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J Cardiovasc Pharmacol. 2000 May;35(5):763-8.
Disparate effects of carvedilol versus metoprolol treatment of stroke-prone spontaneously hypertensive rats on endothelial function of resistance arteries.

Intengan HD, Schiffrin EL.

MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Quebec, Canada.

In human hypertension, blockade of beta-adrenoceptors does not improve resistance artery structure or endothelial dysfunction. We tested in hypertensive rats the hypothesis that carvedilol, a beta-blocker with antioxidant properties, would improve endothelial dysfunction, whereas the beta1-selective blocker, metoprolol, would not. Twenty-week-old SHRSP were treated orally for 10 weeks with carvedilol (50 mg/kg/day) or metoprolol (100 mg/kg/day), with or without hydralazine (25 mg/kg/day), the latter because neither beta-blocker was a very effective blood pressure-lowering agent in this model. Mesenteric arteries (lumen, <300 microm) were studied on a pressurized myograph. After 10 weeks, untreated SHRSP had a systolic blood pressure (mm Hg) of 239+/-3 that was unaffected by carvedilol or metoprolol treatment but decreased (p < 0.05) by hydralazine (187+/-4), carvedilol + hydralazine (221+/-3), and metoprolol + hydralazine (197+/-3). Carvedilol alone improved endothelium-dependent relaxation of resistance arteries, as elicited by the lowest concentration of acetylcholine studied (10(-7) M), whereas metoprolol had no effect. Hydralazine improved endothelial function as elicited by acetylcholine at a dose of 10(-6) M, also found under cotreatment with carvedilol but attenuated by cotreatment with metoprolol. Carvedilol or metoprolol alone had no significant effect on endothelium-independent relaxation produced by a nitric oxide donor (sodium nitroprusside). However, vessels from rats treated with carvedilol + hydralazine exhibited significantly greater relaxation than those from rats treated with metoprolol + hydralazine. These data suggest that carvedilol may have favorable effects on hypertension-related endothelial dysfunction not observed with metoprolol. Neither drug corrected small artery structure in SHRSP.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10813379&dopt=Abstract




J Cardiovasc Pharmacol. 1998 Sep;32(3):443-51.
Comparative effects of carvedilol and metoprolol on cardiac ischemia-reperfusion injury.

Khandoudi N, Percevault-Albadine J, Bril A.

SmithKline Beecham Laboratoires Pharmaceutiques, Saint-Gregoire, France.

The effects of carvedilol, a multiple-action neurohormonal antagonist, and metoprolol, a highly selective beta1 antagonist, were compared on postischemic contractile recovery and contracture. Isolated rabbit hearts were aerobically perfused for 45 min and subjected to zero-flow normothermic ischemia for 30 or 60 min followed by reperfusion for 30 min. Carvedilol and metoprolol were added to the perfusion solution 10 min before inducing ischemia and were maintained in the perfusate throughout reperfusion. Left ventricular developed pressure (LVDP) and left ventricular end-diastolic pressure (LVEDP) were assessed with an intraventricular balloon. Because the volume of the balloon was held constant, an increase in LVEDP reflected an increase in diastolic chamber stiffness or "contracture." After 30 min of ischemia, the carvedilol-treated hearts exhibited a significantly better cardiac function than did control or metoprolol-treated hearts. At the end of reperfusion, the control group LVDP recovered to 21.4+/-9.9% of the preischemic value. With 0.03, 0.1, and 0.3 microM metoprolol, LVDP recovered to 33.2+/-13.6%, 41.7+/-13.0%, and 48.8+/-13.3% of initial developed pressure, respectively. In the carvedilol group, a greater recovery of LVDP was obtained at 0.03, 0.1, and 0.3 microM: 64.0+/-2.5%, 60.4+/-6.3%, and 68.0+/-2.0% of preischemic values, respectively (p < 0.05 vs. controls). Within the first 5 min of reperfusion, LVEDP increased to 70.3+/-2.7 mm Hg in control hearts, indicating a pronounced contracture, whereas metoprolol reduced LVEDP when given at high concentration, 0.3 microM (41.9+/-10.7 mm Hg). Carvedilol, even at the lowest concentration, 0.03 microM, almost completely inhibited the postischemic contracture (16.5+/-4.0 mm Hg; p < 0.05 vs. control and metoprolol). The cardioprotection provided by carvedilol also is observed in hearts subjected to more severe ischemic periods. After 60 min of ischemia, control hearts failed to restore LVDP function; in the metoprolol group, ventricular function recovered to only 4.6+/-3.1%, whereas carvedilol-treated hearts exhibited 23.6+/-1.9% of preischemic values at the end of reperfusion. In addition, carvedilol induced a reduction in ischemic contracture: control, 36.7+/-3 mm Hg; metoprolol, 38.7+/-3.7 mm Hg; and carvedilol, 15.7+/-8.4 mm Hg at 50 min of ischemia. Similarly, carvedilol reduced contracture during the reperfusion compared with metoprolol and control groups (83.2+/-3.4 mm Hg, 106.9+/-3.3 mm Hg, and 107.6+/-4.1 mm Hg, respectively). These data clearly demonstrate that carvedilol was markedly more effective than metoprolol to protect systolic function after ischemia and to reduce postischemic contracture.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9733358&dopt=Abstract

gwsun.medinf.mu-luebeck.de

Carvedilol is a beta-adrenoceptor antagonist with multiple actions, which may contribute to superior cardioprotection in heart failure and myocardial infarction. We hypothesized that carvedilol may modulate presynaptic norepinephrine release in the heart. Therefore, we compared the effects of carvedilol (racemate and both enantiomers) and beta1-selective as well as nonselective beta-adrenoceptor blockers on norepinephrine release in isolated perfused rat hearts under normoxic and brief ischemic conditions. Exocytotic release of endogenous norepinephrine was induced by paired electric field stimulations to compare the release before (S1) and after (S2) beta-adrenoceptor blocker application. Metoprolol, bisoprolol, and pindolol (0.1-10 microM) had essentially no effect on exocytotic norepinephrine release under normoxic and ischemic conditions. In contrast, carvedilol exerted a biphasic concentration-response curve (increase followed by suppression) on norepinephrine release. The increase in norepinephrine release was more pronounced with R-carvedilol than with S-carvedilol, indicating an effect independent from beta-receptor antagonism. During ischemia, the facilitatory effect of carvedilol on norepinephrine release was lost, resulting in a concentration-dependent suppression of the release. These results indicate that carvedilol in contrast to classic beta1-selective and -nonselective beta-adrenoceptor blockers has pronounced effects on cardiac norepinephrine release with a remarkable difference between normoxic and ischemic conditions. Whereas a facilitation of norepinephrine release prevailed in normoxia, we observed a suppression of the release in ischemia. It remains to be established whether this unique action of carvedilol on cardiac sympathetic neurotransmission is of clinical relevance.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10892666&dopt=Abstract












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