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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stress-activated protein kinase (SAPK/JNK) has been implicated in the signaling pathway that leads to cell death. Carvedilol, a new vasodilating beta-adrenoceptor antagonist with potent antioxidant activity, has been shown to convey a high degree of cardioprotection in a variety of experimental models of myocardial ischemia as well as in patients with congestive heart failure. The present study was designed to explore whether the cardioprotective effects of carvedilol involve inhibition of SAPK activation. Ex vivo ischemia (30 min)-reperfusion (60-120 min) of the rabbit heart resulted in 67% reduction of pressure-rate product, 45% necrosis of left ventricular tissue and 62% loss of myocardial creatine kinase (P < 0.01 vs. basal). SAPK levels in the perfused hearts increased markedly following reperfusion (5.6-fold increase, P < 0.01 vs. basal). Carvedilol, at 10 microM, administered at time of reperfusion, enhanced recovery of pressure-rate product by 61%, reduced necrotic size by 65% and decreased myocardial creatine kinase loss by 62% (P < 0.01 vs. vehicle). Carvedilol also inhibited reperfusion-induced activation of SAPK by 61% (P<0.01 vs. vehicle). Carvedilol, at 1 microM, displayed a trend of cardioprotection and inhibition of SAPK activation. Our results suggest that SAPK may play a role in ischemia/reperfusion-induced cardiac injury and inhibition of SAPK activation by carvedilol may contribute to its cardioprotective effects.
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PMID:Carvedilol inhibits activation of stress-activated protein kinase and reduces reperfusion injury in perfused rabbit heart. 959 95

Carvedilol, a selective alpha1 and non-selective beta-adrenoceptor antagonist and antioxidant, has been shown to provide significant cardiac protection in animal models of myocardial ischemia. To further explore the mechanisms contributing to carvedilol cardioprotection efficacy, the effects of carvedilol on hemodynamic variables, infarct size and myeloperoxidase activity (an index of neutrophil accumulation) were compared with a beta1-selective adrenoceptor antagonist, metoprolol. Carvedilol (1 mg/kg) or metoprolol (1 mg/kg or 1 mg/kg + 0.5 mg/kg 90 min later) was given intravenously 5 min before reperfusion. In vehicle-treated rabbits, ischemia (60 min) and reperfusion (180 min) resulted in significant increments in left ventricular end diastolic pressure, large infarcts (59+/-2.6% of area-at-risk) and marked increase in myeloperoxidase activity (0.59+/-0.09 U/100 mg tissue). Carvedilol treatment resulted in sustained reduction of pressure-rate-index and significantly smaller infarcts (22.0+/-2.5%, P < 0.01 vs. vehicle) as well as decreased myeloperoxidase activity (0.186+/-0.056 U/100 mg tissue, P < 0.01 vs. vehicle). The highest dose of metoprolol, 1 mg/kg + 0.5 mg/kg, that resulted in pressure-rate-index comparable to that of 1.0 mg/kg carvedilol, failed to reduce myeloperoxidase activity in the ischemic myocardial tissue, and the infarct size (35+/-3.1%) was significantly larger than in carvedilol-treated animals. Taken together, this study suggests that the superior cardioprotection of carvedilol over metoprolol is not a consequence of hemodynamic variances but possibly the result of the additional pharmacological properties of carvedilol such as the antioxidant and anti-neutrophil effects.
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PMID:Comparison of metoprolol and carvedilol pharmacology and cardioprotection in rabbit ischemia and reperfusion model. 972 Oct 26

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.
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PMID:Comparative effects of carvedilol and metoprolol on cardiac ischemia-reperfusion injury. 973 58

Depriving heart tissue of their blood supply leads to a decrease in high-energy compounds and many metabolic disturbances. Following short periods of ischemia, heart can recover their physiological functions after reperfusion, but prolonged ischemia injures heart irreversibly. Mitochondrial disfunction is one of the most critical events associated to injury irreversibility because regeneration of a high ATP level is indispensable for recovery of cellular functions. Reperfusion injury is also implicated in the irreversible damage of the ischemic heart. Even after a period of ischemia that is too short to injure the heart, reperfusion can cause further irreversible damage. The formation of oxygen radicals caused by reintroduction of O2 is probably the most important factor of this phenomenon. The mitochondrial redox chain is one of the main sources of O2 radicals responsible for causing damage to mitochondria, and thus mitochondria can be damaged during reperfusion. Most probably the opening of the mitochondrial permeability transition pore due to increased production of oxygen radicals is associated with the irreversible disruption of mitochondria for oxidative phosphorylation. Carvedilol, a potent antioxidant, prevents the lipoperoxidation of mitochondrial membranes what suggest a strong contribution to the known cardioprotective activity of this compound through protection of mitochondrial functions.
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PMID:Ischemic heart disease: the role of mitochondria--carvedilol prevents lipid peroxidation of mitochondrial membranes. 983 83

