Comparison of the effects of nitric oxide synthase, guanylate cyclase and potassium channel inhibition on vascular contractions in vitro in the rat

1 We have investigated the differences between the nitric oxide synthase in hibitor L-NMMA, the guanylate cyclase inhibitor methylene blue and the pota ssium channel blockers apamin and charybdotoxin or apamin and iberiotoxin, in their abilities to increase vasoconstrictor responses in rat small mesen teric arterial rings. 2 When administered during the maintained contraction to PGF(2 alpha) (10 m u m), L-NMMA (100 mu m) or the combination of apamin (0.7 mu m) and charybd otoxin (0.1 mu m) significantly increased the contractile response. Methyle ne blue (10 mu m) increased the contraction, but this did not reach signifi cance. However, apamin (0.7 mu m) and iberiotoxin (0.1 mu m) also significa ntly increased the contractile response. 3 The combination of L-NMMA or methylene blue with apamin/charybdotoxin pro duced significantly greater increases in the contractile response to PGF(2 alpha) than achieved individually. 4 Relaxations to acetylcholine (10 mu m) were significantly reduced by L-NM MA or methylene blue but not by apamin in combination with charybdotoxin or iberiotoxin. 5 Since apamin/iberiotoxin had similar effects to apamin/charybdotoxin, it is likely that the actions of these agents involve direct actions on smooth muscle potassium channels rather than inhibition of endothelium-derived hy perpolarising factor (EDHF). These results suggest that endothelium-derived nitric oxide but not EDHF has a major role in modulating vascular tone und er these conditions.