Mechanisms underlying ATP-induced endothelium-dependent contractions in the SHR aorta

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Abstract

In mature spontaneously hypertensive (SHR) and Wistar–Kyoto (WKY) rats, acetylcholine, the calcium ionophore A 23187 and ATP release endothelium-derived contracting factor (EDCF), cyclooxygenase (COX) derivatives that activate thromboxane–endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine have been identified as prostacyclin and prostaglandin (PG) H2 while in response to A 23187 thromboxane A2, along with the two other prostaglandins, contributes to the endothelium-dependent contractions. The purpose of the present study was to identify the EDCFs produced by ATP. Isometric tension and the release of prostaglandins were measured in isolated aortic rings of WKY rats and SHR. ATP produced the endothelium-dependent release of prostacyclin, thromboxane A2 and PGE2 (PGI2 ≫ TXA2 ≥ PGE2 > PGF2α) in a similar manner in aorta from WKY rats and SHR. In SHR aortas, the release of thromboxane A2 was significantly larger in response to ATP than to acetylcholine while that to prostacyclin was significantly smaller. The inhibition of cyclooxygenase with indomethacin prevented the release of prostaglandins and the occurrence of endothelium-dependent contractions. The thromboxane synthase inhibitor dazoxiben selectively abolished the ATP-dependent production of thromboxane A2 and partially inhibited the corresponding endothelium-dependent contractions. U 51605, a non-selective inhibitor of PGI-synthase, reduced the release of prostacyclin elicited by ATP but induced a parallel increase in the production of PGE2 and PGF2α, suggestive of a PGH2-spillover, which was associated with the enhancement of the endothelium-dependent contractions. Thus, in the aorta of SHR, endothelium-dependent contractions elicited by ATP involve the release of thromboxane A2 and prostacyclin with a possible contribution of PGH2.

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