Biomedical subjects

G Z Feuerstein

Publications and source records attributed to G Z Feuerstein.

At least 127 records · Page 7Linked to original sources

PubMed1994

Enhanced leucocyte adhesion to interleukin-1 beta stimulated vascular smooth muscle cells is mainly through intercellular adhesion molecule-1.

OBJECTIVE: The aim was to investigate whether interleukin-1 beta (IL-1 beta) plays a role in modulating the adhesion of monocytes and neutrophils to vascular smooth muscle cells, and to identify what molecules on these cells may be involved in the adhesion. METHODS: Rat aortic smooth muscle cells were challenged with IL-1 beta and tested for adhesion of prelabelled monocytes and neutrophils. Northern analysis, reverse transcription/polymerase chain reaction (RT/PCR), and immunocytochemical staining were used to measure the changes of intercellular adhesion molecule-1 (ICAM-1) and other adhesion molecules in response to IL-1 beta stimulation. Neutralising antibody against ICAM-1 was used to demonstrate a role of ICAM-1 in this IL-1 beta induced adhesion. RESULTS: IL-1 beta induced the adhesion of monocytes and neutrophils to aortic smooth muscle cells in a concentration and time dependent manner. IL-1 beta-induced adhesion was inhibited by preincubation of the cells with an IL-1 receptor antagonist (IL-1ra). Northern analysis and RT/PCR showed that ICAM-1 mRNA represents a predominant adhesion molecule induced by IL-1 beta, and that the expression of ICAM-1 mRNA precedes and parallels the induced adhesion profiles of aortic smooth muscle cells for leucocytes. Immunocytochemical staining confirmed the IL-1 beta induced ICAM-1 expression on the smooth muscle cells. Moreover, a monoclonal anti-rat ICAM-1 antibody produced a concentration dependent inhibition of the IL-1 beta induced adhesion of monocytes and neutrophils to the smooth muscle cells. CONCLUSIONS: IL-1 beta actively regulates functional ICAM-1 expression in vascular smooth muscle cells. The IL-1 beta-induced expression of ICAM-1 on the smooth muscle cells may be an important contributor to the increased adhesion by monocytes and neutrophils to these cells and suggests that IL-1 beta might play a role in the proinflammatory and immune functions of the modified smooth muscle cells during atherosclerosis and restenosis.

Animals↗

PubMed1994

Carvedilol, a new vasodilating beta adrenoceptor blocker antihypertensive drug, protects endothelial cells from damage initiated by xanthine-xanthine oxidase and neutrophils.

OBJECTIVE: Oxygen radical mediated endothelial injury plays an important role in cardiovascular disease. Carvedilol, a new beta blocker and antihypertensive agent, has been shown to have antioxidant activity. The aim of this study was to determine whether carvedilol protects oxygen radical induced endothelial injury. METHODS: Cultured bovine pulmonary artery (BPAEC) and human umbilical vein endothelial cells (HUVEC) were used and oxygen radicals were generated by xanthine-xanthine oxidase or phorbol myristate acetate (PMA) activated human neutrophils. Cell injury was assessed by lactate dehydrogenase (LDH) release and cell death, or 51 Cr release from prelabelled BPAEC. The electron paramagnetic resonance (EPR) spin trapping technique was used to detect the amount of radical spin adducts formed in cell lipids. RESULTS: Carvedilol dose dependently inhibited xanthine-xanthine oxidase induced LDH release from BPAEC and HUVEC, with IC50 values of 3.8 microM and 2.6 microM, respectively, and significantly reduced cell death by xanthine-xanthine oxidase. Other beta blockers tested (propranolol, labetalol, pindolol, and celiprolol) showed a mild effect or no effect at all. Increasing the time of pretreatment with carvedilol enhanced its cell protective effect against oxidative stress. Carvedilol also protected BPAEC dose dependently from PMA activated, neutrophil induced cell injury. Carvedilol had no effect on xanthine oxidase activity. EPR study confirmed that xanthine-xanthine oxidase induced the formation of lipid derived radicals in cell lipids and carvedilol scavenged free radicals, as indicated by the decreased EPR signal. CONCLUSIONS: Carvedilol protects endothelial cells against oxygen radical mediated cell injury and death by scavenging free radicals. The prevention of oxidative injury to endothelial cells might potentially contribute to the clinical beneficial effects of carvedilol as an antihypertensive agent.

