The novel beta-blocker, carvedilol, provides neuroprotection in transient focal stroke.

Savitz SI, Erhardt JA, Anthony JV, Gupta G, Li X, Barone FC, Rosenbaum DM. Author information Abstract 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 SpragueDawley 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 IL1beta 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.

Detailed Clinical Trial Description The main objective of this trial is to assess the efficacy and safety of propranolol in middle cerebral artery stroke patients. The primary hypothesis is as follows: Early administration of

propranolol reduces the frequency of cardiovascular and/or neurological complications including vascular death in the first 30 days after acute ischemic stroke. Secondary hypotheses are as follows: Early administration of propranolol improves neurological and functional outcome of patients with acute ischemic stroke. Early administration of propranolol reduces post-stroke immunodepression and therefore lowers the rate of pneumonia after acute ischemic stroke, without increasing the frequency of auto-aggressive, CNS antigen-specific T cells. Early administration of propranolol influences alterations in cardiologic, electrophysiologic phenomenons as a reaction to autonomic dysregulation after acute ischemic stroke. Early administration of Propranolol reduces growth of infarct as determined by MRI examinations in the first 6 days.

Beta-adrenoreceptor antagonists attenuate brain injury after transient focal ischemia in rats. Goyagi T, Kimura T, Nishikawa T, Tobe Y, Masaki Y Abstract Beta-adrenoreceptor antagonists experimentally reduce cardiac and renal injury after ischemia and are also clinically useful for myocardial infarction and severe burns. In addition, beta-adrenoreceptor antagonists provide neuroprotective effects after focal cerebral ischemia in experimental settings. We conducted the present study to compare the neuroprotective effects of several beta-adrenoreceptor antagonists in rat transient focal cerebral ischemia. Halothane-anesthetized normothermic adult male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion using the intraluminal suture technique confirmed by laser Doppler flowmetry. Rats received an IV infusion of saline 0.5 mL/h, propranolol 100 microg x kg(-1) x min(-1), carvedilol 4 microg x kg(-1) x min(-1), esmolol 200 microg x kg(-1) x min(-1), or landiolol 50 microg x kg(-1) x min(-1) (n = 6 in each group). Infusion was initiated 30 min before middle cerebral artery occlusion and continued for 24 h. Additional rats received esmolol 50 microg x kg(-1) x min(-1) or landiolol 10 microg x kg(-1) x min(-1) intrathecally (IT) via the cisterna magna (n = 5 in each group), according to the same experimental protocol. The neurological deficit score was evaluated at 22 h after reperfusion, and the brains were removed and stained with triphenyltetrazolium chloride for evaluation of infarct volume. Additional rats that received saline, esmolol, and landiolol IV (n = 6 in each group) were allowed to survive for 7 days

followed by measurement of infarct size. Neurological deficit scores were smaller in rats treated with propranolol-IV, carvedilol-IV, esmolol-IV, landiolol-IV, esmolol-IT, and landiolol-IT compared with saline-treated rats (P < 0.05). Cortical and striatum infarct volumes were less in the rats receiving beta-adrenoreceptor antagonists via either IV or IT than in saline-treated rats (P < 0.05). We conclude that beta-adrenoreceptor antagonists improve neurological and histological outcomes after transient focal cerebral ischemia in rats independent of administration route.

Carvedilol, a new antihypertensive drug with unique antioxidant activity: potential role in cerebroprotection. Yue TL, Lysko PG, Barone FC, Gu JL, Ruffolo RR Jr, Feuerstein GZ. Author information Abstract The antioxidant activities of carvedilol have been demonstrated in a wide variety of test systems, including (i) physicochemical (EPR studies), (ii) biochemical (measurement of lipid peroxidation and endogenous antioxidant depletion), (iii) cellular, and (iv) in vivo. The antioxidant activity of carvedilol clearly emanates from the carbazole moiety which is unique to carvedilol. The antioxidant activity resides equally in both of the enantiomers of carvedilol, as well as in some of its metabolites which are devoid of either the alpha 1adrenoceptor blocking activity or beta-adrenoceptor blocking activity. This novel antioxidant property of carvedilol may account, at least in part, for its cerebroprotection. The data discussed in this article suggest that carvedilol may not only provide effective and safe antihypertensive therapy and therefore reduce a major risk factor for stroke, but will also be better able to provide additional benefits to patients by protecting against oxygen free radicals generated during cerebral ischemia and stroke.

Antioxidant action of the antihypertensive drug, carvedilol, against lipid peroxidation. Noguchi N, Nishino K, Niki E.

