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Biomedical subjects

R R Ruffolo

Publications and source records attributed to R R Ruffolo.

At least 55 records · Page 3Linked to original sources
PubMed1996

Carvedilol, a novel vasodilating beta-blocker with the potential for cardiovascular organ protection.

Carvedilol is a vasodilating beta-blocker currently marketed for the treatment of mild to moderate hypertension and application is being filed to the FDA for treatment of congestive heart failure. Carvedilol reduces peripheral vascular resistance by blocking arterial alpha 1-adrenoceptors, thereby producing vasodilation, while preventing reflex tachycardia by blocking cardiac beta 1- and beta 2-adrenoceptors. In addition to the safety and efficacy of carvedilol as an antihypertensive agent, experimental studies indicate that carvedilol also provides significant cardioprotection in animal models of acute myocardial infarction as well as protection against the vascular remodelling that occurs following injury of the vasculature. Recent pharmacological studies have uncovered several novel properties of carvedilol which may function to protect the heart and vasculature from chronic pathological processes, such as ischaemia, atherosclerosis and the remodelling that occurs in the heart and blood vessels as a consequence of pressure overload, injury or shear stress. Specifically, carvedilol, likely as a result of the carbazol moiety, is a potent anti-oxidant. In physicochemical, biochemical and cellular assays carvedilol and several of its metabolites inhibit lipid peroxidation, scavenge oxygen free radicals, inhibit the formation of reactive oxygen radicals and prevent the depletion of endogenous antioxidants, such as vitamin E and glutathione. Moreover, carvedilol blocks the oxidation of low-density lipoproteins (LDL), and thereby prevents the formation of oxidized-LDL which is believed to stimulate foam cell formation and augment the development of atherosclerotic plaque. The ability of carvedilol to prevent the formation of oxidized LDL, in addition to the general anti-oxidant properties of the compound, results in the protection of the endothelium from oxygen free radical injury, and thereby prevents the subsequent events triggered by endothelial damage. Recently, carvedilol has also been shown to inhibit vascular smooth muscle cell proliferation and migration. Because carvedilol can inhibit vascular smooth muscle cell proliferation induced by a wide variety of mitogens (e.g. growth factors, angiotensin II, endothelin, thrombin), it is likely that the site of inhibition occurs at some point beyond the specific mitogen receptors, possibly at a distal common pathway that affects the smooth muscle cell cycle. These unique activities of carvedilol have also been confirmed in vivo in a rat model of neointimal formation following vascular injury by balloon angioplasty, where vascular smooth muscle cell migration and proliferation are the key processes involved in the formation of neointima leading to vascular stenosis. In this model, carvedilol suppressed neointimal growth to a remarkable extent ( > 85% inhibition of neointimal formation) at a dose that is similar to the antihypertensive dose used clinically in hypertensive patients. Taken together, these unique multiple actions of carvedilol provide not only for adequate control of elevated blood pressure, but may also provide for protection of the heart and vasculature from secondary damage due to hypertension itself, as well as from other causes, such as ischaemia, pressure overload, shear stress, vascular injury and atherosclerosis.

Adrenergic beta-Antagonists↗
PubMed1996

Carvedilol, a new beta adrenoreceptor blocker and free radical scavenger, attenuates myocardial ischemia-reperfusion injury in hypercholesterolemic rabbits.

Oxygen-derived free radicals play a critical role in atherogenesis and reperfusion injury. The present experiment evaluated the effects of carvedilol, a new beta adrenoreceptor blocker with potent free radical-scavenging activity, on myocardial ischemia and reperfusion injury in a hypercholesterolemic rabbit model. New Zealand rabbits were fed a normal diet, a high-cholesterol diet, or a high-cholesterol diet supplemented with 1200 ppm carvedilol or propranolol. Eight weeks later, the rabbits were subjected to 60 min of myocardial ischemia followed by 60 min of reperfusion. The nontreated cholesterol-fed animals experienced greater cardiac damage after ischemia and reperfusion than rabbits fed a normal diet (necrosis 51% +/- 4% vs. 28% +/- 3% in the normal-diet group, P < .01). In addition, nontreated cholesterol-fed rabbits showed a significantly decreased vasorelaxant response to ACh in U-46619-precontracted aortic rings (56% +/- 5% vs 90% +/- 3% in the control group, P < .001). Treatment with propranolol neither preserved endothelial function after cholesterol feeding nor reduced neutrophil accumulation in ischemic-reperfused myocardial tissue. Propranolol treatment did significantly decrease HR, pressure-rate index and infarct size (necrosis 33% +/- 4%). Despite their having essentially identical effects on HR and pressure-rate index, carvedilol exerted more profound cardiac protective effects than propranolol (necrosis 19% +/- 3%). Moreover, carvedilol treatment significantly preserved aortic endothelial function and markedly reduced neutrophil accumulation in ischemic-reperfused myocardial tissue. These results indicate that in addition to its beta blocking activity, the antioxidant and endothelial protective activities of carvedilol contributed significantly to its cardiac protective effects after ischemia and reperfusion.

