Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carvedilol's potent antioxidant activity could explain its protective action in brain ischemia, but may not apply to glutamate-induced excitotoxicity in cultured cerebellar granule cells, since glutamate neurotoxicity was not associated with the formation of lipid peroxidative products. Rather, carvedilol diminished the N-methyl-D-aspartate (NMDA)/glycine-induced increase in intracellular calcium ([Ca2+]i), lowering [Ca2+]i by a maximum of 66 +/- 5% (n = 8) with a 50% inhibitory concentration of 0.8 microM. Prior addition of 5 microM dihydropyridines did not shift the dose-response of carvedilol, but did significantly lower the NMDA/glycine-stimulated response to 64% of untreated (n = 8, P = 0.014). Inclusion of 5 microM carvedilol before the additions of NMDA/glycine prevented 85% of the increase in [Ca2+]i. Furthermore, carvedilol displaced 3[H]MK-801 binding to rat brain cortical membranes with a Kd of 29.4 +/- 2.2 microM (n = 6) and no selectively for the glutamate or glycine binding sites. These data therefore suggest that, in addition to its antihypertensive and anti-lipid peroxidative functions, carvedilol has neuroprotective activity as a calcium channel blocker and as a non-competitive inhibitor at the NMDA receptor.
 ...
PMID:Neuroprotective effects of carvedilol, a new antihypertensive, at the N-methyl-D-aspartate receptor. 130 May

Carvedilol is a multiple-action cardiovascular agent that is both a beta-adrenoceptor antagonist and a vasodilator and has recently been made available for the treatment of mild-to-moderate hypertension. Clinical trials are ongoing to establish the efficacy of carvedilol in angina and congestive heart failure. beta-Adrenoceptor antagonists are known to reduce myocardial work secondary to reductions in heart rate and contractility; accordingly, they have been shown to be cardioprotective in animals and in humans. Because carvedilol has beta-adrenoceptor antagonist activity, it also should provide significant cardioprotection. The additional vasodilating activity of carvedilol, which will further reduce myocardial work by decreasing afterload and myocardial wall tension, should provide more salvage of ischemic myocardium than that afforded by a pure beta-adrenoceptor antagonist, such as propranolol. We investigated the ability of carvedilol and propranolol to reduce infarct size in experimental models of acute myocardial infarction in the rat, pig, and dog. The left anterior descending coronary artery was occluded for 30 (rat) or 45 min (pig) and then reperfused for 24 h (rat) or 4 h (pig). In the dog, the left circumflex coronary artery was occluded for 60 min and reperfused for 24 h. Vehicle, carvedilol, or propranolol was administered intravenously 15 min before ischemia (and, in the rat only, repeated 4 h after ischemia). An additional group of dogs was subjected to permanent left anterior descending coronary artery occlusion for 6 h, and carvedilol or propranolol was given 15 min after occlusion. Infarct size was examined on stained tissue sections using quantitative image analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Myocardial protection with carvedilol. 137 42

Patients with hypertension requiring therapy frequently present with concurrent peripheral vascular disease (PVD). This situation must be taken into account for an optimum antihypertensive treatment. In general, in patients with PVD only a cautious and gradual lowering of the blood pressure is recommended, since the decrease in poststenotic perfusion pressure may accentuate the symptoms of occlusive disease. In intermittent claudication--the most frequent manifestation of occlusive disease beta--receptor blockers today are no longer considered to be contraindicated. In the presence of critical ischemia of the legs (pain at rest and/or necroses) beta blockers should only be given with extreme caution. The agents of choice are calcium antagonists, ACE -inhibitors as well as alpha blockers and some newer vasodilating substances (e.g. Carvedilol). Conventional diuretics show disadvantages. An slightly elevated blood pressure in critical leg ischemia helps to improve the poststenotic perfusion of the affected limb. Antihypertensive treatment should not be instituted in patients whose systolic blood pressure is lower than 160 mmHg.
 ...
PMID:[Antihypertensive therapy in arterial occlusive disease]. 168 38

To evaluate the antianginal efficacy of carvedilol, a beta-blocker with vasodilating activity, we performed a randomized double-blind placebo-controlled study of two single doses of carvedilol. Twelve patients (eight males, four females, mean age 57 years) with stable effort angina and a positive exercise ECG with angina underwent treadmill exercise testing 2 h after either placebo, or carvedilol 25 or 50 mg. Both doses of carvedilol reduced resting heart rate but only the 50 mg dose reduced resting blood pressure. Exercise time and time to angina increased by 24% and 35%, respectively, after carvedilol, and ST depression at both maximal and submaximal work levels was reduced. The time to 1 mm ST depression was increased by carvedilol but the heart rate at 1 mm ST depression and maximum ST/heart rate slope were unchanged. Maximum heart rate, systolic pressure, and rate-pressure product were significantly reduced by carvedilol. The 50 mg dose was significantly better than 25 mg in prolonging exercise time and reducing subjective and objective measurements of ischemia, and this was related to significantly greater hemodynamic effects. Carvedilol appears to be effective in preventing or reducing effort angina due to reduced myocardial oxygen demand, and it exhibits an important dose-response effect.
 ...
PMID:Antianginal efficacy of carvedilol, a new beta-blocker with vasodilating action. 245 61

