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Biomedical subjects

R R Ruffolo

Publications and source records attributed to R R Ruffolo.

At least 37 records · Page 2Linked to original sources
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

Pharmacology of the angiotensin II receptor antagonist, eprosartan.

The non-peptide angiotensin II receptor antagonists represent a new class of drugs with demonstrated efficacy in the treatment of hypertension. Eprosartan is a potent, orally active AT(1) receptor antagonist which is chemically distinct from losartan and other non-peptide angiotensin II receptor antagonists. Eprosartan has a high affinity for the angiotensin II AT(1) receptor, but does not interact with the AT(2) receptor, adrenergic receptors or other receptors involved in cardiovascular regulation. In contrast to most other angiotensin II antagonists, eprosartan is a true competitive antagonist of the AT(1) receptor. Eprosartan is effective in antagonising the cardiovascular and renal effects of exogenous angiotensin II in both experimental animals and humans. Furthermore, it is an effective antihypertensive agent when administered to renin-dependent hypertension animal models, and in patients with mild to severe hypertension. The antihypertensive effect of eprosartan is maintained over a 24-h interval following a single dose with no reported dose-dependent adverse side-effects.

Journal Article↗
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↗
PubMed1998

Molecular basis for the stereoselective interactions of catecholamines with alpha-adrenoceptors.

The catecholamines were found to inhibit the binding of the alpha 2-adrenoceptor agonist, [3H]-clonidine, to the recombinant wild type alpha 2a-adrenoceptor (Table 1) with potencies that are consistent with their functional activity in alpha 2-adrenoceptor test systems [6,7]. Mutation of Ser165 to alanine had no significant effect (less than 2-fold) on the affinity of any of the catecholamines for the alpha 2a-adrenoceptor, and in particular, the ratios of affinities between the corresponding (-)- and (+)-enantiomers of the catecholamines were not altered by the point mutation at Ser165. These findings indicate clearly that Ser165, in contrast to predictions made by molecular modeling, plays little if any role in the binding of the catecholamines in general, and cannot be involved in the attachment of the beta-hydroxyl group to the alpha 2a-adrenoceptor. Mutation of either Ser90 on transmembrane helix II or Ser419 on transmembrane helix VII to alanine produced dramatic and selective reductions in the affinity of the (-)-enantiomers of the catecholamines for the alpha 2a-adrenoceptor, with no changes occurring in affinities of the (+)-enantiomers. Thus, the affinities of (-)-norepinephrine and (-)-epinephrine for the Ser90 and Ser419 mutants of the alpha 2a-adrenoceptor were 35-75 fold lower than their affinities for the wild type receptor (Table 1), suggesting that Ser90 and/or Ser419 are involved in the attachment of the beta-hydroxyl groups of the catecholamines to the receptor. Similarly, the affinity of (+/-)-6-fluoronorepinephrine was reduced by 100-fold for the Ser90 mutant receptor (Table 1). Importantly, the affinities of the (+)-enantiomers of the catecholamines, as well as dopamine and epinine, which are the corresponding analogs of norepinephrine and epinephrine which lack the beta-hydroxyl group, were not affected by mutation of Ser90 or Ser419 to alanine (Table 1). Asn293 in transmembrane helix VI has also been proposed to be involved in the interaction of the beta-hydroxyl group of isoproterenol with the beta 2-adrenoceptor [4]. The alpha 2a-adrenoceptor contains three hydroxyl bearing amino acids at a position corresponding to this site (Thr393-Tyr394-Thr395). These amino acids could theoretically form a hydrogen bond with the beta-hydroxyl group of a catecholamine, and therefore could serve as a potential point of attachment. Simultaneous mutation of all three of these amino acids to Ala-Phe-Ala reduced the affinity of the (-)-enantiomers of the catecholamines by 12-20 fold, which is somewhat less than what was observed for mutation of either Ser90 or Ser419 (Table 1). However, in contrast to mutation of Ser90 or Ser419, which had no effect on the affinity of the (+)-enantiomers, mutation of the three residues in transmembrane helix VI did significantly reduce the affinities of the (+)-enantiomers of the catecholamines by approximately 5- to 9-fold, indicating that mutations at these points of the receptor are not selective for the (-)-enantiomers, and are therefore not likely to be involved in the attachment of the beta-hydroxyl group of the catecholamines.

