In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A₂ as endothelium-derived contracting factors

Abstract

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).

Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension

“…However, thromboxane synthase was expressed at a higher level in 36-wk-old SHR than in WKY aorta. This augmented expression of thromboxane synthase may explain why thromboxane A 2 contributes to EDCF-mediated responses triggered by agonists such as adenosine diphosphate, the calcium ionophore A-23187, and endothelin-1 (10,11,32). Aging resulted in an increase in the genomic level of thromboxane synthase.…”

“…EDCF is unlikely to be a single substance but rather is constituted of a mixture of prostanoids, the formation of which depends on the vascular bed, the age, and the condition of the species studied. Thus prostacyclin (9,10,27), endoperoxides (7,14), and thromboxane A 2 (10,11,29) have been proposed as EDCFs. Cyclooxygenase breaks down arachidonic acid to form endoperoxides, which are subsequently converted into prostacyclin, thromboxane A 2 , prostaglandin D, prostaglandin E, and/or prostaglandin F by their respective synthases (3,20).…”

Endothelium-Dependent Contractions in Hypertension

“…23 Lowering the extracellular calcium concentration reduces endothelium-dependent contractions, 24 whereas calcium ionophores, in particular, A23187, evoke endotheliumdependent contractions. [25][26][27][28][29] During endothelium-dependent contractions induced by acetylcholine, the endothelial cytosolic calcim concentration increases 28,29 and this increment is larger in aortae of spontaneously hypertensive rats (SHR) than in those of normotensive Wistar-Kyoto rats, in line with the larger EDCF-mediated responses in the preparations of the hypertensive strain. 8,28,30 Taken in conjunction, those findings imply that an increase in endothelial cytosolic calcium concentration is the initiating event leading to the release of EDCF.…”

Oxygen‐derived free radicals mediate endothelium‐dependent contractions in femoral arteries of rats with streptozotocin‐induced diabetes

“…Endothelium-and cyclooxygenase-dependent contractions are prominent in the aorta of the spontaneously hypertensive rat (Lüscher and Vanhoutte, 1986;Yang et al, 2004a, b;Tang et al, 2007), the abdominal aorta of the diabetic rabbit and the femoral artery of the diabetic rat (Shi et al, 2007). The endothelium-derived contracting factor can be prostacyclin, thromboxane A 2 , endoperoxides, prostaglandin E 2 , hydroxyl radicals or superoxide anions depending on the animal model, the preparation and the agonist used Auch-Schwelk et al, 1990;Yang et al, 2004a, b;Gluais et al, 2005Gluais et al, , 2006Shi et al, 2007). Oxygen-derived free radicals facilitate endothelium-dependent contractions, and antioxidants effectively decreased them in the aorta of spontaneously hypertensive rats Yang et al, 2002Yang et al, , 2003bTang et al, 2007).…”