Autacoids mediate coronary vasoconstriction induced by nitric oxide synthesis inhibition

Inhibition of nitric oxide (NO) synthesis results in coronary vasoconstriction. Using a Langendorff rat heart preparation, we tested the hypothesis that this vasoconstriction is caused by the unopposed effect of the autacoids prostaglandin H-2. (PGH(2)) or thromboxane A(2) (TxA(2)) or both through a mechanism that involves oxygen free radicals. The vasoconstriction induced by NO synthesis inhibition was studied with two different NO synthase inhibitors, N-omega-nitro-L-arginine methyl ester (L-NAME) and N-omega-monomethyl-L-arginine (L-NMMA). We found that the decrease in coronary flow (CF) induced by L-NAME (from 19.3 +/- 0.9 to 13.2 +/- 0.9 ml/min; p < 0.001) and L-NMMA (from 20.1 +/- 0.4 to 15.0 +/- 0.3 ml/min; p < 0.001) was completely blocked by the cyclooxygenase inhibitor indomethacin. A different cyclooxygenase inhibitor (ibuprofen), a PGH(2)/TxA(2)-receptor antagonist (SQ29548), and a TxA(2) synthase inhibitor (CGS 13080) also completely abolished the vasoconstrictor effect of L-NAME, suggesting that this vasoconstriction is mediated by TxA(2). Two different scavengers of superoxide radical anions (O-2(-)), the enzyme superoxide dismutase (SOD) and a cell-permeable SOD mimic, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), also blocked the vasoconstriction induced by NO synthesis inhibition. In contrast, catalase, which inactivates hydrogen peroxide (H2O2), failed to do so, indicating that O-2(-) is needed for the vasoconstrictor effect of L-NAME, whereas H2O2 is not. To determine whether O-2(-) acts on the conversion of PGH(2) to TxA(2) or at the receptor or postreceptor level, we studied whether the vasoconstriction induced by exogenous PGH(2) or the TxA(2) receptor agonist U46619 is blocked by scavengers of O-2(-). CF decreased by 50% with PGH(2) (from 21 +/- 2.1 to 10.6 +/- 5.8 ml/min; p < 0.01), and this decrease was abolished by SOD and Tempol but not catalase. However, SOD had no effect on the vasoconstriction induced by U46619, which decreased CF by 45% (from 17.3 +/- 2.5 to 9.5 +/- 1.8 mI/min; p < 0.01). In addition, PGH, increased the release of TxB(2) (the stable metabolite of TxA(2)) in the coronary effluent (from 5.1 +/- 1.2 to 136.1 +/- 11.8 pg/ml/min). The release of TxB(2) was significantly lower in hearts treated with SOD (76.8 +/- 14.2 pg/ml/min) and CGS (65.7 +/- 13.9 pg/ml/min). We conclude that the coronary vasoconstriction induced by inhibition of NO synthesis is the result of the unopposed effect of the autacoid TxA(2) through activation of its receptor, and that O-2(-) is necessary for conversion of PGH(2) to TxA(2).