ANGIOTENSIN AT(1) RECEPTOR INHIBITION - EFFECTS ON HYPERTROPHIC REMODELING AND ACE EXPRESSION IN RATS WITH PRESSURE-OVERLOAD HYPERTROPHY DUE TO ASCENDING AORTIC-STENOSIS

Background We tested the hypothesis that long-term administration of t he specific angiotensin II subtype 1 (AT(1))-receptor blocker BMS-1862 95 will regress hypertrophy and modify left ventricular angiotensin co nverting enzyme (ACE) expression in rats with ascending aortic stenosi s. Methods and Results Six weeks after surgery, rats with ascending ao rtic stenosis were randomized to receive either the AT(1)-receptor blo cker BMS-186295 50 mg . kg(-1). d(-1) (n = 49), amlodipine 2.5 mg . kg (-1). d(-1) (n = 48) as a positive control for systemic vasodilation, or no drug (n = 48) and compared with sham-operated rats (n = 39). Dru g treatment was continued for 15 weeks. Left ventricular ACE mRNA leve ls were measured by ribonuclease protection assay. The left ventricula r/body weight ratio was increased 43% in hearts from rats with untreat ed left ventricular hypertrophy (LVH) versus control hearts (P < .05). However, there was no difference in either the left ventricular/body weight ratio (2.78 +/- 0.08 versus 2.81 +/- 0.20 mg/g; P = NS) or myoc yte cross-sectional area in the AT(1)-blocker-treated versus untreated LVH hearts. Amlodipine also showed no effect on regression of hypertr ophy. In vivo left ventricular systolic pressure was significantly hig her in untreated LVH versus sham-operated rats (193 +/- 8 versus 118 /- 4 mm Hg; P < .05), and there was a similar severe elevation of left ventricular systolic pressure in the AT(1)-blocker- and amlodipine-tr eated LVH groups (189 +/- 9 and 188 +/- 16 mm Hg; P = NS versus untrea ted LVH). In vivo left ventricular end-diastolic pressure was higher i n the untreated LVH than in the sham-operated rats (14.8 +/- 2.3 versu s 7.0 +/- 0.5 mm Hg; P < .05). Left ventricular end-diastolic pressure was lower in the AT(1)-blocker-treated (11.0 +/- 1.7 mm Hg) and amlod ipine-treated rats (11.5 +/- 1.8 mm Hg) and was similar to left ventri cular end-diastolic pressure in the sham-operated rats (P = NS). Left ventricular ACE mRNA levels were elevated in untreated LVH rats but we re normalized in both the AT(1)-blocker-treated rats and amlodipine-tr eated rats. Conclusions Long-term AT(1)-receptor blockade did not regr ess LVH in rats with persistent systolic pressure overload due to asce nding aortic stenosis. However, both AT(1)-receptor blockade anti amlo dipine improved in vivo left ventricular end-diastolic pressure in ass ociation with the normalization of left ventricular ACE mRNA levels.