SYNERGISTIC INTERACTION BETWEEN ENDOTHELIUM-DERIVED NO AND PROSTACYCLIN IN PULMONARY-ARTERY - POTENTIAL ROLE FOR K-ATP(+) CHANNELS

1 The aim of the present study was to assess interactions between nitr ic oxide (NO) and prostacyclin (PGI(2)) during endothelium-dependent r elaxations evoked by bradykinin, calcium ionophore (A23187) and acetyl choline in canine isolated pulmonary artery. 2 Relaxations to low conc entrations of bradykinin and A23187 were abolished by combined inhibit ion of NO-synthase (by N-omega-nitro-L-arginine methyl ester L-NAME, 3 0 mu M) and cyclo-oxygenase (indomethacin, 10 mu M), suggesting mediat ion by NO and PGI(2). The individual contributions of NO and PGI(2) to the dilator responses were quantified by use of areas above the separ ate indomethacin-insensitive and L-NAME-insensitive components of the concentration-effect curves, respectively. Individually, NO and PGI(2) accounted for only 53+/-5% and 16+/-9% of total bradykinin-induced re laxation, and 46+/-10% and 20+/-9% of total A23187-induced relaxation, suggesting that NO and PGI? acted synergistically to cause endotheliu m-dependent relaxation. 3 Relaxation to low concentrations of acetylch oline was abolished by L-NAME but not affected by indomethacin, sugges ting the response was mediated solely by NO with no interaction from P GI(2). 4 Glibenclamide (1 mu M), an inhibitor of ATP-sensitive potassi um (K-ATP(+)) channels, inhibited responses to bradykinin or A23187 bu t did not affect relaxations evoked by acetylcholine. Glibenclamide di d not affect endothelium-independent relaxations to PGI(2) or the NO-d onor, 3-morpholinosydnonimine (SIN-1). 5 With bradykinin, glibenclamid e attenuated total relaxation by 49%+/-8%, but did not alter the indiv idual NO and PGI(2)-mediated components of the response. Glibenclamide abolished the synergistic interaction between endothelium-derived NO and PGI(2). 6 At high concentrations, bradykinin, A23187 or acetylchol ine caused endothelium-dependent relaxation that was insensitive to L- NAME+indomethacin. With bradykinin or A23187, this component of relaxa tion was inhibited by glibenclamide, whereas with acetylcholine, glibe nclamide had no effect. 7 The synergistic interaction between endothel ium-derived NO and PGI(2) in canine pulmonary artery is mediated by ac tivation of K-ATP(+) channels, presumably by an endothelium-derived hy perpolarizing factor (EDHF). The pattern of endothelial dilator mediat ors and the presence of this synergistic interaction is dependent on t he nature of the endothelial stimulus.