The safety and efficacy of adding oral carvedilol (25 mg twice daily) to standardized treatment of unstable angina was assessed in a multicenter, randomized, double-blind, placebo- controlled trial on 116 patients with acute unstable angina. Patients were monitored in an intensive care unit and underwent 48-hour Holter monitoring to assess transient ischemia. Carvedilol as adjunctive therapy resulted in a significant reduction of median heart rate (65 vs 75 beats/min, p <0.05), mean systolic blood pressure (133 vs 130 mm Hg, p <0.05), and mean rate-pressure product (8,337 vs 10,042, p <0.05). Carvedilol reduced the ischemic burden during 48 hours of treatment by 75% (49 vs 204 minutes), including a 36% reduction of patients with ischemic episodes (p <0.05), a 66% reduction of the mean number of ischemic episodes (8 vs 24, p <0.05), and a 76% reduction in the mean duration of ischemic episodes (50 vs 205 minutes, p <0.05). Side effects occurred in 8 of 59 patients (13.6%) in the carvedilol group and in 5 of 54 patients (8.8%) given placebo. Although not significant, the early onset of maximal blood pressure reduction and the delayed effect on heart rate were closely correlated to drug-induced hypotension and bradycardia in the carvedilol group. Thus, carvedilol as an adjunctive to standardized treatment effectively reduces heart rate and blood pressure, and thus the ischemic burden in patients with unstable angina pectoris, but requires close monitoring of patients at risk for bradycardia or hypotension.
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PMID:Usefulness of carvedilol in unstable angina pectoris. 1080 96

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.
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PMID:Differential effects of carvedilol on norepinephrine release in normoxic and ischemic heart. 1089 66

Carvedilol is a vasodilating beta-blocker and antioxidant approved for treatment of mild to moderate hypertension. angina, and congestive heart failure. Metoprolol is a beta1-selective adrenoceptor antagonist. When carvedilol and metoprolol were recently compared in clinical trials for heart failure, each showed beneficial beta-blocker effects such as improved symptoms, quality of life, exercise tolerance, and ejection fraction, with no between-group differences. When thiobarbituric acid reactive substance (TBARS) levels were measured in serum as an indirect marker of free radical activity, there were also no between-group differences. However, we had noted superior cardioprotection by carvedilol in comparison to metoprolol in ischemia and reperfusion models. We therefore examined antioxidant activity directly in cells and tissues. Here we show that in cultured rat cerebellar neurons, and in brain and heart membranes, carvedilol has far greater antioxidant activity than metoprolol, which is essentially inactive as an antioxidant in these model systems. The antioxidant activity of carvedilol could be explained by a greater degree of lipophilicity, as measured by its ClogP value of 3.841 as contrasted to a ClogP value of 1.346 for metoprolol. Alternatively, the molecular structure of carvedilol favors redox recycling, which the structure of metoprolol does not. Therefore, carvedilol could have additional pharmacologic effects that are favorable for long-term therapy.
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PMID:A comparison of carvedilol and metoprolol antioxidant activities in vitro. 1094 72

Increasing evidence supports a role for oxidative stress, proinflammatory cytokines, and apoptosis in the pathophysiology of focal ischemic stroke. Previous studies have found that the multi-action drug, carvedilol, is a mixed adrenergic antagonist, and that it behaves as an antioxidant and inhibits apoptosis. In the current study, the authors investigated whether carvedilol provides protection in focal cerebral ischemia and whether this protection is associated with reduced apoptosis and the downregulation of the inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin- 1beta (IL-1beta). Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) by an intraluminal filament technique. Carvedilol (1, 3, and 10 mg/kg) was injected daily subcutaneously 2 or 4 days before the induction of ischemia. Neurologic scores, infarct volumes, TUNEL staining, and mRNA levels of TNF-alpha and IL-1beta were assessed at 24 hours reperfusion. The effect of carvedilol on microvascular cortical perfusion was studied with continuous laser-Doppler flowmetry. Twenty-four hours after MCAO, carvedilol at all three doses reduced infarct volumes by at least 40% and reduced neurologic deficits on average by 40% compared with vehicle-treated controls when given 2 or 4 days before the induction of ischemia. This protection was not mediated by changes in temperature or blood flow. Treatment with all three dose regimens resulted in fewer TUNEL positive cells compared with controls. At 24 hours reperfusion, carvedilol decreased TNF-alpha and IL-1beta expression by 40% to 50% in the ipsilateral ischemic cortex compared with the contralateral controls. The results of the current study indicate that carvedilol is neuroprotective in focal cerebral ischemia and may protect the ischemic brain by inhibiting apoptosis and attenuating the expression of TNF-alpha and IL-1beta.
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PMID:The novel beta-blocker, carvedilol, provides neuroprotection in transient focal stroke. 1095 Mar 80

