Influence of Zaprinast on vascular tone and vasodilator responses in the cat pulmonary vascular bed

Abstract

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)

Potential Benefits of Peroxynitrite

“…These results show the hindlimb vasodilator responses to PN, and to the NO donors, sodium nitroprusside and DEA/NO, were enhanced in duration at a time when vasodilator responses to the beta 2 receptor agonist, albuterol, were not altered. These data along with the observation that the type 4 cAMP phosphodiesterase inhibitor, rolipram, did not alter the duration of the response to PN, provides evidence in support of the hypothesis that PN induced vasodilation in the cat circulation is mediated, at least, in part by a cGMP-dependent mechanism [222,223]. Although experiments with zaprinast provide evidence in support of a cGMP dependent mechanism, additional support for this mechanism could be derived from experiments with inhibitors of guanylate cyclase and of cGMP dependent protein kinase.…”

Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats.

“…Cyclic GMP-specific PDEs are concentrated in the retina, platelets, and lung (20). Several studies in the isolated lung circulation have confirmed a role for PDE5 in modulating pulmonary artery smooth muscle cell tone during acute vasoconstriction (8,27). In contrast, in the systemic circulation, it appears that cGMP-PDE may be less important than cAMP-PDEs, particularly milrinone-inhibitable PDE3 (18,28).…”

High-altitude pulmonary hypertension

“…This abundance of PDE5 in the lungs provides a mechanism for relatively selective pulmonary vasodilatation with little systemic hypotension. Agents with PDE5 inhibitory activity reduce Ppa in animal models [38]. ALDASHEV et al [39] studied the effects of sildenafil in 14 HAPH patients and reported a reduction in P pa, with an improvement in 6-min walk distance and an increase in cardiac index after 3 months.…”