Carvedilol, A Novel Cardiovascular Agent, Inhibits Development of Vascular and Ventricular Hypertrophy in Spontaneously Hypertensive Rats

Abstract

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.

Different Effects on Inhibition of Cardiac Hypertrophy in Spontaneously Hypertensive Rats by Monotherapy and Combination Therapy of Adrenergic Receptor Antagonists and/or the Angiotensin II Type 1 Receptor Blocker under Comparable Blood Pressure Reduction

“…They also found that even though the blood pressure-reducing effect of the β adrenergic receptor blocker was less than that of the α1 blocker, the increase of heart weight was inhibited by the β Since left ventricular BNP mRNA expression by combination therapy with doxazosin and atenolol was significantly lower than that by atenolol monotherapy, the antihypertrophic effects may be enhanced when α1 and β adrenergic receptor antagonists are combined. Similarly, it has been reported that administration of carvedilol, which is an αβ adrenergic receptor antagonist, inhibits the development of cardiac hypertrophy in SHR (35). It has been indicated that α1 adrenergic receptor blockers reduce the unfavorable effect of β blockers on insulin sensitivity and lipid metabolism (36).…”

Effect of celiprolol therapy on arterial dilatation in experimental hypertension

“…On the basis of previous reports, the degree of cardiovascular hypertrophy in SHR is not only governed by the level of blood pressure, but also by enhanced cellular responses to various growth factors such as angiotensin II (Dzau et al, 1991). Moreover, chronic fl-adrenoceptor antagonism has been reported either to reduce moderately (Lauva & Tomanek, 1985;Ohlstein et al, 1994) or not to affect heart weights in SHR (Chatelain et al, 1981). Nevertheless, morphological studies of the vasculature revealed that media smooth muscle hypertrophy of the mesenteric artery was significantly reduced by both of the present doses of celiprolol in SHR.…”

“…This suggests that the antihypertrophic property of celiprolol may not be solely related to the haemodynamic changes induced by the treatment, and that other factors such as inhibition of neurohumoral activation or cellular growth may also be involved. Indeed it has been suggested that the antihypertrophic effect of carvedilol on vascular smooth muscle is mediated by a combination of haemodynamic and anti-mitogenic effects (Ohlstein et al, 1994). ACh relaxes arteries in an endothelium-dependent manner via the release of the endothelium-derived relaxing factor (EDRF), which stimulates smooth muscle soluble guanylate cyclase and elevates intracellular cyclic GMP (Moncada et al, 1991).…”

Carvedilol: Molecular and Cellular Basis for Its Multifaceted Therapeutic Potential

“…Carvedilol has been demonstrated to significantly reduce left ventricular and vascular hypertrophy in spontaneously hypertensive rats (74). The antihypertrophic property of carvedilol is partly independent of its antihypertensive effect.…”