Dissociation of endothelial cell dysfunction and blood pressure in
shr.
Tesfamariam, Belay, and Martin L. Ogletree,.
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical
Research Institute, Princeton, New Jersey 08543
APStracts 2:0051H, 1995.
This study was designed to examine the impairment of endothelium
-dependent relaxation in spontaneously hypertensive rats (SHR), to
determine whether endothelial cell function is normalized by in vivo
treatment with a thromboxane A2 / prostaglandin endoperoxide (TP)
receptor blocker and to establish whether endothelial dysfunction
contributes to the elevated blood pressure. In isolated aortic rings
from SHR, endothelium-dependent relaxations caused by acetylcholine,
adenosine diphosphate and [alpha]-thrombin were markedly impaired compared
to those from Wistar-Kyoto (WKY) normotensive rats. Arachidonic acid
-induced contractions were significantly enhanced in aorta from SHR.
In contrast, relaxations caused by direct smooth muscle vasodilators,
nitroprusside and cromakalim, and contractions caused by U-46619 were
not different between SHR and WKY rats. Treatment of SHR with the
oral TP receptor antagonist, ifetroban, at 20 and 50 mg/kg per day
fully restored endothelium-dependent relaxation toward normal.
However, ifetroban produced no effect on blood pressure in SHR. In
vitro incubation of aortic rings from SHR with ifetroban also
normalized relaxations to acetylcholine but had no effect in aorta
from WKY. In contrast, the thromboxane A synthase inhibitor,
dazoxiben, only partially improved abnormal acetylcholine-induced
relaxations in aorta from SHR. The results demonstrate that
endothelial cell dysfunction in hypertension can be restored to
normal by selective TP receptor blockade. Furthermore, endothelial
cell dysfunction and TP receptor activation may not significantly
contribute to elevated systemic blood pressure in SHR.
Received 7 September 1994; accepted in final form February 7
1995.
APS Manuscript Number H803-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 February 1995.