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Biomedical subjects

R R Ruffolo

Publications and source records attributed to R R Ruffolo.

At least 19 recordsLinked to original sources
PubMed1998

SB 211475, a metabolite of carvedilol, reduces infarct size after myocardial ischemic and reperfusion injury in rabbits.

The aim of this study was to investigate the effect of SB 211475, a metabolite of carvedilol with weak alpha1-adrenoceptor antagonism and antioxidant effect, on myocardial reperfusion injury and infarct size in anesthetized rabbits. The rabbits were subjected to 60 min of regional myocardial ischemia and 180 min of reperfusion. SB 211475 was administered either as 0.3, 1.0 or 3.0 mg/kg and compared to vehicle and carvedilol (1 mg/kg) treated animals. The lowest dose of SB 211475 (0.3 mg/kg) did not reduce infarct size compared to vehicle, whereas SB 211475 1.0 or 3.0 mg/kg reduced infarct size significantly compared to vehicle (41.2 +/- 2.2% and 40.5 +/- 2.8% vs. 59.1 +/- 3.9%, p < 0.05). Carvedilol reduced infarct size significantly more than SB 211475 1.0 and 3.0 mg/kg (28.8 +/- 3.9% vs. 41.2 +/- 2.2% and 40.5 +/- 2.7%, p < 0.05). Carvedilol and SB 211475 1.0 and 3.0 mg/kg reduced myeloperoxidase activity to the same extent, indicative of reduced inflammation. Rate-pressure product did not differ between doses of SB 211475. In conclusion, SB 211475 in the two highest doses reduced infarct size by protecting from reperfusion injury, possibly by reduced neutrophil accumulation. The superior cardiac protective effect of carvedilol over SB 211475 are most likely due to its adrenergic pharmacology including non-selective beta- and alpha1-adrenoceptor antagonism.

Adrenergic alpha-Antagonists↗
PubMed1998

Comparison of metoprolol and carvedilol pharmacology and cardioprotection in rabbit ischemia and reperfusion model.

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.

Adrenergic alpha-Antagonists↗
PubMed1998

Carvedilol inhibits activation of stress-activated protein kinase and reduces reperfusion injury in perfused rabbit heart.

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.

Adrenergic beta-Antagonists↗
PubMed1998

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

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.

Adrenergic beta-Antagonists↗
PubMed1998

Recent observations with beta-adrenoceptor blockade. Beneficial effects in hypertension and heart failure.

Carvedilol is a third-generation vasodilating beta-blocker initially approved for the treatment of hypertension. It lowers systemic arterial blood pressure without causing reflex tachycardia and preserves renal function. More recently, carvedilol has been shown to reduce morbidity and mortality in patients with congestive heart failure. This reduction may occur in part via beta-blockade and alpha 1-adrenoceptor blockade, the latter resulting in vasodilation. Importantly, carvedilol and several of its metabolites are potent antioxidants that may inhibit the oxidation of norepinephrine and the subsequent formation of toxic intermediates, such as reactive free radicals in the myocardium. As a result, carvedilol inhibits the expression of certain genes involved in myocardial damage, such as intracellular adhesion molecule-1, free-radical-induced activation of transcription factors, and programmed cell death or apoptosis. In this respect, carvedilol represents a new therapy for the treatment of hypertension and congestive heart failure and combines, in one molecule, a number of potentially beneficial properties.

Adrenergic beta-Antagonists↗
PubMed1998

Effects of a hydroxylated metabolite of the beta-andrenoreceptor antagonist, carvedilol, on post-ischaemic splachnic tissue injury.

1 Reactive oxygen species have been demonstrated to play a critical role in post-ischaemic tissue injury. The present experiment was designed to evaluate the effects of SB 211475, a hydroxylated metabolite of the new beta-adrenoceptor antagonist, carvedilol, on rat splanchnic ischaemia (SI, 60 min) and reperfusion(R)-induced shock and tissue injury. 2 Administration of SB 211475 two min before R attenuated SI/R injury in a dose-dependent manner. At doses of 0.5 mg kg(-1) and 1.0 mg kg(-1), SB 211475 exerted significant anti-shock and endothelial protective effects, characterized by prolonged survival times, increased survival rates, attenuated increases in tissue myeloperoxidase activity and haematocrits, and preserved endothelium-dependent vasorelaxation. 3 Administration of 1 mg kg(-1) carvedilol attenuated shock-induced tissue injury and endothelial dysfunction. However, administration of 0.5 mg kg(-1) carvedilol had no protective effects on post-ischaemic tissue injury. 4 Previous studies have shown that SB 211475 has virtually no beta-blocking activity but possesses more potent antioxidant activity than carvedilol. In the present study, SB 211475 exerted more potent protective effects than the parent compound, suggesting that this metabolite of carvedilol is superior to carvedilol with regard to its protection against post-ischaemia tissue injury.