Adrenergic beta-Antagonists↗

PubMed1994

Interleukin-8. A mitogen and chemoattractant for vascular smooth muscle cells.

Interleukin-8 (IL-8) is a chemokine produced by a variety of cell types involved in atherogenesis and is chemotactic for neutrophils and lymphocytes. A recent study has shown that IL-8 is angiogenic and induces proliferation and chemotaxis of endothelial cells. The present study was undertaken to find out whether IL-8 is also mitogenic and chemotactic for vascular smooth muscle cells. IL-8 induced a concentration-dependent (0.1 to 10 nmol/L) stimulation of DNA synthesis and cell proliferation in both human and rat aortic smooth muscle cells. In addition, IL-8 stimulated smooth muscle cells to produce prostaglandin E2, which can inhibit IL-8-induced smooth muscle cell proliferation. In the presence of indomethacin (5 mumol/L), IL-8 (1 nmol/L) stimulated an increase in human and rat aortic smooth muscle cell number during a 3-day period of incubation by 61 +/- 16% and 59 +/- 7% (n = 4), respectively. IL-8 also increased DNA synthesis in human and rat aortic smooth muscle cells by 98 +/- 10% and 151 +/- 27% (n = 5), respectively. Moreover, IL-8 stimulated rat aortic smooth muscle cell migration by 20-fold over the control value, with an EC50 value of 0.83 nmol/L; this chemotactic activity of IL-8 was also potentiated by indomethacin. Exposure of smooth muscle cells to IL-8 caused rapid and transient expression of the immediate-early genes c-fos and zif268 mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.

The observation that levels of the mitogenic peptide endothelin-1 are elevated in the human coronary sinus after percutaneous transluminal coronary angioplasty (PTCA) has implicated endothelin-1 in the etiology of vascular restenosis. The present study examined this hypothesis in both an in vitro and an in vivo rat model of neointimal formation by using the novel nonpeptide endothelin receptor antagonist SB 209670. In vitro, endothelin-1 (1 nmol/L) induced a ninefold increase in rat aortic vascular smooth muscle [3H]thymidine incorporation. This endothelin A receptor-mediated effect was completely inhibited by SB 209670 (IC50, 6.2 +/- 2.2 nmol/L). In vivo, acute intra-arterial administration of exogenous endothelin-1 (5 to 500 pmol/kg over a 30-minute period immediately after angioplasty) dose-dependently augmented the degree of neointimal formation (by up to 150% when assessed 14 days after surgery). This response was evident as early as 7 days after angioplasty. Hemodynamic studies indicated that this action was unrelated to a systemic pressor action of the peptide. Administration of SB 209670 (2.5 mg/kg IP, twice a day for 3 days before and for 2 weeks after surgery) reduced neointimal formation by approximately 50% relative to control animals. Thus, the data indicate for the first time that (1) endothelin-1 promotes neointimal formation in vivo and (2) endogenous endothelin-1 is involved in the pathogenesis of angioplasty-induced lesion formation in the rat. Endothelin receptor antagonists such as SB 209670 may therefore serve as useful adjuncts to PTCA, attenuating the degree of vascular restenosis observed after vascular wall injury.