Catecholamines↗
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↗
PubMed1997

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade.

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.

Acrylates↗
PubMed1997

Hypercholesterolemia impairs a detoxification mechanism against peroxynitrite and renders the vascular tissue more susceptible to oxidative injury.

Previous studies have shown that glutathione (GSH) plays a central role in the protection against peroxynitrite (ONOO-) toxicity. The present study evaluated the changes of the GSH cytoprotective system against ONOO- in hypercholesterolemia and determined the effects of carvedilol, a beta-blocker with free radical-scavenging activity, on these hypercholesterol-induced changes. New Zealand White rabbits were fed either a normal diet, a high-cholesterol diet, or a high-cholesterol diet supplemented with either carvedilol or propranolol. Eight weeks later, the rabbits were killed, and the thoracic aortas were isolated. Total GSH content of aortic tissue, vasorelaxation response of aortic rings to exogenous ONOO-, No regeneration from ONOO- by aortic homogenate, and ONOO(-)-induced aortic tissue injury were examined. Hypercholesterolemia decreased tissue GSH content (0.52 +/- 0.08 versus 0.86 +/- 0.04 mumol/g in control, P < .01), attenuated the vasorelaxation response to ONOO- (40 +/- 4.1% versus 76 +/- 3.2%, P < .01), reduced NO regeneration from ONOO- (387 +/- 40 versus 662 +/- 51 pmol, P < .01), and potentiated ONOO(-)-induced vascular tissue injury (37 +/- 4.4% versus 14 +/- 2.6% of increase in lactate dehydrogenase release after 3-morpholinosydnonimine exposure, P < .01). Treatment of the hypercholesterolemic rabbits with carvedilol, but not propranolol, significantly preserved tissue GSH content (0.79 +/- 0.05 mumol/g, P < .01 versus nontreated hypercholesterolemic rabbits), restored the vasorelaxation to ONOO- (61 +/- 2%, P < .01), increased NO regeneration from ONOO- (583 +/- 39 pmol, P < .01), and attenuated ONOO(-)-induced tissue injury (19 +/- 1.8%, P < .01). These results suggest that hypercholesterolemia impairs the GSH-mediated detoxification mechanism against ONOO- and renders the vascular tissue more susceptible to oxidative injury. Carvedilol, a novel vasodilating beta-blocker with antioxidant activity, significantly preserved this self-defense system and protected tissue from oxidant injury.

Animals↗
PubMed1997

Recent advances in the identification of alpha1- and alpha2-adrenoceptor subtypes: therapeutic implications.

The cloning of multiple subtypes of both alpha1- and alpha2-adrenoceptors has renewed interest in the therapeutic application of agents interacting with these receptors. Effort has primarily been directed towards the design of uroselective alpha1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia (BPH). Evidence is accumulating for the involvement of a novel alpha1-adrenoceptor, designated as alpha1L-adrenoceptor, in alpha1-adrenoceptor-mediated smooth muscle contraction in prostatic and other urogenital tissues. While several antagonists showing a high degree of uroselectivity in animal models have been identified, their clinical superiority over the currently available alpha1-adrenoceptor antagonists has not yet been demonstrated. It is possible that the interaction with alpha1-adrenoceptors, as yet uncharacterised subtypes, at non-prostatic sites contributes to the therapeutic activity of this drug class in BPH. The alpha1-adrenoceptor subtypes involved in the control of vascular tone are currently being evaluated, and the profile of interaction with the various alpha1-adrenoceptor subtypes may play a key role in the efficacy of cardiovascular drugs such as carvedilol. Alpha2-adrenoceptor agonists are now being employed for a variety of therapeutic applications, most involving actions on receptors within the central nervous system (CNS). These agents are useful in the treatment of hypertension, glaucoma, opiate withdrawal and attention deficit hyperactivity disorder (ADHD), and as analgesics and adjuncts to general anaesthesia. While subtype selectivity has not yet been applied to the design of new alpha2-adrenoceptor agonists for these applications, recent gene mutation/knock-out experiments have identified the alpha2-subtypes involved in some of these actions, and optimisation of a therapeutic profile may be possible. Furthermore, the design of agents combining affinities for multiple adrenoceptor subtypes, or the combination of a specific adrenoceptor affinity profile with another pharmacological action, may offer advantages over molecules selective for an individual adrenoceptor subtype.