Adrenergic beta-Antagonists↗
PubMed1998

Pharmacologic characterization of the novel, orally available endothelin-A--selective antagonist SB 247083.

Competition radioligand binding with [125I]ET-1 at human cloned ETA and ETB receptors demonstrated ET-A selective affinity by SB 247083 (Ki 0.41 and 467 nM, respectively). Accordingly, similar competitive, functional ETA receptor antagonism was observed. In vitro, SB 247083 exhibited a Kb of 3.5 +/- 0.3 nM (ET-1--induced rat aortic contraction). SB 247083 was significantly less potent as a functional ETB antagonist (Kb 0.34 +/- 0.01 microM; S6c-induced rabbit pulmonary artery contraction). In contrast to ETB-selective and mixed ETA/B antagonists, and consistent with its ETA-selective profile, in vivo administration of SB 247083 was not associated with an elevation in plasma ET-1 levels. Pharmacodynamic and pharmacokinetic studies revealed that SB 247083 was effectively absorbed from the gastrointestinal tract. A single bolus dose inhibited the hemodynamic actions of ET-1 for up to 8 h, consistent with a molecule shown to be 46% bioavailable. Therefore, the present study demonstrates that SB 247083, a unique chemical entity, represents a potent class of nonpeptide, orally active ETA-selective antagonists.

Animals↗
PubMed1998

Neurohormonal activation, oxygen free radicals, and apoptosis in the pathogenesis of congestive heart failure.

A variety of pathophysiologic processes are activated in patients with congestive heart failure (CHF), and some of these have been implicated in the progression of the disease. The most important processes to be activated in CHF are the neurohormonal systems, which include the renin-angiotensin system, the sympathetic nervous system, and the endothelin system. In addition to the neurohormonal systems, the formation of reactive oxygen free radicals is increased in patients with CHF. It has been postulated that stimulation of neurohormonal pathways and the formation of oxygen free radicals ultimately lead to the activation of a family of transcription factors that are involved in cardiac remodeling, which is a hallmark of CHF. In addition, the formation of oxygen free radicals has been implicated in the process of apoptosis or programmed cell death, which may be responsible for a continued loss of myocardial cells, resulting in the progressive decrease in left ventricular function that occurs over time in patients with CHF. Carvedilol is a multiple-action neurohormonal antagonist that is effective in slowing the progression of CHF. In double-blind, placebo-controlled clinical trials, carvedilol decreased mortality by 65% (p <0.001) and significantly reduced hospitalization. Carvedilol is a nonselective beta-blocker and vasodilator, the latter activity resulting from alpha1-adrenoceptor blockade. The hemodynamic responses produced by carvedilol result primarily from the blockade of beta1-, beta2-, and alpha1-adrenoceptors. Carvedilol reduces total peripheral vascular resistance and preload without significantly compromising cardiac output or eliciting reflex tachycardia. Carvedilol is also a potent antioxidant that may protect the myocardium from damage produced by oxygen radicals and, as a consequence of its antioxidant activity, carvedilol also inhibits apoptosis in the myocardium. The ability of carvedilol to inhibit apoptosis in the heart may be responsible, in part, for the ability of the drug to reduce mortality and to inhibit the progression of CHF.

Adrenergic beta-Antagonists↗
PubMed1998

Evaluation of intrinsic sympathomimetic activity of bucindolol and carvedilol in rat heart.

Many beta-adrenoceptor antagonists are weak partial agonists, possessing significant intrinsic sympathomimetic activity (ISA). Under certain conditions, ISA may be deleterious through stimulation of beta 1- and/or beta 2-adrenoceptors in the heart. Drugs with ISA are particularly problematic in the treatment of congestive heart failure since agents that activate cardiac beta-adrenoceptors, such as xamoterol, have been associated with increases in the incidence of arrhythmia and mortality. Carvedilol was recently approved for the treatment of congestive heart failure, and bucindolol is currently in large clinical trials for this indication. In the present study, the ISA of bucindolol and carvedilol was evaluated in a standard model used to investigate ISA, the pithed rat. Both compounds produced dose-dependent inhibition of the positive-chronotropic effects of the non-selective beta-adrenoceptor agonist, isoproterenol, confirming that these drugs are beta-adrenoceptor antagonists. However, cumulative administration of bucindolol (10-1,000 micrograms/kg i.v.) in the pithed rat produced a significant dose-related increase in heart rate. The maximal increase in heart rate produced by bucindolol was 44% of that obtained with isoproterenol (90 +/- 6vs. 205 +/- 11 bpm, respectively). In marked contrast, cumulative administration of carvedilol (10-1,000 micrograms/kg i.v.) had no significant effect on resting heart rate in the pithed rat. The maximal increase in heart rate elicited by bucindolol (1,000 micrograms/kg i.v.) was inhibited by treatment with the competitive beta-adrenoceptor antagonist, propranolol (99 +/- 8.7 vs. 26 +/- 2.6 bpm), confirming that the ISA observed with bucindolol was mediated through stimulation of myocardial beta-adrenoceptors. Carvedilol, which had no ISA, antagonized the ISA of bucindolol, and was as effective as propranolol in blocking the ISA of bucindolol (99 +/- 8.7 vs. 27 +/- 2.3 bpm). In summary, bucindolol and carvedilol are both potent beta-adrenoceptor antagonists in the pithed rat: however, only bucindolol possesses beta-adrenoceptor-mediated ISA.

