1 In the spontaneously hypertensive rat (SHR) and aging Wistar-Kyoto rats (WKY), acetylcholine releases an endothelium-derived contracting factor (EDCF) produced by endothelial cyclooxygenase-1, which stimulates thromboxane A 2 receptors (TP receptors) on vascular smooth muscle. The purpose of the present study was to identify this EDCF by measuring changes in isometric tension and the release of various prostaglandins by acetylcholine. 2 In isolated aortic rings of SHR, U 46619, prostaglandin (PG) H 2 , PGF 2a , PGE 2 , PGD 2 , prostacyclin (PGI 2 ) and 8-isoprostane, all activate TP receptors of the vascular smooth muscle to produce a contraction (U 46619)8-isoprostane ¼ PGF 2a ¼ PGH 2 4PGE 2 ¼ PGD 2 4PGI 2 ). The contractions produced by PGH 2 and PGI 2 were fast and transient, mimicking endothelium-dependent contractions. PGI 2 did not relax isolated aortic rings of WKY and SHR. 3 Acetylcholine evoked the endothelium-dependent release of thromboxane A 2 , PGF 2a , PGE 2 , PGI 2 and most likely PGH 2 (PGI 2 )PGF 2a XPGE 2 4TXA 2 48-isoprostane, PGD 2 ). Dazoxiben abolished the production of thromboxane A 2 , but did not influence the endothelium-dependent contractions to acetylcholine. 4 The release of PGI 2 was significantly larger in the aorta of SHR than in WKY, and the former was more sensitive to the contractile effect of PGI 2 than the latter. The inhibition of PGI-synthase was associated with an increase in PGH 2 spillover and the enhancement of acetylcholine-induced endothelium-dependent contractions. 5 Thus, in the aorta of SHR and aging WKY, the endothelium-dependent contractions elicited by acetylcholine most likely involve the release of PGI 2 with a concomitant contribution of PGH 2 .
In mature spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), acetylcholine and the calcium ionophore A-23187 release endothelium-derived contracting factors (EDCFs), cyclooxygenase derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine are most likely prostacyclin and prostaglandin (PG)H(2), whereas those released by A-23187 remain to be identified. Isometric tension and the release of PGs were measured in rings of isolated aortas of WKY and SHR. A-23187 evoked the endothelium-dependent release of prostacyclin, thromboxane A(2), PGF(2alpha), PGE(2), and possibly PGH(2) (PGI(2) >> thromboxane A(2) = PGF(2alpha) = PGE(2)). In SHR aortas, the release of prostacyclin and thromboxane A(2) was significantly larger in response to A-23187 than to acetylcholine. In response to the calcium ionophore, the release of thromboxane A(2) was significantly larger in aortas of SHR than in those of WKY. In both strains of rat, the inhibition of cyclooxygenase-1 prevented the release of PGs and the occurrence of endothelium-dependent contractions. Dazoxiben, the thromboxane synthase inhibitor, abolished the A-23187-dependent production of thromboxane A(2) and inhibited by approximately one-half the endothelium-dependent contractions. U-51605, an inhibitor of PGI synthase, reduced the release of prostacyclin elicited by A-23187 but induced a parallel increase in the production of PGE(2) and PGF(2alpha), suggestive of a PGH(2) spillover, which was associated with the enhancement of the endothelium-dependent contractions. These results indicate that in the aorta of SHR and WKY, the endothelium-dependent contractions elicited by A-23187 involve the release of thromboxane A(2) and prostacyclin with a most likely concomitant contribution of PGH(2).
1 This study was designed to determine whether the endothelium-dependent hyperpolarizations evoked by acetylcholine in guinea-pig carotid artery involve a cytochrome P450 metabolite and whether they are linked to the activation of two distinct populations of endothelial K Ca channels, SK Ca and IK Ca. 2 The membrane potential was recorded in the vascular smooth muscle cells of the guinea-pig isolated carotid artery. All the experiments were performed in the presence of N o -L-nitro arginine (100 mM) and indomethacin (5 mM). 3 Under control conditions (Ca 2 þ : 2.5 mM), acetylcholine (10 nM to 10 mM) induced a concentrationand endothelium-dependent hyperpolarization of the vascular smooth muscle cells. Two structurally different specific blockers of SK Ca , apamin (0.5 mM) or UCL 1684 (10 mM), produced a partial but significant inhibition of the hyperpolarization evoked by acetylcholine whereas charybdotoxin (0.1 mM) and TRAM-34 (10 mM), a nonpeptidic and specific blocker of IK Ca, were ineffective. In contrast, the combinations of apamin plus charybdotoxin, apamin plus TRAM-34 (10 mM) or UCL 1684 (10 mM) plus TRAM-34 (10 mM) virtually abolished the acetylcholine-induced hyperpolarization. 4 In the presence of a combination of apamin and a subeffective dose of TRAM-34 (5 mM), the residual hyperpolarization produced by acetylcholine was not inhibited further by the addition of either an epoxyeicosatrienoic acid antagonist, 14,15-EEZE (10 mM) or the specific blocker of BK Ca , iberiotoxin (0.1 mM). 5 In presence of 0.5 mM Ca 2 þ , the hyperpolarization in response to acetylcholine (1 mM) was significantly lower than in 2.5 mM Ca 2 þ . The EDHF-mediated responses became predominantly sensitive to charybdotoxin or TRAM-34 but resistant to apamin. 6 This investigation shows that the production of a cytochrome P450 metabolite, and the subsequent activation of BK Ca , is unlikely to contribute to the EDHF-mediated responses in the guinea-pig carotid artery. Furthermore, the EDHF-mediated response involves the activation of both endothelial IK Ca and SK Ca channels, the activation of either one being able to produce a true hyperpolarization.
The present study was designed to determine whether or not an increase in endothelial intracellular concentration of calcium ([Ca2+]i) evokes endothelium-dependent contractions in the aorta from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Acetylcholine, adenosine triphosphate (ATP) and the calcium ionophore, A 23187, produced endothelium-dependent relaxations in isolated aortic rings of both WKY and SHR. These relaxations in response to the three agonists were significantly smaller in the SHR when compared with the WKY. Endothelium-dependent contractions to acetylcholine, ATP and A 23187 were observed only in the aorta isolated from the SHR. In the presence of NG-nitro-L-arginine, an NO synthase inhibitor, the endothelium-dependent contractions in response to acetylcholine, ATP and A 23187 were potentiated significantly in the aorta SHR and were unmasked in that of WKY. However, the contractions were still significantly greater in SHR than in WKY. These contractions were abolished by indomethacin and valeryl salicylate (two cyclo-oxygenase inhibitors) as well as by S 18886 (a TP-receptor antagonist), indicating that the endothelium-dependent contraction produced by the three agonists share the same characteristics. The results of the present study indicate that the release/generation of endothelium-derived contracting factor, requires an increase in endothelial [Ca2+]i.
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