Adrenergic beta-Antagonists↗
PubMed1996

The selectivity in vitro of the stereoisomers of the beta-3 adrenoceptor agonist BRL 37344.

The stimulation by BRL 37344 of lipolysis in rat adipose tissues, and of relaxation of the rat distal colon, is mediated by the beta-3 adrenoceptor. The stereochemical requirements of the beta-3 adrenoceptor are poorly understood. The activities of the four stereoisomers of BRL 37344 (i.e., two pairs of diastereoisomers) on three beta-3 adrenoceptor-mediated responses (brown and white adipose tissue lipolysis and relaxation of distal colon) have been determined and compared with those responses mediated by beta-1 adrenoceptors (increase in atrial rate) and beta-2 adrenoceptors (uterine relaxation). The potency order for the stereoisomers (RR>RS=SR>>SS) was the same for all tissues, regardless of whether the response was mediated by beta-1, beta-2 or beta-3 adrenoceptors. These results indicate that both chiral centers are determinants of agonist potency at all three subtypes of the beta adrenoceptor. Furthermore, agonist activity at beta-1, beta-2 and beta-3 adrenoceptors resides predominantly with the RR enantiomer. Finally, the RR enantiomer of BRL 37344 was a more potent agonist in brown adipocytes (EC50 = 3.3 +/- 0.8 nM) than in white adipocytes (EC50 = 5.7 +/- 0.9 nM) or colon (EC50 = 27.5 +/- 7.7 nM).

Adrenergic beta-Agonists↗
PubMed1996

Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: experimental profile of BRL-32872.

In the search for novel antiarrhythmic agents, compounds with a diversity of electrophysiological actions have been suggested to result in treatments with potentially improved efficacy but with reduced proarrhythmic risk. To test this hypothesis, the antiarrhythmic versus proarrhythmic profile of BRL-32872, a novel agent with combined potassium and calcium channel blocking activity, was assessed in two different in vivo models of ventricular arrhythmia. Furthermore, the effects of potassium and calcium channel antagonists given either alone or in combination were assessed in the same models. Dogs with myocardial infarction received intravenously either vehicle, BRL-32872, the class III antiarrhythmic agent, E-4031, verapamil or a combination of E-4031 with verapamil (n = 8 per group). Ventricular tachyarrhythmias were induced by programmed electrical stimulation (PES). BRL-32872 (0.1, 0.3, 1.0 mg/kg) significantly increased QTc interval (from 387 +/- 10 to 462 +/- 19 msec.sec-1/2 at 1.0 mg/kg, P < .01). Ventricular effective refractory periods were increased in normal and infarcted areas (P < .01). Similar effects were observed with E-4031 (0.1, 0.3, 1.0 mg/kg). Verapamil (0.03, 0.1, 0.3 mg/kg) reduced heart rate, mean arterial pressure and, to a lesser extent, (+)dP/dtmax. Verapamil did not change QTc interval and ventricular effective refractory periods, but increased PR interval (P < .001). PES-induced tachyarrhythmias were not changed by vehicle or increasing doses of verapamil. E-4031 reduced the severity of arrhythmias from sustained ventricular tachycardia (VT) to nonsustained VT (7 dogs at 1.0 mg/kg, P = .013 vs. vehicle). BRL-32872 (0.1 and 0.3 mg/kg) suppressed the induction of sustained VT in six dogs (P = .02 vs. vehicle). In the presence of BRL-32872, 1.0 mg/kg, five dogs became noninducible to PES (P = .013 vs. vehicle). Combination of E-4031 (0.1 mg/kg) with verapamil provided a degree of protection that was similar to that observed with BRL-32872. In a second model, the proarrhythmic potential of BRL-32872 was assessed in anesthetized rabbits sensitized to develop torsades de pointes (TdP). BRL-32872 was compared with the class III antiarrhythmic agents, E-4031, dofetilide, clofilium and RP-58866. The pure class III antiarrhythmic agents induced TdP in 50 to 90% of the rabbits, and prolonged QT interval by 20 to 50%. BRL-32872 (10 micrograms/kg/min) increased QT interval by 35 +/- 5%, but did not promote TdP. In additional experiments, verapamil reduced the incidence of TdP induced by E-4031. These results show that BRL-32872 is a potent antiarrhythmic compound in a model of PES-induced arrhythmias and induces fewer proarrhythmic events than typical class III antiarrhythmic agents. The effects observed with BRL-32872 suggest that a compound with a combination of potassium (class III) and calcium (class IV) channel antagonistic properties might constitute a novel antiarrhythmic agent with reduced proarrhythmic risk.

