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Carvedilol prevents severe hypertensive cardiomyopathy and remodeling
F C Barone1, W G Campbell, A H Nelson
1Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Frank_C_Barone@SBPHRD.Com
Insights
Carvedilol significantly reduced cardiac damage in rats with severe hypertension. This drug offers cardioprotection by suppressing hypertension-induced cardiac remodeling and myopathies without lowering blood pressure.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Hypertension Research
Background:
- Carvedilol is a beta-blocker with antioxidant properties used for hypertension, angina, and heart failure.
- Previous studies show carvedilol provides cardiac protection and reduces left ventricle hypertrophy.
Purpose of the Study:
- To investigate the effects of carvedilol on heart pathology in stroke-prone spontaneously hypertensive rats with severe hypertension.
Main Methods:
- Rats were fed a high-salt, high-fat diet, with some groups receiving carvedilol (1200 or 2400 ppm).
- A control group received the diet without carvedilol, and another group received a normal diet.
- Evaluated cardiovascular parameters and developed histopathologic indices to assess cardiac remodeling and pathology over 18 weeks.
Main Results:
- Carvedilol did not affect systolic blood pressure but slightly reduced heart rate.
- A significant, dose-dependent reduction in total cardiac histologic damage was observed (54% and 82% at low and high doses).
- Carvedilol dose-dependently reduced coronary artery hypertrophy/hyperplasia, myofiber degeneration, inflammation, fibrosis, microthrombosis, and microinfarction, and normalized cardiac mass and left ventricle dimensions.
Conclusions:
- Carvedilol demonstrates significant cardioprotection against severe hypertension-induced cardiac remodeling and myopathies.
- These benefits occur at doses that do not lower systemic blood pressure.
Background:
Carvedilol (Coreg/Kredex) is an unselective vasodilating beta-blocker with potent antioxidant activity used in the treatment of hypertension, angina, and congestive heart failure. In previous studies, carvedilol has been demonstrated to confer significant cardiac protection in acute ischemic paradigms and reduction of left ventricle hypertrophy in spontaneously hypertensive rats.
Objective:
To examine the effects of carvedilol on discrete histopathologic changes in the heart induced by severe hypertension in stroke-prone spontaneously hypertensive rats.
Design:
Three groups of stroke-prone spontaneously hypertensive rats were maintained on 1% NaCl drinking solution and a high-fat (24.5%) diet (salt-fat diet). Two of these groups had their salt-fat diet supplemented by 1200 or 2400 ppm carvedilol. The third group had the same diet but it was not supplemented with drug and this group served as a control. We fed a fourth group of stroke-prone spontaneously hypertensive rats a normal diet and used this group to define cardiac changes induced by salt-fat diet.
Methods:
In total, 33 stroke-prone spontaneously hypertensive rats from these four groups (n = 7-9 in each group) survived for 18 weeks under these treatment regimens and were evaluated in terms of cardiovascular parameters and several quantitative and semiquantitative histopathologic indices that we developed to identify and compare cardiac muscle and vascular pathology/remodeling.
Results:
Administration of carvedilol had no effect on systolic blood pressure (range for all salt-fat diet groups 288 +/- 8 to 294 +/- 6 mmHg compared with the value for the normal diet group of 228 +/- 12 mmHg) whereas heart rate was slightly reduced (by 10-18%; P<0.05). Administration of carvedilol produced a significant (P<0.01) dose-related decrease in total cardiac histologic damage (i.e. the sum of several histopathologic indices) induced by the salt-fat diet (i.e. it reduced damage by 54 and 82% at low and high doses, respectively). Specifically, administration of carvedilol produced dose-dependent reductions in histopathologic indices of coronary artery hypertrophy (by up to 88%), hyperplasia (by up to 89%), degeneration of myofiber (by up to 91%), myocardial inflammation (by up to 100%), cardiac fibrosis (by up to 67%), arterial microthrombosis (by up to 95%), and myocardial microinfarction (by up to 100%; all P<0.01). Salt-fat diet induced an increase in total cardiac mass and left ventricle-intraventricular septum cross-sectional area that was completely eliminated by administration of carvedilol (P<0.01).
Conclusions:
These data indicate that carvedilol provides remarkable cardioprotection, by suppressing severe hypertension-induced cardiac remodeling and myopathies at doses that do not reduce systemic blood pressure.