Basal or Stimulated Release? Evidence of EDRF (NO) Release by TP-Receptor Agonist U46619

Abstract

Many vasoconstrictor substances have been demonstrated as being vasodilators through the mechanism of endothelium-derived relaxing factor (EDRF)-nitric oxide (NO) release. The authors have hypothesized that all naturally secreted vasoconstrictor substances may potentially be vasodilators as well in order to maintain an adequate physiological vascular tone and have suggested a new term (vasoactivator) for vasoconstrictors. They have recently found that the vasoconstriction induced by a mimetic (U46619) of thromboxane A2 (TXA2), a naturally secreted vasoconstrictor substance released from platelets, may be markedly influenced by the presence of endothelium in the porcine coronary artery (PCA). This may be due to basal (spontaneous) release of EDRF (NO) or stimulated biosynthesis/release by thromboxane A2. The present study was designed to further investigate whether stimulated release of EDRF (NO) by TXA2 exists. PCA rings were mounted in organ baths under a physiologic pressure. The concentration-contraction curves to U46619 were compared in endothelium-intact (+E, n=7) and endothelium- denuded (—E, n=4) rings. At the maximal contraction induced by U46619 (-6.5 log M), NG-nitro-L-arginine (L-NNA, -4 log M) was added. In separate experiments, at resting condition, L-NNA (-4 log M) or U46619 (-7.7 log M) was added and the force changes were recorded. After twenty minutes, U46619 (-7.7 log M) or L-NNA (-4 log M) was added to study the force developed. U46619-induced contraction forces were signifi cantly higher in the -E rings at the concentrations of -9.5 to -7.5 log M and L-NNA induced further contractions in the +E (P < 0.01) but not in the -E rings. In resting conditions, L-NNA induced 0.12 g and further addition of U46619 (-7.7 log M) induced 8.8 g contraction force (P < 0.0001). On the other hand, U46619 (-7.7 log M) induced only 0.88 g contraction force whereas further addition of L-NNA induced a large force (7.43 g, P < 0.0001). The authors conclude that although basal release exists in the PCA this cannot explain the large difference between the +E arteries and the -E or L-NNA incubated arteries, and therefore, TXA2 stimulates EDRF (NO) biosynthesis/release in the porcine coronary artery.