Carvedilol, a selective alpha(1) and non-selective beta-adrenoceptor antagonist and antioxidant, has been shown to provide significant cardiac protection in animal models of myocardial ischemia. To further explore the mechanisms contributing to the efficacy of carvedilol cardioprotection, the effects of carvedilol on hemodynamic variables, infarct size and myeloperoxidase activity (an index of neutrophil accumulation) were compared with a beta(1) selective adrenoceptor antagonist, bisoprolol. Carvedilol (1 mg/kg) or bisoprolol (1 mg/kg) was given intravenously 5 min before reperfusion. In vehicle-treated rabbits, ischemia (45 min) and reperfusion (240 min) resulted in significant increases in left ventricular end diastolic pressure, large myocardial infarction (64.7+/-2.6% of area-at-risk) and a marked increase in myeloperoxidase activity (64+/-14 U/g protein in area-at-risk). Carvedilol treatment resulted in sustained reduction of the pressure-rate-index and significantly smaller infarcts (30+/-2.9, P<0.01 vs. vehicle) as well as decreased myeloperoxidase activity (26+/-11 U/g protein in area-at-risk, P<0.01 vs. vehicle). Administration of bisoprolol at 1 mg/kg resulted in a pressure-rate-index comparable to that of carvedilol and also decreased infarct size (48.4+/-2.5%, P<0.001 vs. vehicle, P<0.05 vs. carvedilol), although to a significantly lesser extent than that observed with carvedilol. Treatment with bisoprolol failed to reduce myeloperoxidase activity in the ischemic myocardial tissue. In addition, carvedilol, but not bisoprolol, markedly decreased cardiac membrane lipid peroxidation measured by thiobarbituric acid formation. Taken together, this study suggests that the superior cardioprotection of carvedilol over bisoprolol is possibly the result of carvedilol's antioxidant and anti-neutrophil effects, not its hemodynamic properties.
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PMID:Comparison of bisoprolol and carvedilol cardioprotection in a rabbit ischemia and reperfusion model. 1101 Oct 41

The antioxidant effects of carvedilol and its analog BM-910228 (also known as SB 211475) were studied in rat liver mitochondria as well as their action on mitochondrial bioenergetics. Carvedilol and BM-910228 inhibited ADP/Fe(2+)-initiated lipid peroxidation (measured in mitochondrial membranes as thiobarbituric acid reactive substances and oxygen consumption) with IC(50) values of 10.9 and 0. 33 microM, respectively. Under the same conditions, the IC(50) value for Trolox C was 18.8 microM. At the same concentration range showing antioxidant activity both compounds prevent the collapse of transmembranar electric potential induced by ADP/Fe(2+) on respiring mitochondria. Furthermore, both carvedilol and BM-910228 do not display toxic effects on mitochondria up to the concentration showing maximal antioxidant effects ( approximately 40 microM for carvedilol and approximately 1 microM for BM-910228). At higher concentrations of carvedilol (>40 microM), however, the phosphorylation efficiency of mitochondria is depressed as deduced from a decrease in respiratory control and in the ADP/oxygen ratio. The Brand approach was used to assess the effects of carvedilol on oxidative phosphorylation. We found that carvedilol stimulated membrane proton leak and inhibited substrate oxidation, but had no measurable effect on phosphorylation reactions. Because carvedilol exerts its antioxidant properties for nontoxic concentrations, its therapeutic interest is reinforced because it may potentially prevent mitochondrial dysfunctions associated to cell death in several pathophysiological states where excessive production of reactive oxygen species by mitochondria is well documented (e.g., ischemia/reperfusion). Additionally, its hydroxylated analog BM-910228 with notable superior antioxidant activity may significantly contribute to the known therapeutic effects of carvedilol.
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PMID:Effects of carvedilol and its analog BM-910228 on mitochondrial function and oxidative stress. 1108 37


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