Journal Article↗
PubMed1996

Endothelin receptors: receptor classification, novel receptor antagonists, and potential therapeutic targets.

The development of endothelin receptor antagonists has progressed rapidly since the initial discovery of endothelin. Highly potent, orally active nonpeptide endothelin receptor antagonists have been identified, and are being used as pharmacological tools to elucidate the role of endothelin in pathological disorders. Subtype selective endothelin receptor antagonists will also be useful in understanding the physiological and pathological roles of the different subtypes of the endothelin receptors. The selectivity profile for the ideal endothelin receptor antagonist is presently unknown, and it may actually be that the optimal profile for a compound may depend on the clinical indication. In the near future, data from clinical trials with endothelin receptor antagonists will become available and will help to establish the role of endothelin in the etiology of human disease, as well as to provide valuable information concerning the optimum endothelin receptor subtype selectivity for antagonists needed for therapeutic agents.

Amino Acid Sequence↗
PubMed1996

The use of alpha-adrenoceptor antagonists in the pharmacological management of benign prostatic hypertrophy: an overview.

Benign prostatic hypertrophy (BPH) produces symptomatic urethral obstruction in a significant percentage of older men. Since the incidence of BPH is age related, the clinical and economic impact of this disease will continue to progress as average lifespan increases. BPH is associated with growth of both glandular and stromal elements of the prostate gland. Glandular hyperplasia can be partially reversed by withdrawal of androgenic tone with androgen receptor antagonists or steroid-5-alpha-reductase inhibitors. However, the reduction in prostatic size produced by these agents has little effect on the dynamic tone induced by nerve mediated contraction of stromal smooth muscle. This tone is mediated by activation of alpha-adrenoceptors. Therefore the alpha-adrenoceptor antagonists represent a useful pharmacological approach to the treatment of BPH. Studies in isolated strips of human prostate show that either exogenous alpha-adrenoceptor agonists or electrical field stimulation will induce contraction. Studies with selective antagonists such as prazosin show that this response is mediated by the alpha 1-adrenoceptor, even though radioligand binding studies show the presence of alpha 1 and alpha 2 adrenoceptor subtypes in approximately equal density. Following the cloning of multiple alpha 1-adrenoceptors, the contractile response in human prostate has been assigned to the alpha 1A adrenoceptor. However, recent data would suggest a functional role for another subtype, which has not yet been cloned, and designated as alpha 1L based on a relatively low affinity for prazosin. Clinical trials have shown efficacy of a variety of alpha-adrenoceptor antagonists in BPH, including non-selective agents such as phenoxybenzamine, as well as a variety of selective alpha 1-adrenoceptor antagonists, most structurally related to prazosin. The agents most commonly employed at the present time include the prazosin analogs terazosin, doxazosin and alfuzosin, as well as the structurally unrelated indoramin and tamsulosin. The design of new alpha 1-antagonists for BPH has concentrated on agents producing preferential blockage of urogenital vis-á-vis vascular alpha 1-adrenoceptors, based either on selectivity for the alpha 1A-adrenoceptor subtype or on functional uroselectivity in animal models. While these newer agents offer the prospect of reducing the incidence of the cardiovascular side effects associated with current therapy their superiority over nonselective alpha 1-adrenoceptor antagonists remains to be demonstrated in the clinical setting.

Adrenergic alpha-Antagonists↗