Angioplasty, Balloon↗

PubMed1994

Tumor necrosis factor-alpha expression in ischemic neurons.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is a cytokine with diverse proinflammatory actions, including endothelial leukocyte adhesion molecule expression. Since leukocytes infiltrate into ischemic brain lesions, the present study was conducted to examine whether TNF-alpha messenger RNA (mRNA) and peptide are expressed in the brain after experimental focal stroke and before leukocyte accumulation. METHODS: TNF-alpha mRNA and protein expression were monitored in the ischemic and nonischemic cerebral cortex of rats after focal ischemia produced by permanent middle cerebral artery occlusion. The effect of TNF-alpha administered by microinjection into the brain cortex on leukocyte adherence to brain capillaries was also studied. RESULTS: Induction of TNF-alpha mRNA, normalized to a standard reference rat macrophage TNF-alpha mRNA, was detected as early as 1 hour after middle cerebral artery occlusion. TNF-alpha mRNA was elevated by 3 hours (29 +/- 6% versus 2 +/- 1% in sham-operated rats) only in the ischemic cortex, with peak expression at 12 hours (104 +/- 8%; P < .01). Five days after middle cerebral artery occlusion, TNF-alpha mRNA levels in ischemic cortex were still significantly elevated (38 +/- 5%; P < .05). Also, TNF-alpha mRNA expression was greater in the ischemic cortex of spontaneously hypertensive rats than in normotensive rats (P < .05). Double-labeling, immunohistochemical studies revealed the presence of TNF-alpha protein localized within nerve fibers in the evolving infarct at 6 and 12 hours after ischemia and further expression in the tissues immediately adjacent to the infarct 24 hours after ischemia. After 5 days, the neuronally localized peptide had diminished greatly, but macrophages located within the infarcted tissues were immunoreactive. Cortical microinjections of TNF-alpha (10 ng in 1 microL) produced a significant neutrophil adherence/accumulation in capillaries and small blood vessels 24 hours later. CONCLUSIONS: These results represent the first demonstration that focal cerebral ischemia in rats results in elevated TNF-alpha mRNA and protein in ischemic neurons. The neuronal expression of peptide appears to facilitate the infiltration of inflammatory cells that can further exacerbate tissue damage in cerebral ischemia and might contribute to increased sensitivity and risk in focal stroke.

Animals↗

PubMed1994

Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha.

The cytokine tumor necrosis factor (TNF-alpha) is a pleotrophic polypeptide that plays a significant role in brain immune and inflammatory activities. TNF-alpha is produced in the brain in response to various pathological processes such as infectious agents [e.g., human immunodeficiency virus (HIV) and malaria], ischemia, and trauma. TNF-alpha mRNA is rapidly produced in response to brain ischemia within 1 h, reaches a peak at 6-12 h post ischemia, and subsides 1-2 days later. TNF-alpha mRNA expression corresponds in a temporal fashion to other cytokines such as interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (KC), and IL-1 and precedes the infiltration of inflammatory cells into the injured zone. TNF-alpha is present early in neuronal cells in and around the ischemic tissue (penumbra), yet at later time points, the peptide is found in macrophages in the infarcted tissue. TNF-alpha has been demonstrated to cause expression of proadhesive molecules on the endothelium, which results in leukocyte accumulation, adherence, and migration from capillaries into the brain. Furthermore, TNF-alpha activates glial cells, thereby regulating tissue remodeling, gliosis, and scar formation. Thus, evidence is emerging in support of a role for TNF-alpha in injury induced by infectious, immune, toxic, traumatic, and ischemic stimuli. TNF-alpha promotes inflammation by stimulation of capillary endothelial cell proinflammatory responses and thereby provides leukocyte adhesion and infiltration into the ischemic brain. The evidence generated so far suggests that agents that suppress TNF-alpha's production or actions will reduce leukocyte infiltration into ischemic brain regions and thereby diminish the extent of tissue loss.

Brain↗

PubMed1994

Platelet-activating factor: a putative neuromodulator and mediator in the pathophysiology of brain injury.

Platelet-activating factor (1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine [PAF]) is a potent lipid autocoid produced by many cell types. PAF is produced by cultured rat cerebellar neurons and human fetal brain cells, and has been extracted from brain tissue. Multiple PAF receptors have been demonstrated in brain tissue. PAF stimulates intracellular Ca2+ mobilization and phosphatidylinositol (PI) metabolism in transformed neuronal cell lines via the PAF receptor, to which both pertussis toxin (PTX)-sensitive and -insensitive G protein appear to couple. PAF has potent actions on cerebral vessels and cerebral metabolism when administered in vivo. Direct neuronal effects of PAF, such as inhibition of acetylcholine release, are observed in vitro. Excessive PAF production in pathological states of the nervous system, such as neurotrauma and stroke, has been shown. In multiple studies in rodent and non-rodent models using highly specific and potent PAF antagonists, reversal or prevention of key consequences of brain injury, such as hypoperfusion following ischemia, reperfusion and edema, inflammatory cell accumulation, neurologic/motor deficits, and neuronal salvage, has been demonstrated. These studies taken together support a role for PAF as an important mediator in the pathophysiology of brain injury.

