CARVEDILOL, A NOVEL CARDIOVASCULAR AGENT, INHIBITS DEVELOPMENT OF VASCULAR AND VENTRICULAR HYPERTROPHY IN SPONTANEOUSLY HYPERTENSIVE RATS

The effects of carvedilol, a novel cardiovascular agent, were evaluate d in developing spontaneously hypertensive rats (SHR) for effects on h emodynamics, and the ability to effect the development of left ventric ular, and vascular hypertrophy associated with chronic hypertension. C hronic oral administration of low dose carvedilol (20 mg/kg/day) was i nitiated when rats were 5 weeks of age, and experiments progressed unt il 14 weeks of age. Carvedilol-treated SHR had significantly reduced s ystolic blood pressures and heart rates throughout the duration of the experiment, and had significantly reduced ventricle/body weights by a pproximately 9.0%. Morphologic analysis of tertiary branches of the me senteric artery revealed that carvedilol-treated SHR had significant r eductions in medial cross-sectional area, Carvedilol produced concentr ation-dependent inhibition of basal [H-3]thymidine incorporation in cu ltured SHR vascular smooth muscle cells, as well as by stimulation pro duced by PDGF (1 nM), EDGF (1 nM), thrombin (0.5 U/ml), or endothelin- 1 (1 nM), indicating that carvedilol had direct anti-mitogenic activit y. The present studies demonstrate that low dose carvedilol produced s ustained reductions in blood pressure and heart rate in developing SHR that were accompanied by significant inhibition in the development of vascular and myocardial hypertrophy. The morphological changes induce d by carvedilol may be mediated by a combination of hemodynamic effect s, as well as by direct anti-mitogenic effects on vascular smooth musc le.