Adrenergic beta-Antagonists↗
PubMed1998

Effects of eprosartan on renal function and cardiac hypertrophy in rats with experimental heart failure.

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (-33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (-12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.

Acrylates↗
PubMed1998

Carvedilol: preclinical profile and mechanisms of action in preventing the progression of congestive heart failure.

Many pathophysiological processes are activated in patients with congestive heart failure, and several of these have been implicated in the progression of the disease. The most important processes to be activated in heart failure are the neurohormonal systems, which include the reninangiotensin system, the sympathetic nervous system and the endothelin system. In addition to the neurohormonal systems, the formation of reactive oxygen free radicals is increased in congestive heart failure. It has been proposed that the activation of neurohormonal pathways and the formation of oxygen free radicals ultimately lead to the activation of a family of transcription factors that are involved in cardiac and vascular remodelling which are hallmarks of congestive heart failure. In addition, the formation of oxygen free radicals has been implicated in the process of apoptosis, or programmed cell death, which may contribute to the continued loss of myocardial cells resulting in progressive decreases in left ventricular function, while at the same time contributing to the cardiac remodelling process which subsequently creates a pro-arrhythmic environment in the myocardium. Carvedilol is a novel multiple-action neurohormonal antagonist that has been shown to be effective in the management of congestive heart failure. Carvedilol also possesses a number of additional activities which may inhibit many of the chronic pathophysiological processes that are involved in the progression of congestive heart failure.

Adrenergic alpha-Antagonists↗
PubMed1998

CVT-124, a novel adenosine A1 receptor antagonist with unique diuretic activity.

Administration of the selective adenosine A1 receptor antagonist, CVT-124, to conscious chronically instrumented rats resulted in significant increases in urine flow rate and sodium excretion without affecting potassium excretion or renal hemodynamics. Its maximum effect was twice that of hydrochlorothiazide which was associated with a significant kaliuresis. The diuretic effect of CVT-124 was less than that observed with furosemide; however, furosemide administration was associated with a large increase in potassium excretion as well as a reduction in glomerular filtration rate. When given at equinatriuretic doses, CVT-124 enhanced the diuretic and natriuretic activity of furosemide without further increasing potassium excretion. In contrast, the combination of hydrochlorothiazide and furosemide resulted in a 3-fold increase in potassium excretion. These data suggest that CVT-124 possesses unique diuretic activity and, as such, it represents a potential new therapeutic in fluid retaining disorders. In addition, its unique mechanism of action suggests that CVT-124 would be effective in otherwise diuretic-resistant patients.

Animals↗
PubMed1997

Protective effects of carvedilol in the myocardium.

Beta blockers have long been used in the treatment of systemic hypertension, where they effectively lower blood pressure and, in so doing, they decrease left ventricular hypertrophy. The sympathetic nervous system is activated in patients with congestive heart failure, and therefore it is logical that beta blockers may also provide benefit in these patients. As such, beta blockers are currently being evaluated in several large clinical trials in congestive heart failure. One particular drug, carvedilol, is a third-generation vasodilating beta blocker that is marketed for the treatment of hypertension. The drug lowers systemic arterial blood pressure without producing reflex tachycardia and preserves renal function. Carvedilol decreases mortality by 65% and decreases hospitalization by 29% in patients with congestive heart failure. The effects of carvedilol in heart failure may result, at least in part, from beta blockade as well as vasodilation, the latter resulting from alpha(1)-adrenoceptor blockade. Interestingly, carvedilol has a number of additional properties that may also provide benefit in these patients. Carvedilol and several of its metabolites are potent antioxidants that may inhibit catecholamine toxicity resulting from the oxidation of norepinephrine and the subsequent formation of toxic intermediates, including the generation of reactive oxygen free radicals in the myocardium. As a result of its antioxidant activity, carvedilol also blocks the expression of several genes involved in myocardial damage and cardiac remodeling, and the drug inhibits free radical-induced activation of transcription factors and programmed cell death (apoptosis). Carvedilol is a novel beta blocker that is highly effective in the treatment of hypertension and congestive heart failure, and combines in one molecule a number of important pharmacologic properties.