Animals↗

PubMed1993

Cytokine-induced neutrophil chemoattractant mRNA expressed in cerebral ischemia.

Cytokine-induced neutrophil chemoattractant (CINC), originally identified as a chemoattractant in rat kidney epithelial cells, is related to human 'gro' and murine 'KC'. The proteins encoded by these genes belong to the chemokine alpha superfamily, most of which have neutrophil chemotactic activity. Since brain chemokines may play a significant role in neutrophil accumulation in cerebral ischemia which can contribute to the extent of tissue injury in stroke, we examined the expression of CINC mRNA in the cerebral cortex of rats subjected to focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Significant CINC mRNA expression was observed in the ipsilateral (ischemic) cortex from 6 h (17.3 +/- 3.7%, n = 6, P < 0.05) to 24 h (32.1 +/- 3.7%, n = 5, P < 0.01) with a peak at 12 h (43.9 +/- 3.7%, n = 6, P < 0.01) after MCAO. Five days post-MCAO, CINC mRNA levels were no longer elevated. No significant CINC mRNA expression was observed in the contralateral (control) cortex. These studies suggest that message for the neutrophil chemoattractant CINC is induced early in brain tissue subjected to ischemia, and therefore supports the possibility that brain-derived chemokines support the infiltration of circulating inflammatory cells following focal stroke.

Animals↗

PubMed1993

Neuron-specific enolase increases in cerebral and systemic circulation following focal ischemia.

Neuron-specific enolase (NSE) is an isoform of the glycolytic enzyme, enolase, and is found in neurons and neuroendocrine cells. We evaluated cerebral immunohistologic and plasma changes in NSE in rats from 2 h to 15 days following permanent or transient middle cerebral artery occlusion (MCAO). At 1-2 days post-MCAO, loss of NSE immunofluorescence from within neurons to the extracellular space was observed in the infarcted areas of all MCAO animals. NSE also was identified intravascularly throughout the brain following MCAO. NSE in plasma was determined by a specific radioimmunoassay. Plasma NSE following permanent or transient MCAO was increased significantly from that observed in controls (2.8 +/- 0.3 ng/ml) beginning at 2 h and persisting for 2.5 days post-MCAO (maximum levels of 8.8 +/- 0.9 to 9.6 +/- 0.5 ng/ml after 6-12 h; P < 0.05, n = 4-9). Quantified contralateral forelimb and hindlimb neurological deficits in these animals were significant and persisted for at least 15 days following MCAO but were not observed following sham surgery. These data suggest that MCAO-induced cortical infarction and neurological dysfunction is associated with neuronal depletion and vascular redistribution of brain NSE resulting in a measurable increase in plasma NSE. Such diffusion of NSE into the cerebral vasculature and systemic circulation from ischemic tissue can be expected to serve as a marker for the incidence of cerebral damage in acute and chronic ischemic brain infarcts.

Animals↗

PubMed1993

Interleukin-8 is chemotactic for vascular smooth muscle cells.

The chemotactic activity of interleukin-8 for human aortic smooth muscle cells was investigated in Transwell cell culture chamber using a polycarbonate membrane with pores of 8 microns. Interleukin-8 stimulated the smooth muscle cell migration time and dose dependently in the range between 10(-11) and 10(-8) M. At 10 nM of interleukin-8, the number of migrated smooth muscle cells increased by 40-fold over the basal level, and this stimulation was almost completely abolished by anti-interleukin-8 antibody. Checkerboard analysis showed that the response of smooth muscle cell to interleukin-8 was chemotactic. These results suggest that interleukin-8 may play a role in the pathogenesis of arterial intimal thickening and atherosclerosis.

Aorta↗

PubMed1993

Carvedilol, a cardiovascular drug, prevents vascular smooth muscle cell proliferation, migration, and neointimal formation following vascular injury.