Animals↗
PubMed1995

Carvedilol prevents low-density lipoprotein (LDL)-enhanced monocyte adhesion to endothelial cells by inhibition of LDL oxidation.

Cultured human umbilical vein endothelial cells oxidize low-density lipoproteins (LDL), assessed as increase in thiobarbituric acid reactive substance formation and oxidized LDL-induced cytotoxicity (lactate dehydrogenase (LDH) release). Endothelial cell-generated oxidized also enhances the adhesiveness of endothelial cells to monocytes. Carvedilol, a new vasodilating beta-adrenoceptor antagonist, inhibits the oxidation of LDL by endothelial cells and reduces oxidized LDL-induced LDH release from endothelial cells in a concentration-dependent manner with IC50 values of 2.56 and 1.38 microM, respectively. Moreover, carvedilol inhibits oxidized LDL-induced adhesion of monocytes to the endothelial cells in a similar concentration-dependent manner. Under the same conditions, propranolol, atenolol, pindolol and labetalol had only weak or no consistent effects on both LDL oxidation by endothelial cells and adhesion of monocytes to the endothelial cells. Monoclonal antibodies against human intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) or E-selectin (ELAM-1) partially blocked oxidized LDL-stimulated adhesion of endothelial cells to monocytes. The inhibitory effects of carvedilol on LDL oxidation and monocyte adhesion to endothelial cells may protect blood vessels from atherosclerotic processes associated with oxidized LDL-induced injuries.

Adrenergic beta-Antagonists↗
PubMed1995

Discovery of adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage.

Focal brain ischemia is the most common event leading to stroke in humans. To understand the molecular mechanisms associated with brain ischemia, we applied the technique of mRNA differential display and isolated a gene that encodes a recently discovered peptide, adrenomedullin (AM), which is a member of the calcitonin gene-related peptide (CGRP) family. Using the rat focal stroke model of middle cerebral artery occlusion (MCAO), we determined that AM mRNA expression was significantly increased in the ischemic cortex up to 17.4-fold at 3 h post-MCAO (P < 0.05) and 21.7-fold at 6 h post-MCAO (P < 0.05) and remained elevated for up to 15 days (9.6-fold increase; P < 0.05). Immunohistochemical studies localized AM to ischemic neuronal processes, and radioligand (125I-labeled CGRP) displacement revealed high-affinity (IC50 = 80.3 nmol) binding of AM to CGRP receptors in brain cortex. The cerebrovascular function of AM was studied using synthetic AM microinjected onto rat pial vessels using a cranial window or applied to canine basilar arteries in vitro. AM, applied abluminally, produced dose-dependent relaxation of preconstricted pial vessels (P < 0.05). Intracerebroventricular (but not systemic) AM administration at a high dose (8 nmol), prior to and after MCAO, increased the degree of focal ischemic injury (P < 0.05). The ischemia-induced expression of both AM mRNA and peptide in ischemic cortical neurons, the demonstration of the direct vasodilating effects of the peptide on cerebral vessels, and the ability of AM to exacerbate ischemic brain damage suggests that AM plays a significant role in focal ischemic brain injury.

Adrenomedullin↗
PubMed1995

Possible structural and functional relationships between imidazoline receptors and alpha 2-adrenoceptors.

Although it is now well established that imidazoline receptors and alpha 2-adrenoceptors are discrete entities with distinct endogenous ligands, the two receptor classes apparently have several common features. While the catecholamines stimulate alpha 2-adrenoceptors but not imidazoline receptors, agmatine, a guanidine analog that may be an endogenous imidazoline receptor ligand, can interact with both I1 and I2 imidazoline receptors as well as alpha 2-adrenoceptors, although, interestingly, other guanidines such as guanabenz are highly selective for alpha 2-adrenoceptors versus I1 receptors. Most I1 receptor agonists such as moxonidine, rilmenidine, and clonidine can also stimulate alpha 2-adrenoceptors, and the same physiological response is produced by activation of central I1 receptors and alpha 2-adrenoceptors, but their anatomical locations differ. The imidazoline idazoxan is an antagonist at I1, I2, and alpha 2-receptors, but minor structural alterations of idazoxan can result in molecules with selectivity for either alpha 2-adrenoceptors or imidazoline receptors. The precise mode of interaction of imidazoline agonists and antagonists with the alpha 2-adrenoceptor is not yet understood, and structures of the imidazoline receptors are still unknown. Nevertheless, the fact that many agents can stimulate or block both receptor classes, combined with the fact that alpha 2-adrenoceptors and I1 receptors can mediate identical physiological responses, suggests that many common structural features may be present.

