Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats: effect of endothelin receptor antagonism.

Abstract

Apoptosis or programmed cell death could be greater than normal in various cardiovascular disorders, particularly in the heart. Apoptosis might contribute to remodeling of blood vessels in hypertension and could participate in regulation of vascular hypertrophy/hyperplasia. To investigate apoptosis in deoxycorticosterone acetate (DOCA)-salt hypertension and to determine whether endothelin-1, whose expression is enhanced in these rats, plays a role in apoptosis. We administered two orally active endothelin-A (ET[A])-selective receptor antagonists, A-127,722.5 (30 mg/kg per day) and LU 135,252 (50 mg/kg per day), to establish whether antigrowth effects of these ET(A) antagonists are in part mediated through apoptosis. Apoptosis was evaluated by radiolabeling of 3' OH ends of fragmented DNA, extracted from aortas, using terminal deoxynucleotidyl transferase, to show the presence of internucleosomal DNA splicing as 'DNA laddering'. Its presence was confirmed by in-situ end-labeling. Systolic blood pressure was slightly but significantly lower in treated than it was in untreated DOCA-salt hypertensive rats by a mean of 26 mmHg (P < 0.01) after 4 weeks of treatment with A-127,722.5 and by 19 mmHg (P < 0.01) in rats treated with LU 135,252. Aortic cross-sectional area (CSA) was significantly greater (P < 0.001) in DOCA-salt rats than it was in uninephrectomized controls. This increased CSA was normalized by both ET(A) antagonists. DOCA-salt rats exhibited a greater degree of apoptosis (evaluated by DNA 'laddering') in aorta (353 +/- 14 pixels/microg DNA) than did control rats (232 +/- 10 pixels/microg DNA, P < 0.01). The magnitude of apoptosis was significantly greater (P < 0.01) in aorta of endothelin-antagonist-treated than it was in aorta of untreated DOCA-salt hypertensive rats. In-situ end-labeling confirmed that more apoptosis had occurred in the media of aorta from DOCA-salt hypertensive rats and the further increase found after treatment with the ET(A) antagonists. An increase in apoptosis occurs in aorta of DOCA-salt hypertensive rats, probably as a physiologic counterpart of growth in this hypertensive model. ET(A) antagonists may act in part by accentuating the apoptosis, thereby inducing a blunting of vascular growth, which could also contribute to their antihypertensive effects.