Carvedilol is a cardiovascular drug currently used for the treatment of hypertension. Clinical studies have recently demonstrated efficacy in angina and congestive heart failure. Recently, carvedilol has been shown to attenuate oxygen free radical-initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis induced by a wide variety of growth factors. These findings are of interest since smooth muscle proliferation and abnormal lipid metabolism are proposed to play an important role in the pathogenesis of atherosclerotic plaque formation and in development of stenotic lesions following vascular injury by balloon angioplasty and coronary artery bypass grafting. On the basis of these observations, the antiproliferative actions of carvedilol have been explored in detail. In human cultured pulmonary artery vascular smooth muscle cells, carvedilol (0.1-10 microM) produced a concentration-dependent inhibition of the mitogenesis stimulated by platelet-derived growth factor, epidermal growth factor, thrombin, and serum, with IC50 values ranging from 0.3 to 2.0 microM. Carvedilol also produced a concentration-dependent inhibition of vascular smooth muscle cell migration induced by platelet-derived growth factor, with an IC50 value of 3 microM. The extensive neointimal formation that occurs following balloon angioplasty of rat carotid arteries was markedly attenuated by carvedilol (1 mg/kg, i.p.; twice daily starting 3 days before angioplasty and continuing until 14 days after angioplasty). Quantitative image analysis demonstrated that carvedilol reduced the neointimal growth following angioplasty by 84% without altering either medial or adventitial cross-sectional areas. These observations indicate that carvedilol may also be effective in the treatment of pathological disorders principally associated with abnormal vascular smooth muscle growth, such as atherosclerosis and acute vascular wall injury induced by angioplasty or coronary artery bypass grafting.

Angioplasty, Balloon↗

PubMed1993

Brain alpha-tocopherol levels are not altered following ischemia/reperfusion-induced cerebral injury in rats and gerbils.

alpha-Tocopherol (alpha-TC) is considered an important endogenous brain antioxidant. The utility of brain alpha-TC levels as an index of in vivo lipid peroxidation has recently been suggested. Therefore, we explored the significance of alpha-TC levels in brains to ischemic insults associated with global or focal cerebral ischemia. Four ischemic models were used and alpha-TC was measured by HPLC. Brain alpha-TC levels in gerbils exposed to 20 min bilateral carotid artery occlusion (CAO) and 60 min reperfusion was 10.8 +/- 2.1 micrograms/g (x +/- S.D., n = 6) vs. 10.8 +/- 1.8 micrograms/g (n = 6) in sham controls. In gerbils subjected to 3 h unilateral CAO and 2 h RP, a procedure marked by neurological abnormalities, brain alpha-TC levels of ischemic and non-ischemic hemispheres were essentially the same (10.7 +/- 1.6 vs. 10.1 +/- 1.4 micrograms/g, n = 4). In rats subjected to 80 min unilateral middle cerebral artery occlusion followed by 60 min reperfusion, or 6 h occlusion without reperfusion, the brain alpha-TC levels in ipsilateral ischemic and contralateral non-ischemic cortex were not different (12.1 +/- 1.2 vs. 11.9 +/- 2.6 micrograms/g or 12.2 +/- 1.6 vs. 13.4 +/- 1.2 micrograms/g, n = 4-8). Our results demonstrated that brain alpha-TC levels can not be used as index of ischemia/reperfusion related lipid peroxidation or tissue injury.

Animals↗

PubMed1993

Development of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study.

Development and resolution of the lesion produced by occlusion of the middle cerebral artery (MCAO) was studied through quantitative planimetry and histologic/immunohistochemical techniques. MCAO, performed in spontaneously hypertensive rats (SHR), initially (1-3 days) produced large, consistent cerebral cortical infarctions and an increase in ipsilateral hemispheric size (i.e., swelling) quantitated by planimetry on 2,3,5-triphenyltetrazolium chloride (TTC)-stained gross tissue sections. These initial changes correlated well with changes identified from 2 h to 3 days using hematoxylin and eosin stained histologic tissue sections and immunohistochemical techniques including: the progressive development of a cortical area of pan necrosis, infiltration of neutrophils into infarcted tissues, and activation of astroglia. During the initial 2 days following MCAO, glial fibrillary acidic protein immunoreactive cells increased in number and became larger and more intensely fluorescent medial to the cortical infarct. At 5 to 15 days, both the infarct and the ipsilateral hemisphere decreased in size. These changes correlated with the presence of abundant macrophages, and cavitation of the lesion along its medial border. Also during this period, a loose connective tissue matrix formed along the superficial aspect of the infarct. This connective tissue contained fibroblasts, extracellular matrix immunoreactive for laminin and collagen, capillary buds indicating neovascularization, and abundant macrophages. By the final timepoint (30 days), necrotic tissue could no longer be detected in either gross or histologic tissue sections, the inflammatory infiltrate had resolved, and the connective tissue was removed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Mouse strain differences in susceptibility to cerebral ischemia are related to cerebral vascular anatomy.

