Clinical studies conducted with carvedilol suggest that beta-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many beta-adrenoceptor antagonists are weak partial agonists and possess significant intrinsic sympathomimetic activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective beta1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED50 = 5 and 40 microgram/kg, respectively) and SHHF rats (ED50 = 6 and 30 microgram/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast, carvedilol and bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by xamoterol and bucindolol was inhibited by treatment with propranolol, carvedilol, and betaxolol (beta1-adrenoceptor antagonist) but not by ICI 118551 (beta2-adrenoceptor antagonist) in neonatal rat. When the beta-adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast, GTP-sensitive ligand binding and tissue adenylate cyclase activity were not sensitive methods for detecting beta-adrenoceptor partial agonist activity in the heart. In summary, xamoterol and bucindolol, but not carvedilol and bisoprolol, exhibited direct beta1-adrenoceptor-mediated ISA in normal and heart failure rats.
Carvedilol, a new vasodilating beta-adrenoceptor antagonist and a potent antioxidant, produces a high degree of cardioprotection in a variety of experimental models of ischemic cardiac injury. Recent clinical studies in patients with heart failure have demonstrated that carvedilol reduces morbidity and mortality and inhibits cardiac remodeling. The present study was designed to explore whether the protective effects of carvedilol on the ischemic myocardium include inhibition of apoptosis of cardiomyocytes and, if so, to determine its mechanism of action. Anesthetized rabbits were subjected to 30 minutes of coronary artery occlusion followed by 4 hours of reperfusion. Detection of apoptosis of cardiomyocytes was based on the presence of nucleosomal DNA fragments on agarose gels (DNA ladder) and in situ nick end labeling. Carvedilol (1 mg/kg IV), administered 5 minutes before reperfusion, reduced the number of apoptotic myocytes in the ischemic area from 14.7 +/- 0.4% to 3.4 +/- 1.8% (77% reduction, P<.001). Propranolol, administered at equipotent beta-blocking dosage, reduced the number of apoptotic myocytes to 8.9 +/- 2.1% (39% reduction, P<.05). DNA ladders were observed in the hearts of all six vehicle-treated rabbits but only one of six carvedilol-treated rabbits (P<.01). Immunocytochemical analysis of rabbit hearts demonstrated an upregulation of Fas protein in ischemic cardiomyocytes, and treatment with carvedilol reduced both the intensity of staining as well as the area stained. Myocardial ischemia/reperfusion led to a rapid activation of stress-activated protein kinase (SAPK) in the ischemic area but not in nonischemic regions. SAPK activity was increased from 2.1 +/- 0.3 mU/mg (basal) to 8.9 +/- 0.8 mU/mg after 30 minutes of ischemia followed by 20 minutes of reperfusion. Carvedilol inhibited the activation of SAPK by 53.4 +/- 6.5% (P<.05). Under the same conditions, propranolol (1 mg/kg) had no effect on SAPK activation. Taken together, these results suggest that carvedilol prevents myocardial ischemia/reperfusion-induced apoptosis in cardiomyocytes possibly by downregulation of the SAPK signaling pathway, by inhibition of Fas receptor expression, and by beta-adrenergic blockade. The former two actions represent novel and important mechanisms that may contribute to the cardioprotective effects of carvedilol.
The present study was undertaken to assess the effect of carvedilol, a new vasodilating beta-adrenoceptor blocker with antioxidant activity, on the oxidation of low-density lipoproteins (LDL) by rat aortic smooth muscle cells (RASMC). LDL oxidation was assessed as thiobarbituric acid reactive substances (TBARS) formation and increase in electrophoretic mobility. Oxidized (ox) LDL-induced cytotoxicity was assessed as lactate dehydrogenase release (LDH) from cells and ox-LDL-enhanced adhesiveness of the RASMC for leukocytes was also determined. Carvedilol inhibited TBARS formation and LDH release from RASMC with IC50 values of 1.74 and 1.62 microM, respectively. Under the same conditions, the IC50 values of probucol and nicardipine were 2.33 and 5.60 microM, respectively, for inhibition of TBARS and 5.16 and 12.10 microM, respectively, for inhibition of LDH release; propranolol, atenolol, pindolol and labetalol, at concentrations up to 100 microM, had virtually no effect on either variable. RASMC-dependent ox-LDL stimulated the adhesive properties of RASMC for both monocytes and neutrophils in a concentration- and time-dependent manner, which were prevented when the RASMC were treated with carvedilol (IC50 2.07 microM for monocytes and 1.12 microM for neutrophils), whereas other beta blockers, at concentrations up to 30 microM, had only mild effects. The monoclonal antirat intercellular adhesion molecule-1 antibody partially inhibited ox-LDL-induced adhesion of RASMC for monocytes and neutrophils. Northern analysis demonstrated that ox-LDL induced intracellular adhesion molecule-1 messenger RNA expression on RASMC, which was inhibited by carvedilol and probucol via inhibition of LDL oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
Splanchnic artery occlusion (SAO) followed by reperfusion results in circulatory shock in which oxygen-derived free radicals play an important role. Carvedilol, a novel beta adrenoceptor antagonist and a vasodilator, has been recently shown to exert potent antioxidant effects in multiple cell model systems. In the present experiment, we investigated the effect of carvedilol on SAO shock. Pentobarbital-anesthetized rats were subjected to 60 min of SAO followed by 120 min of reperfusion. Administration of 1 mg/kg carvedilol 10 min before reperfusion prolonged survival time (P < .05) and attenuated the increases in tissue myeloperoxidase activities (P < .01) and hematocrits (P < .001). Moreover, carvedilol significantly preserved superior mesenteric artery endothelial function (P < .01). Similar protection was seen in SAO shock rats treated with the superoxide free-radical scavenger superoxide dismutase. Except for a moderate attenuation of an increase in hematocrits, protective effects were not seen in SAO shock rats treated with the prototypic beta blocker propranolol. These results indicate that in murine SAO shock, carvedilol affords significant protection, which may be achieved through maintenance of tissue blood perfusion, quenching of oxygen free radicals, preservation of vascular endothelial function, and inhibition of neutrophil-endothelial interaction and its resultant increased microvascular permeability.
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