Endothelium-dependent hyperpolarization in isolated arteries taken from animals treated with NO-synthase inhibitors

To study the effects of chronic in vivo inhibition of NO synthase on endoth elium-dependent hyperpolarization, cell-membrane potential (in individual v ascular smooth-muscle cells) and changes in tension (in isolated rings) wer e recorded from isolated canine coronary arteries and guineapig carotid art eries and aortas. In coronary arteries taken from control dogs and contract ed with U46619, acetylcholine- and bradykinin-induced endothelium-dependent relaxations, which were unaffected by short-term in vitro exposure to indo methacin but were inhibited partially by L-nitro-arginine (LNA). In coronar y arteries taken from dogs treated over the long term in vivo with LNA (30 mg/kg on the first day and 20 mg/kg the 7 following days, i.v.), the respon se to acetylcholine and bradykinin was inhibited when compared with arterie s from control dogs. Short-term in vitro exposure to LNA or indomethacin or both did not influence the effects of either agonist. In these arteries, t he hyperpolarizing response to acetylcholine, observed in the presence of L NA and indomethacin, was enhanced, whereas that to bradykinin was partially inhibited. In the guinea pig isolated aorta, the relaxation to bradykinin was abolished by long-term in vivo treatment with L-nitro-arginine-methyl-e ster (L-NAME; 1.5 mg/ml, in the drinking water for greater than or equal to 4 days). In the isolated guinea pig carotid artery studied in the presence of LNA and indomethacin, acetylcholine induced a hyperpolarization that wa s not significantly affected by long-term in vivo treatment with L-NAME. Th ese findings indicate that endothelium-dependent hyperpolarizations are mai ntained during long-term inhibition of NO synthase and probably act as a ba ck-up mechanism to elicit endothelium-dependent relaxations.