and S-nitroso-L-cysteine (CysNO)] decreased lobar arterial pressure in a frequency-dependent and dose-related manner. After treatment with Zaprinast, the decreases in lobar arterial pressure in response to efferent vagal stimulation, the endothelium-dependent vasodilators, and the nitrovasodilators were not changed, whereas the duration of the vasodilator responses as measured by the half times was increased significantly. Vasodilator responses to adenosine, albuterol, and pinacidil were not altered by Zaprinast. These data suggest that cGMP hydrolysis in the lung is rapid and that endothelium-derived NO is important in stimulating basal cGMP production and in regulating vascular tone.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
T J
TJ
McMahon
L J
LJ
Ignarro
P J
PJ
Kadowitz
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002415:Cats; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D011688:Purinones / Q000494:pharmacology*; D014630:Vagus Nerve / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D011688:Purinones; D009569:Nitric Oxide; D001120:Arginine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast; D000241:Adenosine; D019331:NG-Nitroarginine Methyl Ester