Hypoxic vasoconstriction of rat main pulmonary artery: Role of endogenous nitric oxide, potassium channels, and phosphodiesterase inhibition

This study investigated the influence of NO, potassium (K+) channel blockade, and the phosphodiesterase inhibitors (PDEIs) theophylline (nonselective PDEI), siguazodan (PDE3I), rolipram (PDE4I), and zaprinast (PDE5I) on rat isolated main pulmonary artery hypoxic (95% N-2 and 5% CO,) vasoconstriction. Hypoxic vasoconstriction increased by 27% (p < 0.01) in the presence of the NO synthase inhibitor L-NAME (10(-4) M), and by 15% (p < 0.05) in the presence of the K-ATP channel blocker glibenclamide (10(-6) M), without potentiation by the combination of these two drugs. Hypoxic vasoconstriction decreased by 28% (p < 0.01) in presence of the K-v-voltage-dependent channel blocker 4-aminopyridine (10(-3) M), whereas the other KC channel blockers, charybdotoxin (BKCa, large-conductance Ca2+-sensitive K+ channels) and apamin (SKCa, small-conductance Ca2+-sensitive K+ channels) had no effect. The nonselective PDEI theophylline induced a concentration-dependent relaxation (pD(2) = 4.05, E-max = 90% [expressed as a percentage of maximal relaxation induced by papaverine 10(-4) M]). Among the selective PDEIs, siguazodan was significantly (p < 0.01) more efficient than rolipram and zaprinast (E-max values were 84%, 67%, and 58%, respectively) and significantly (p < 0.05) more potent than zaprinast (pD(2) values were 6.48, 6.34, and 6.16 for siguazodan, rolipram, and zaprinast). Glibenclamide and L-NAME significantly (p < 0.05) shifted the concentration-response curve (CRC) for zaprinast to the right, and L-NAME shifted the CRC significantly to the right for siguazodan. In the presence of L-NAME, glibenclamide had no effect on the CRC of zaprinast. We conclude that (a) NO exerts a permanent inhibitory effect against hypoxic vasoconstriction that might be mediated in part by an activation of K-ATP channels; (b) a 4-aminopyridine-sensitive K+ channel is involved in vasoconstriction under hypoxic conditions; (c) PDEs 3 and 5 are the predominant PDE isoforms in rat pulmonary artery relaxation; and (d) NO and K-ATP, but neither BKCa, SKCa, nor K-v channels, are involved in the relaxant effect of PDEIs.