The consequences of cerebral ischemia were studied in three different strains (BDF, CFW, and BALB/C) of mice. The different strains exhibited significant differences in susceptibility to 24-h focal ischemia. Following middle cerebral artery occlusion (MCAO), infarct volumes (mm3) were 5 +/- 3 in BDF, 15 +/- 5 in CFW, and 23 +/- 3 in BALB/C mice (p < 0.05). MCAO plus ipsilateral common carotid artery occlusion (CCAO) resulted in infarct volumes of 15 +/- 9 in BDF, 38 +/- 10 in CFW, and 72 +/- 12 in BALB/C mice (p < 0.05). In addition, MCAO plus CCAO produced death by 24 h in 42% of CFW and 67% of BALB/C mice, but not in any BDF mice (p < 0.05). CCAO alone produced multifocal hemispheric infarctions in 36% of BALB/C mice but not in the other two strains. Brains of all mouse strains subjected to sham surgery were free of any ischemic injury. Arterial blood pressures, blood gases, and blood cell profiles were relatively similar for the three mouse strains. However, carbon black studies of the cerebrovascular anatomy revealed an incomplete circle of Willis (i.e., a significant decrease in the frequency of patent posterior communicating arteries) for BALB/C compared with BDF mice (p < 0.05), with CFW mice being intermediary. Based on these anatomical data, BALB/C mice also were evaluated following transient global brain ischemia produced by bilateral CCAO. BALB/C mice exhibited a > 85% reduction in cortical microvascular perfusion and EEG power within 1 min of bilateral CCAO. Also, hippocampal neuronal CA1 damage and mortality over 7 days were related to the duration of global brain ischemia (p < 0.05). These data demonstrate a significant difference between mouse strains in their sensitivity to cerebral ischemia that appears to be related, at least in part, to the functional vascular anatomy at the level of the posterior communicating arteries. In particular, we point out the potential usefulness of BALB/C mice as a sensitive and reproducible model of focal and global ischemia.

Animals↗

PubMed1993

Cardioprotective potential of carvedilol.

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)

Adrenergic beta-Antagonists↗

PubMed1993

Carvedilol, a new antihypertensive agent, prevents lipid peroxidation and oxidative injury to endothelial cells.

The protective effects of carvedilol, a new beta-adrenergic receptor blocker and vasodilating antihypertensive agent, against oxygen free radical-mediated injury were studied in cultured bovine endothelial cells and compared with five other beta-blockers. Carvedilol dose-dependently inhibited oxygen radical-induced lipid peroxidation (50% inhibition at 2.6 mumol/L) and glutathione depletion (50% inhibition at 1.8 mumol/L) in the cells. Under the same conditions, other beta-blockers--propranolol, labetalol, pindolol, atenolol, and celiprolol--had only mild or no effect. Moreover, carvedilol protected against oxygen radical--mediated cell damage, as assessed by cellular lactate dehydrogenase release, with a 50% inhibition at 4.1 mumol/L and increased the cell survival in a dose-dependent manner, whereas other beta-blockers had mild or no effects. Pretreatment of the cells with carvedilol for 7 days significantly enhanced the protective effects of carvedilol. Using 2-methyl-2-nitrosopropane as a trapping agent, the spin adduct in cell lipids was monitored by electron paramagnetic resonance. Carvedilol dose-dependently decreased the intensity of the free radical signals, indicating its free radical-scavenging ability. The prevention of oxidative injury to endothelial cells might potentially contribute to the clinical beneficial effects of carvedilol as an antihypertensive agent.

Adrenergic beta-Antagonists↗

PubMed1993

Myocardial protection by the novel vasodilating beta-blocker, carvedilol: potential relevance of anti-oxidant activity.