The potent antioxidant activity of carvedilol could explain part of its protective action in brain ischemia, and interaction as a low-affinity non-competitive (uncompetitive) antagonist of the N-methyl-D-aspartate (NMDA) receptor would provide rapid channel blockade at this subtype of glutamate receptor. We have now found carvedilol to be neuroprotective (PC50 = 306 nM) against 40 microM veratridine which kills cerebellar granule cell neurons in 60 min regardless of energy state. Carvedilol was also a potent inhibitor (IC50 = 1.7 microM) of veratridine-stimulated 3[H]aspartate release from preloaded neurons, caused by reversal of the Na(+)-dependent glutamate transporter. Veratridine caused a sustained 4.3-fold increase in intracellular Ca2+ ([Ca2+]i) up to 368 nM (n = 22). Carvedilol reversed the [Ca2+]i levels by a maximum of 73% with an IC50 of 0.9 microM. Such reversal of [Ca2+]i was facilitated by Na+/Ca2+ exchange since the stoichiometry of exchange could be disrupted by prior treatment with 1 microM ouabain to inhibit the Na+/K+ pump. These data suggest that, in addition to its antihypertensive effects, antioxidant activity and ability to act as a non-competitive inhibitor at the NMDA receptor, carvedilol has additional neuroprotective activity as a Na+ channel modulator and glutamate release inhibitor.
 ...
PMID:Neuroprotective effects of carvedilol, a new antihypertensive, as a Na+ channel modulator and glutamate transport inhibitor. 791 41

Carvedilol is a multiple-action cardiovascular agent that is a nonselective beta-adrenoceptor antagonist and a vasodilator. beta-Adrenoceptor antagonists reduce myocardial work, secondary to reductions in heart rate and contractility, both in animals and in humans. For these reasons, carvedilol may improve survival of acutely ischemic myocardium. The additional vasodilating activity of carvedilol, further reducing myocardial work by decreasing afterload and ventricular wall tension, may provide additional salvage over that afforded by beta-adrenoceptor blockade alone. The comparative ability of carvedilol and propranolol to reduce infarct size in experimental models of acute myocardial infarction in the rat, pig and dog has been investigated utilizing a variety of experimental techniques. In the pig, the calcium channel antagonist, diltiazem, was also included as a second comparator agent. Infarct size was examined on stained tissue sections using quantitative image analysis. In the rat, carvedilol (1 mg/kg) reduced infarct size by 47% (p < 0.01, n = 11), and in the pig, carvedilol, at doses of 0.3 and 1 mg/kg, reduced infarct size by 46% (p < 0.05, n = 6) and 89% (p < 0.001, n = 6), respectively. In dogs subjected to ischemia and reperfusion, carvedilol (1 mg/kg) reduced infarct size by 78% (p < 0.02, n = 6), and in dogs subjected to permanent left anterior descending coronary artery occlusion, carvedilol, at doses of 0.3 and 1 mg/kg, reduced infarct size by 46 and 63%, respectively (p < 0.02, n = 12-16). In all studies, the extent of myocardial survival on carvedilol exceeded that on propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cardioprotective potential of carvedilol. 810 60

In one-kidney rats the resting blood flow in the renal artery was recorded for 10 minutes then the artery was clipped for one hour and the following reperfusion blood flow was registered again for 10 minutes. The animals were divided into three groups: Series A, untreated control animals. Series B, two weeks before renal ischemia the rats were fed a diet containing 0.1% of BM-14.190, a derivate of carvedilol. Series C the rats received a diet with 0.1% of carvedilol. The resting renal blood flow was 4.58 +/- 0.13 ml/min (x +/- S.E.M.) in series A whereas 6.36 +/- 0.41 ml/min. in series B and 5.87 +/- 0.59 ml/min. in series C (p < 0.01), also the reperfusion blood flow in series B and C was significantly higher (p < 0.01) i.e. 3.65 +/- 0.25 ml/min. and 3.08 +/- 0.33 ml/min. respectively than in series A, 1.08 +/- 0.13 ml/min. The ischemia and the ensuing reperfusion elicited in series A serious injury, especially in renal proximal tubules and their reticulin skeleton whereas the renal injury in series B and C was of a markedly lesser degree. Carvedilol and its derivate BM-14.190 possess beside vasodilatory potency and alpha- and beta-adrenoceptor blocking activity a potent scavenger property. This may be the cause of the protective effect preventing the ischemia and reperfusion injury in the renal tissue.
 ...
PMID:[Protective effect of carvedilol on renal circulation and tissue injury in reperfusion of ischemic kidneys in rats]. 818 81

