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Chronic carvedilol reduces mortality and renal damage in hypertensive stroke-prone rats
F C Barone1, A H Nelson, E H Ohlstein
1Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Insights
Carvedilol and propranolol, beta-blockers, significantly improved survival and reduced neurobehavioral deficits in stroke-prone rats. Carvedilol offered greater protection against organ damage and mortality in this severe hypertension model.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Nephrology
Background:
- Hypertension models are crucial for understanding stroke and cardiovascular disease.
- Beta-blockers are widely used for hypertension management.
- Novel agents like carvedilol offer potential benefits beyond traditional beta-blockade.
Purpose of the Study:
- To evaluate the efficacy of carvedilol and propranolol in a stroke-prone spontaneously hypertensive rat model.
- To assess their impact on survival, neurobehavioral deficits, and cardiovascular and renal pathology.
- To compare the protective effects of carvedilol versus propranolol.
Main Methods:
- Stroke-prone spontaneously hypertensive rats were administered 1% NaCl and a high-fat diet.
- Treatment groups received carvedilol (1200 or 2400 ppm) or propranolol (2400 ppm).
- Control groups received no drug supplement; various physiological and pathological parameters were measured.
Main Results:
- Both carvedilol and propranolol demonstrated beta-adrenoceptor blockade, reduced heart rate, and protected against neurobehavioral deficits and mortality.
- Carvedilol showed a greater reduction in plasma renin activity, aldosterone levels, renal histopathological damage, and cardiac hypertrophy compared to propranolol.
- Even a lower dose of carvedilol significantly reduced renal damage without affecting organ mass or renal function.
Conclusions:
- Carvedilol and propranolol provide significant protection in a genetic model of severe hypertension.
- Carvedilol exhibits superior protective effects against organ pathology, neurobehavioral deficits, and premature death compared to propranolol.
- These findings highlight carvedilol's potential as a therapeutic agent in severe hypertensive conditions.
Abstract:
The effects of carvedilol, a novel vasodilating beta-blocker and antioxidant, and propranolol on survival, neurobehavioral deficits, cardiovascular parameters, plasma renin, plasma aldosterone levels and renal pathology were determined in stroke-prone spontaneously hypertensive rats. Stroke-prone spontaneously hypertensive rats were allowed access to 1% NaCl as the drinking solution and a high fat diet supplemented with carvedilol (1200 or 2400 ppm) or propranolol (2400 ppm). The control group consisted of stroke-prone spontaneously hypertensive rats placed on the same diet with no drug supplement. Animals fed propranolol had a blood level of 864 +/- 68 ng/ml, whereas carvedilol-fed animals had blood levels of 24 +/- 4 ng/ml at 1200 ppm and 471 +/- 145 ng/ml at 2400 ppm. Carvedilol and propranolol treatment resulted in significant beta adrenoceptor blockade. Both compounds reduced heart rate, but had no significant effects on systolic arterial blood pressure. Carvedilol- and propranolol-treated animals also exhibited significant, prolonged protection from neurobehavioral deficits and mortality (P < .01). Elevated plasma renin activity and aldosterone levels seen in untreated controls were significantly decreased by propranolol (P < .05), and to a considerably greater extent by the same dose of carvedilol (P < .01). Carvedilol decreased renal histopathological damage and cardiac hypertrophy to a greater extent (P < .01) than propranolol (at equal doses). Both carvedilol (P < .01)- and propranolol (P < .01)-treated animals had considerably reduced renal damage at 18 weeks of treatment. Carvedilol reduced renal damage more than propranolol (P < .05). In addition, the lower (1200 ppm) dose of carvedilol, which decreased neurobehavioral deficits and mortality, had no significant effects on organ mass or renal function, but significantly (P < .01) reduced renal damage. These data indicate that both beta adrenoceptor blockers, especially carvedilol to a considerably greater degree, convey significant protection in a genetic model of severe hypertension that results in renal and cardiovascular organ pathology, neurobehavioral deficits and premature death.