Adrenergic alpha-Antagonists↗
PubMed1997

Congestive heart failure and genomic medicine: a look into the 21st century.

Congestive heart failure (CHF) has emerged as one of the leading cardiovascular disorders in developed countries, as indicated by the prevalence of the disease; the incidence of hospitalization, morbidity, and mortality; and its global economic burden. Furthermore, it is expected that heart failure and other cardiovascular disorders will become the major disease burdens in developing countries by the year 2020. It is well established that pharmacological therapy of CHF, although still not optimum, improves patient quality of life and reduces morbidity and mortality. However, CHF remains a relentlessly progressive disease. In this brief review an attempt is made to explore the contemporary, state-of-the-art pharmacological approach to the treatment of heart failure, the unmet medical need that still remains, and the potential impact of genomic medicine on the treatment of heart failure in the 21st century.

Genetic Therapy↗
PubMed1997

Pharmacology of carvedilol: rationale for use in hypertension, coronary artery disease, and congestive heart failure.

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.

Adrenergic beta-Antagonists↗
PubMed1997

Carvedilol inhibits aortic lipid deposition in the hypercholesterolemic rat.

The effects of carvedilol, a vasodilating beta-blocker with antioxidant activity, and nifedipine, a calcium channel blocker, were investigated on aortic lipid deposition and the accumulation of monocytes and foam cells at the sites of atherosclerotic lesions in rats subjected to a hypercholesterolemic diet. Fifty rats were randomly assigned to the following experimental groups: (1) regular rat chow (n = 5); (2) regular rat chow supplemented with a high-cholesterol diet (1% cholesterol and 1% cholic acid; n = 15); (3) a high-cholesterol diet plus nifedipine (n = 15), and (4) a high-cholesterol diet plus carvedilol (n = 15). Animals were maintained on these diets for 12 weeks. None of the treatment groups had blood pressures that were outside the normotensive range, and no significant differences in plasma lipid levels were observed among the high-cholesterol diet and drug-treated groups. There was a significantly lower lipid content (p < 0.001) in the thoracic aortas of the nifedipine-treated (211 +/- 23 nmol/mm2) and carvedilol-treated (182 +/- 23 nmol/mm2) groups compared to cholesterol-fed controls (242 +/- 27 nmol/mm2). Furthermore, carvedilol-treated animals showed significantly less (p < 0.001) lipid accumulation than did the nifedipine-treated animals. The number of monocytes and foam cells were decreased in both drug-treated groups compared to animals receiving high-cholesterol diets without drug treatment. The results demonstrate that treatment with carvedilol or nifedipine can significantly inhibit lipid deposition in the aorta and reduce monocyte and foam cell accumulation, and that carvedilol is significantly more effective than nifedipine in inhibiting lipid deposition.

Adrenergic beta-Antagonists↗
PubMed1997

Ser165 of transmembrane helix IV is not involved in the interaction of catecholamines with the alpha-2a-adrenoceptor.

Molecular modeling studies have predicted that the beta-hydroxyl group of the catecholamines interacts with the beta 2-adrenoceptor at the serine residue at position 165 (Ser165) located on transmembrane helix IV; however, this has not been confirmed by site-directed mutagenesis. It has been inferred that this site, which is conserved in all of the nine known alpha- and beta-adrenoceptor subtypes, is also involved in the interaction of catecholamines with the alpha 2a-adrenoceptor. To test the hypothesis that the beta-hydroxyl group of the catecholamines interacts with Ser165 of the alpha 2a-adrenoceptor, we prepared a mutant alpha 2a-adrenoceptor where Ser165 was mutated to alanine. Mutation of Ser165 of the alpha 2a-adrenoceptor to alanine had no effect on the affinity of dopamine (which lacks the beta-hydroxyl group) or either enantiomer of norepinephrine or epinephrine (both of which possess the beta-hydroxyl group), indicating that Ser165 is not involved in the interaction of the catecholamines with the alpha 2a-adrenoceptor. We have previously shown that mutation of Ser90, located in transmembrane helix II, to either alanine or cysteine produces a selective reduction in the affinity of the (-)-enantiomers of the catecholamines for the alpha 2a-adrenoceptor, with no effect on the (+)-enantiomers or the corresponding beta-desoxy analogs. This is consistent with the known stereoselectivity involved in the interactions of catecholamines with the alpha 2a-adrenoceptor. The results of the present investigation indicate that Ser165 is not involved in the interaction of catecholamines with the alpha 2a-adrenoceptor. Because all known alpha-adrenoceptor subtypes have a serine residue at a position corresponding to Ser90 of the alpha 2a-adrenoceptor, it would appear that this site represents an important point for attachment of the beta-hydroxyl group of catecholamines.

Alanine↗