1. The aim of the present study was to assess interactions between nitric oxide (NO) and prostacyclin (PGI2) during endothelium-dependent relaxations evoked by bradykinin, calcium ionophore (A23187) and acetylcholine in canine isolated pulmonary artery. 2. Relaxations to low concentrations of bradykinin and A23187 were abolished by combined inhibition of NO-synthase (by N(ω)-nitro-L-arginine methyl ester L-NAME, 30 μM) and cyclo-oxygenase (indomethacin, 10 μM), suggesting mediation by NO and PGI2. The individual contributions of NO and PGI2 to the dilator responses were quantified by use of areas above the separate indomethacin-insensitive and L-NAME-insensitive components of the concentration-effect curves, respectively. Individually, NO and PGI2 accounted for only 53 ± 5% and 16 ± 9% of total bradykinin-induced relaxation, and 46 ± 10% and 20 ± 9% of total A23187-induced relaxation, suggesting that NO and PGI2 acted synergistically to cause endothelium-dependent relaxation. 3. Relaxation to low concentrations of acetylcholine was abolished by L-NAME but not affected by indomethacin, suggesting the response was mediated solely by NO with no interaction from PGI2. 4. Glibenclamide (1 μM), an inhibitor of ATP-sensitive potassium (K+A(ATP)) channels, inhibited responses to bradykinin or A23187 but did not affect relaxations evoked by acetylcholine. Glibenclamide did not affect endothelium-independent relaxations to PGI2 or the NO-donor, 3-morpholinosydnonimine (SIN-1). 5. With bradykinin, glibenclamide attenuated total relaxation by 49 ± 8%, but did not alter the individual NO and PGI2-mediated components of the response. Glibenclamide abolished the synergistic interaction between endothelium-derived NO and PGI2. 6. At high concentrations, bradykinin, A23187 or acetylcholine caused endothelium-dependent relaxation that was insensitive to L-NAME + indomethacin. With bradykinin or A23187, this component of relaxation was inhibited by glibenclamide, whereas with acetylcholine, glibenclamide had no effect. 7. The synergistic interaction between endothelium-derived NO and PGI2 in canine pulmonary artery is mediated by activation of K+(ATP) channels, presumably by an endothelium-derived hyperpolarizing factor (EDHF). The pattern of endothelial dilator mediators and the presence of this synergistic interaction is dependent on the nature of the endothelial stimulus.
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