Author information Abstract The action of carvedilol, a vasodilating, beta-adrenoceptor blocking agent, against lipid peroxidation has been the subject of many studies, but the results reported thus far are contradictory. In an attempt to define the antioxidant mechanism of carvedilol against lipid peroxidation, the dynamics of the action of carvedilol were studied in several oxidation systems. We investigated the reactivity of carvedilol toward radicals and its inhibitory effect on lipid peroxidation induced by several kinds of initiating species such as azo compounds and metal ions in solution, micelles, membranes, and low-density lipoprotein. Carvedilol exerted poor reactivity toward phenoxyl, alkoxyl, and peroxyl radicals in acetonitrile solution nor did it show an appreciable antioxidant effect against either the peroxyl radical-induced oxidation of methyl linoleate in acetonitrile or against phosphatidylcholine liposomal membranes in aqueous suspension. Carvedilol completely inhibited the ferric ion-induced oxidation of methyl linoleate micelles by sequestering ferric ions, but not by reducing hydroperoxide. It was shown that carvedilol enhanced the oxidation of micelles induced by either methemoglobin or peroxyl radical. Carvedilol, which was added exogenously, did not suppress the oxidation of isolated low-density lipoprotein induced by peroxyl radical or cupric ion. These results show that carvedilol does not act as a radical-scavenging antioxidant, but that it does act most efficiently as an antioxidant against ferric ion-induced oxidation by sequestering ferric ion.

Beta-adrenoreceptor antagonists attenuate brain injury after transient focal ischemia in rats. Goyagi T, Kimura T, Nishikawa T, Tobe Y, Masaki Y. Author information Abstract Beta-adrenoreceptor antagonists experimentally reduce cardiac and renal injury after ischemia and are also clinically useful for myocardial infarction and severe burns. In addition, beta-adrenoreceptor antagonists provide neuroprotective effects after focal cerebral ischemia in experimental settings. We conducted the present study to compare the neuroprotective effects of several beta-adrenoreceptor antagonists in rat transient focal

cerebral ischemia. Halothane-anesthetized normothermic adult male Sprague-Dawley rats were subjected to 2 h of middle cerebral artery occlusion using the intraluminal suture technique confirmed by laser Doppler flowmetry. Rats received an IV infusion of saline 0.5 mL/h, propranolol 100 microg x kg(-1) x min(-1), carvedilol 4 microg x kg(-1) x min(-1), esmolol 200 microg x kg(-1) x min(-1), or landiolol 50 microg x kg(-1) x min(-1) (n = 6 in each group). Infusion was initiated 30 min before middle cerebral artery occlusion and continued for 24 h. Additional rats received esmolol 50 microg x kg(-1) x min(-1) or landiolol 10 microg x kg(-1) x min(-1) intrathecally (IT) via the cisterna magna (n = 5 in each group), according to the same experimental protocol. The neurological deficit score was evaluated at 22 h after reperfusion, and the brains were removed and stained with triphenyltetrazolium chloride for evaluation of infarct volume. Additional rats that received saline, esmolol, and landiolol IV (n = 6 in each group) were allowed to survive for 7 days followed by measurement of infarct size. Neurological deficit scores were smaller in rats treated with propranolol-IV, carvedilol-IV, esmolol-IV, landiolol-IV, esmolol-IT, and landiolol-IT compared with saline-treated rats (P < 0.05). Cortical and striatum infarct volumes were less in the rats receiving beta-adrenoreceptor antagonists via either IV or IT than in saline-treated rats (P < 0.05). We conclude that beta-adrenoreceptor antagonists improve neurological and histological outcomes after transient focal cerebral ischemia in rats independent of administration route.

Poor protective effect of beta blockers confined to ischemic stroke By Eleanor McDermid 22 December 2008 J Hypertens 2009; 27: 174180 MedWire News: The weaker protection against stroke seen with beta blockers relative to other antihypertensive agents is confined to ischemic stroke, a study suggests. We also found that poor compliance with antihypertensive pharmacotherapy was an important risk factor in stroke development, for both ischemic and hemorrhagic type, say Jung-Der Wang (National Taiwan University, Taipei) and colleagues.

The researchers studied a cohort of 29,759 patients with newly diagnosed uncomplicated hypertension, 1078 of whom suffered stroke during an average follow-up of 38.8 months. Overall, and in contrast to previous studies, the risk for stroke did not differ according to the type of antihypertensive patients were taking. The increased stroke risk with beta blockers (by 27% relative to other antihypertensives) emerged only when the analysis was restricted to ischemic stroke. Our findings indicated that outcomes research might provide additional evidence for improving clinical guidelines, as the processes in randomized clinical trials might not be able to take care of all conditions in the daily practices of clinicians, Wang et al comment in the Journal of Hypertension. For all types of stroke among these low-risk, uncomplicated hypertensive patients in our study, the control of their hypertension seemed to be a more important factor than the choice of antihypertensive agent. Based on prescription claim rates, patients were compliant with their medication regimen 42.1% of the time, on average. The risk for stroke increased with decreasing medication compliance, by 1.5, 1.8, and 1.9 fold for compliance of 4069%, 2039%, and less than 20%, compared with at least 70%. Male gender, older age, and the presence of diabetes or heart disease also raised stroke risk, after accounting for confounders.