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 evaluated in developing spontaneously hypertensive rats (SHR) for effects on hemodynamics, and the ability to effect the development of left ventricular, and vascular hypertrophy associated with chronic hypertension. Chronic oral administration of low dose carvedilol (20 mg/kg/day) was initiated when rats were 5 weeks of age, and experiments progressed until 14 weeks of age. Carvedilol-treated SHR had significantly reduced systolic blood pressures and heart rates throughout the duration of the experiment, and had significantly reduced ventricle/body weights by approximately 9.0%. Morphologic analysis of tertiary branches of the mesenteric artery revealed that carvedilol-treated SHR had significant reductions in medial cross-sectional area. Carvedilol produced concentration-dependent inhibition of basal [3H]thymidine incorporation in cultured SHR vascular smooth muscle cells, as well as by stimulation produced by PDGF (1 nM), EDGF (1 nM), thrombin (0.5 U/ml), or endothelin-1 (1 nM), indicating that carvedilol had direct anti-mitogenic activity. The present studies demonstrate that low dose carvedilol produced sustained 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 induced by carvedilol may be mediated by a combination of hemodynamic effects, as well as by direct anti-mitogenic effects on vascular smooth muscle.
Ohlstein
E H
EH
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Vickery
L
L
Arleth
A
A
Barone
F
F
Sung
C P
CP
Camden
A
A
McCartney
L
L
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology*; D006332:Cardiomegaly / Q000517:prevention & control*; D000077261:Carvedilol; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D004247:DNA