AIM: Carvedilol is a multiple action antihypertensive drug with potential use in angina and congestive heart failure. The pharmacological profile of carvedilol includes both beta-adrenoceptor blockade and vasodilation, the latter primarily a result of alpha 1-adrenoceptor blockade. Since many beta-blockers have cardioprotective properties, the present study was designed to determine whether carvedilol is also cardioprotective. Because oxygen radicals are believed to influence ischemic tissue injuries, a secondary study was designed to determine whether carvedilol has anti-oxidant actions which could contribute to cardioprotective properties of carvedilol. METHODS: Four different models of acute myocardial infarction in were examined in three animal species, and the effects of carvedilol were compared to those of propranolol. First, in rats subjected to 30 min of cardiac ischemia followed by 24 h of reperfusion, carvedilol was administered both pre- and post-ischemia (1 mg/kg, intravenously). Second, minipigs were subjected to 45 min of cardiac ischemia followed by 4 h of reperfusion, with carvedilol pretreatment (0.3 or 1 mg/kg intravenously). Third, dogs were subjected to 1 h of cardiac ischemia followed by 24 h of reperfusion with carvedilol pretreatment (1 mg/kg, intravenously) or to permanent coronary occlusion (6 h) with carvedilol pretreatment (0.3 or 1 mg/kg, intravenously). Finally, to examine the anti-oxidant activity of carvedilol, pig myocardial membranes were exposed to oxidizing systems that elicit lipid peroxide products assessed as thiobarbituric acid-reactive substances (TBARS). RESULTS: In the rats, carvedilol reduced the infarct size by 47% (P < 0.01), in contrast to propranolol, which is inactive in this model. In the minipigs the infarct size was reduced by 46 and 89% (P < 0.01) with carvedilol at 0.3 and 1 mg/kg, respectively; at comparable beta-adrenoceptor blocking doses, carvedilol produced a significantly greater reduction in the infarct size than propranolol (89 versus 48%). In dogs, carvedilol reduced the infarct size by 78% (P < 0.05) compared to the 64% reduction produced by propranolol. In dogs with permanent coronary occlusion, carvedilol produced dose-dependent reductions in the infarct size of 46 and 63% for 0.3 and 1 mg/kg, respectively (P < 0.05), compared to propranolol which did not reduce the infarct size in this model. Carvedilol inhibited lipid peroxidation in a dose-dependent manner with a 50% inhibitory concentration (IC50) of 5 mumol/l. Moreover, superoxide generation by activated human neutrophils in vitro was also inhibited by carvedilol with an IC50 of 28 mumol/l. Finally, carvedilol was shown to scavenge oxygen free radicals in a cell-free system with an IC50 of 25 mumol/l. CONCLUSIONS: Taken together, these data indicate that carvedilol is a potent cardioprotective drug, which presumably acts by multiple mechanisms, possibly including a novel anti-oxidant effect that is not shared by other beta-blockers.

Adrenergic beta-Antagonists↗

PubMed1992

Carvedilol, a new antihypertensive, prevents oxidation of human low density lipoprotein by macrophages and copper.

Growing evidence indicates that oxidized low-density lipoprotein (LDL) may promote atherogenesis. Therefore, inhibition of LDL oxidation may impede this process. Carvedilol is a vasodilating, beta-adrenoceptor blocking agent. As a new antihypertensive drug, carvedilol is unique by virtue of its potent antioxidant activity. Therefore, we tested the ability of carvedilol to inhibit the oxidation of LDL by either macrophages or Cu2+. Carvedilol inhibited LDL oxidation by macrophages in a dose-dependent manner, with an IC50 value of 3.8 microM, as assessed by a thiobarbituric acid reactive substance (TBARS) assay. Under the same conditions, propranolol showed only a mild inhibitory effect (IC50 > 100 microM), while pindolol, atenolol and labetalol had almost no effect. Carvedilol, at 10 microM, almost completely inhibited the macrophage-induced increase in electrophoretic mobility of LDL, while other beta-blockers at 50-300 microM had no significant effect. Carvedilol inhibited superoxide release from mouse macrophages, which correlated well with its inhibition of LDL oxidation. Carvedilol also inhibited Cu(2+)-induced LDL oxidation with an IC50 value of 17 microM, while all other beta-blockers were inactive up to 300 microM. These observations suggest that carvedilol might not only be an effective antihypertensive drug, but might also be effective in prevention of atherosclerosis.

Adrenergic beta-Antagonists↗