DISSOCIATION OF ENDOTHELIAL-CELL DYSFUNCTION AND BLOOD-PRESSURE IN SHR

This study was designed to examine the impairment of endothelium-depen dent relaxation in spontaneously hypertensive rats (SHR), to determine whether endothelial cell function is normalized by in vivo treatment with a thromboxane A(2)-prostaglandin endoperoxide (TP)-receptor block er, and to establish whether endothelial dysfunction contributes to th e elevated blood pressure. In isolated aortic rings from SHR, endothel ium-dependent relaxations caused by acetylcholine, adenosine diphospha te, and alpha-thrombin were markedly impaired compared with those from Wistar-Kyoto (WKY) normotensive rats. Arachidonic acid-induced contra ctions were significantly enhanced in aorta from SHR. In contrast, rel axations caused by direct smooth muscle vasodilators, nitroprusside an d cromakalim, and contractions caused by U-46619 were not different be tween SHR and WKY rats. Treatment of SHR with the oral TP-receptor ant agonist, ifetroban, at 20 and 50 mg kg-1 . day(-1) fully restored endo thelium-dependent relaxation toward normal. However, ifetroban produce d no effect on blood pressure in SHR. In vitro incubation of aortic ri ngs from SHR with ifetroban also normalized relaxations to acetylcholi ne but had no effect in aorta from WKY. In contrast, the thromboxane A synthase inhibitor, dazoxiben, only partially improved abnormal acety lcholine-induced relaxations in aorta from SHR. The results demonstrat e that endothelial cell dysfunction in hypertension can be restored to normal by selective TP-receptor blockade. Furthermore, endothelial ce ll dysfunction and TP-receptor activation may not significantly contri bute to elevated systemic blood pressure in SHR.