Effects of phosphodiesterase inhibitors on hypoxic pulmonary vasoconstriction. Influence of K+ channels and nitric oxide

We studied the relaxant effects of the cyclic nucleotide phosphodiesterase inhibitors theophylline (non-selective), rolipram (type IV, 3',5'-cyclic mo nophosphate (cAMP)-specific) and zaprinast (type V, 3',5'-cyclic monophosph ate (cGMP)-specific) on the hypoxic vasoconstriction in the isolated perfus ed rat lung and the involvement of K+ channels and nitric oxide (NO) in the se effects. K+ channels were inhibited by glibenclamide, charybdotoxin, apa min and 4-aminopyridine and nitric oxide synthase by L-N-G-nitroarginine me thyl ester (L-NAME). Hypoxic ventilation produced a significant pressure re sponse. L-NAME and 4-aminopyridine increased this response. Rolipram, zapri nast and theophylline shared the ability to oppose the hypoxic pulmonary va soconstriction. The order of potency was zaprinast > rolipram > theophyllin e. Glibenclamide partially inhibited the relaxant effects of rolipram and t heophylline. Charybdotoxin inhibited the dilator response to rolipram. Apam in inhibited partially the vasodilation induced by rolipram and zaprinast. 4-Aminopyridine inhibited partially the relaxant effects of theophylline. L -NAME failed to block the effects of the three compounds. These data illust rate different pharmacological profiles according to the phosphodiesterase inhibitors and support the potential interest of selective inhibitors as re laxant agents in pulmonary vessels. (C) 2001 Elsevier Science B.V. All righ ts reserved.