We examined the effect of carvedilol as compared with that of a combination of propranolol and doxazosin on lethal reperfusion injury in 21 feline hearts subjected to 40-min regional ischemia and 180-min reperfusion. A control group (n = 7) was compared with one group given carvedilol, a nonselective beta - and alpha 1-adrenoceptor blocker and antioxidant (n = 7) and another group given nonselective beta - and alpha 1-adrenoceptor blockade with propranolol and doxazosin (n = 7) during initial reperfusion. Infarct size (IS: percent of area at risk, AAR) determined by staining the myocardium with triphenyl tetrazolium chloride (TTC), was reduced both in the carvedilol-treated group (median 1.8%, p < 0.05) and in the group given propranolol/doxazosin (median 6.5%, p < 0.05) as compared with controls (median 14.4%). Treatment with carvedilol reduced IS more than did treatment with propranolol/doxazosin (p < 0.05). Longitudinal segment shortening measured with sonomicrometry, improved in both treatment groups as compared with control (p < 0.05), but to a greater extent in the group treated with carvedilol. In circumferential segments, only carvedilol significantly improved segment shortening. The incidence of ventricular fibrillation (VF) after reperfusion was reduced in both treatment groups as compared with control. Oxidized glutathione and thiobarbituric acid-reactive substances (TBARS) measured at the end of reperfusion did not differ between groups. Carvedilol protected against lethal reperfusion injury mainly through blockade of adrenoceptors.
 ...
PMID:Carvedilol protects against lethal reperfusion injury through antiadrenergic mechanisms. 887 88

Carvedilol is a novel, multiple-action cardiovascular drug that is currently approved in many countries for the treatment of hypertension. The reduction in blood pressure produced by carvedilol results primarily from beta-adrenoceptor blockade and vasodilation, the latter resulting from alpha 1-adrenoceptor blockade. These actions, as well as several of the other activities of carvedilol, are associated with cardioprotection in animal models that occurs to a degree that is greater than that observed with other drugs. The multiple actions of carvedilol may also provide the underlying rationale for the use of the drug in the treatment of coronary artery disease and congestive heart failure. By virtue of being both a beta-blocker and a vasodilator, carvedilol significantly decreases myocardial work by reducing all three components of myocardial oxygen demand, namely, heart rate, contractility, and wall tension. The vasodilatory effects of carvedilol reduce afterload, and the resulting decrease in impedance to left ventricular ejection offsets the negative inotropic effect that would normally result from beta-blockade. As a consequence, stroke volume and cardiac output are maintained or even increased in animals and in patients with congestive heart failure who are treated with carvedilol. Carvedilol and several of its metabolites are potent antioxidants, and this activity may account, in part, for the cardioprotective effects of the drug observed in animal models of acute myocardial ischemia and, in theory, could also serve to protect the myocardium of patients with hypertension, coronary artery disease, and congestive heart failure, in which oxidative stress is now recognized to occur. The antioxidant effects of carvedilol may both inhibit the direct cytotoxic actions of reactive oxygen radicals and prevent oxygen-radical induced activation of transcription factors and genes associated with inflammatory and remodeling processes. Accordingly, carvedilol inhibits the gene expression of the intracellular adhesion molecule-1 (ICAM-1), an adhesion molecule for polymorphonuclear leukocytes, which typically infiltrate the myocardium under conditions of ischemia and may exacerbate ischemic injury. The antioxidant activity of carvedilol has been shown to inhibit the oxidation of low density lipoprotein (LDL) in vitro, thereby preventing the formation of this cytotoxic and atherogenic form of LDL. It follows, therefore, that in animal models of hyperlipidemia, carvedilol attenuates aortic lipid accumulation and decreases the aortic content of monocytes and foam cells, and at the same time it has been shown to preserve endothelial integrity and function. These actions of carvedilol are not shared by other beta-blockers or by other drugs currently used in the management of hypertension, coronary artery disease, or congestive heart failure. The multiple actions of carvedilol may provide the underlying pharmacologic rationale for the use of this drug in the treatment of patients with coronary artery disease or congestive heart failure, and these actions may account, at least in part, for the reduction in mortality produced by carvedilol in clinical trials involving patients with congestive heart failure. Likewise, these actions of carvedilol may also provide protection, beyond that afforded from reduction in blood pressure, against secondary organ damage in hypertensive patients treated with the drug.
 ...
PMID:Pharmacology of carvedilol: rationale for use in hypertension, coronary artery disease, and congestive heart failure. 921 Oct 17

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.
 ...
PMID:Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvedilol. 946 87


1 2 3 4 Next >>