AUTACOIDS MEDIATE CORONARY VASOCONSTRICTION INDUCED BY NITRIC-OXIDE SYNTHESIS INHIBITION

Inhibition of nitric oxide (NO) synthesis results in coronary vasocons triction. Using a Langendorff rat heart preparation, we tested the hyp othesis that this vasoconstriction is caused by the unopposed effect o f 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 th at 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 cyclo oxygenase 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 vasoc onstrictor effect of L-NAME, suggesting that this vasoconstriction is mediated by TxA(2). Two different scavengers of superoxide radical ani ons (O-2(-)), the enzyme superoxide dismutase (SOD) and a cell-permeab le 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), fa iled to do so, indicating that O-2(-) is needed for the vasoconstricto r effect of L-NAME, whereas H2O2 is not. To determine whether O-2(-) a cts on the conversion of PGH(2) to TxA(2) or at the receptor or postre ceptor level, we studied whether the vasoconstriction induced by exoge nous PGH(2) or the TxA(2) receptor agonist U46619 is blocked by scaven gers 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 a nd Tempol but not catalase. However, SOD had no effect on the vasocons triction 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 r elease of TxB(2) (the stable metabolite of TxA(2)) in the coronary eff luent (from 5.1 +/- 1.2 to 136.1 +/- 11.8 pg/ml/min). The release of T xB(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 c oronary vasoconstriction induced by inhibition of NO synthesis is the result of the unopposed effect of the autacoid TxA(2) through activati on of its receptor, and that O-2(-) is necessary for conversion of PGH (2) to TxA(2).