Abstract 335: Prostaglandin I 2 Receptor Blockade Contracts Rat Renal Arteries and Facilitates Endothelium-Dependent Contractions.

Abstract

Endothelium-dependent contractions are augmented in human hypertension and in isolated preparations, including renal arteries, from hypertensive animals. Renal vasomotor tone is essential in the regulation of arterial blood pressure and renal arteries are highly sensitive to vasoconstrictor prostanoids including prostacyclin, identified as endothelium-derived contracting factor (EDCF) activating thromboxane prostanoid (TP) receptors. However, the mechanisms underlying increased EDCF responses in hypertension are not completely resolved. Isometric tension was measured, in wire myographs, in renal arterial rings from spontaneously hypertensive (SHR) and age (38-52 weeks)-matched Wistar Kyoto (WKY) rats. Responses were compared under control conditions and after incubation with indomethacin (10 -5 mol/L, cyclooxygenase inhibitor), ketanserin (10 -6 mol/L, 5-HT 2 receptor antagonist), CAY10441 (10 -6 mol/L, prostaglandin I 2 [IP] receptor antagonist), and S18886 (10 -7 mol/L, TP receptor antagonist). All experiments were performed in the presence of L-NAME (3 x 10 -4 mol/L) to exclude effects of endothelium-derived NO. Surprisingly, CAY10441 (10 -10 to 10 -6 mol/L) contracted renal arterial rings from both strains; the contraction at the highest concentration was significantly larger in SHR (15±0.7 mN) than in WKY (10±1.5 mN) preparations ( n =10, P <0.05). This phenomenon was blunted by indomethacin, ketanserin, but not S18886. After washout and re-incubation, EDCF responses to acetylcholine (10 -8 to 10 -4 mol/L) were similar between SHR and WKY preparations in the presence of CAY10441 ( E max 72.6±5.3% and 67.4±3.8% KCl, n =8), but significantly larger than under control conditions ( n =4-8, P <0.05). S18886 prevented EDCF responses in the absence but not in the presence of CAY10441. Contractions to prostacyclin [in the presence of indomethacin] were facilitated by CAY10441 in rings from both strains and no longer prevented by S18886, although the TP receptor antagonist abolished contractions to U46619 (10 -11 to 3 x 10 -6 mol/L). These data suggest that: a) inhibitory IP receptors reduce renal vasomotor tone; b) IP and TP receptors form heterodimers; and c) endogenous serotonin contributes to the action of prostacyclin in rat renal arteries.