The cardiovascular profile of the
angiotensin AT1 receptor antagonist,
GR138950, and the influence of potential compensatory homeostatic mechanisms on this profile, were investigated in renal artery ligated hypertensive (RALH) rats.
GR138950 caused a marked reduction in blood pressure associated with immediate
tachycardia in conscious RALH rats. The
antihypertensive action of
GR138950 appeared biphasic; an immediate fall in blood pressure, which plateaued within 1 h, and which was followed by a further slow decline that reached maximum between 5-7 h after administration. The
tachycardia caused by
GR138950 was attenuated by
atenolol and was abolished by combined pretreatment with
atenolol and
atropine methyl nitrate. However, the
antihypertensive profile of
GR138950 was unchanged by these pretreatments. The resting blood pressure and the
antihypertensive effect of
GR138950, in RALH rats, were unaffected by the
vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylene propionyl(1)-O-Me-Tyr2,Arg8]-
vasopressin. Thus, vasopressinergic mechanisms are not involved in either maintaining blood pressure in RALH rats, or in compensating for the fall in blood pressure caused by
GR138950. In anaesthetized RALH rats,
GR138950 caused a marked fall in blood pressure that was accompanied by an increase in heart rate along with sustained increases in renal and splanchnic sympathetic nerve activity. In summary, the biphasic fall in blood pressure evoked by
GR138950 in RALH rats can not be explained on the basis of changes in autonomic control of the heart, alteration of
vasopressin-mediated
vasoconstrictor mechanisms or overall suppression of central sympathetic outflow. Rather, increased
vasoconstrictor tone might serve to oppose the initial fall in blood pressure.