Animals↗
PubMed1995

Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection.

Carvedilol is a vasodilating, beta-adrenoceptor antagonist currently marketed for the treatment of mild to moderate hypertension. Carvedilol acts to reduce total peripheral resistance by blocking peripheral vascular alpha 1-adrenoceptors, thereby producing systemic arterial vasodilation, while at the same time inhibiting reflex tachycardia through the blockade of myocardial beta-adrenoceptors. In addition to its established efficacy and safety as an antihypertensive agent, carvedilol has been shown to produce significant cardioprotection in experimental animal models of acute myocardial infarction, with the most dramatic effect being observed in the pig model of myocardial ischaemia and reperfusion, where the reduction in infarct size reached 91%. Recent pharmacological studies have revealed additional novel properties of carvedilol which may account for the marked protection produced by the drug in the ischaemic myocardium and which may also result in protection against other chronic pathological processes, such as atherosclerosis and acute vascular injuries. The latter arise from surgical procedures, such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Specifically, carvedilol, as well as some of its hydroxylated metabolites, are potent antioxidants. In physicochemical, biochemical and cellular assays, carvedilol and several of its metabolites prevent lipid peroxidation and the depletion of endogenous antioxidants, such as vitamin E and glutathione. Moreover, carvedilol and its metabolites prevent the oxidation of LDL to oxidized LDL, the latter being directly cytotoxic and known to activate monocytes/macrophages and to stimulate foam cell formation. In addition, carvedilol was found to inhibit both rat and human vascular smooth muscle cell proliferation and migration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1995

Cardioprotection and thrombolysis by anistreplase in anesthetized dogs.

Anistreplase is a thrombolytic agent comprising a complex of streptokinase, lys-plasminogen, and a p-anisoyl group, which temporarily protects the catalytic center of the enzyme complex. Streptokinase was previously shown to reduce infarct size (IS) in dogs with a fibrin-rich clot in the left anterior descending coronary artery (LAD) without necessarily producing reperfusion. Therefore, we hypothesized that IS in this model would be reduced by anistreplase. In addition, we studied the effect of tissue-type plasminogen activator (t-PA) on IS, testing our hypothesis in anesthetized dogs in which thrombin (100 U) and calcium (50 microliters, 0.05 M) were sequentially injected into the LAD to form a thrombus, anistreplase [0.01, 0.05, or 0.10 U/kg intravenous (i.v.) bolus], t-PA (0.1, 0.5, 2, or 8 micrograms/kg/min infusion for 60 min) or vehicle (VEH) was administered 55 min later. Anistreplase (0.05 or 0.10 U/kg) significantly (p < 0.05) reduced clot weight (VEH 22 +/- 3 mg; anistreplase 0.05 U/kg, 13 +/- 4 mg; anistreplase 0.10 U/kg, 0.7 +/- 0.6 mg), increased incidence of reperfusion (VEH 0%; anistreplase 0.05 U/kg, 42%; anistreplase 0.10 U/kg, 100%) and reduced IS (VEH 23 +/- 3%; anistreplase, 0.05 U/kg, 14 +/- 2%; anistreplase 0.10 U/kg, 15 +/- 2%). t-PA reduced thrombin weight (VEH 26 +/- 3 mg; 2 micrograms/kg/min t-PA 12 +/- 4; 8 micrograms/kg/min t-PA 2 +/- 2 mg) and increased incidence of reperfusion (VEH 0%; 2 micrograms/kg/min 75%; 8 micrograms/kg/min 100%), but IS was not altered (VEH 19 +/- 3%; 0.1 microgram/kg/min 18 +/- 3%; 0.5 microgram/kg/min 23 +/- 2%; 2 micrograms/kg/min 16 +/- 5%; 8 micrograms/kg/min: 19 +/- 3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1995

Vascular alpha-adrenoceptors: from the gene to the human.

Adrenoceptors can be subdivided into three major types, the alpha 1-, alpha 2-, and beta-adrenoceptors. Each of these types can be further subdivided into three subtypes, based on pharmacological characteristics. Molecular cloning techniques have supported this subclassification. Recent data now suggest that alpha-adrenoceptor subtypes identified by pharmacological and molecular techniques correspond well, although species orthologs of several adrenoceptor subtypes have been identified. The secondary structure of the adrenoceptors has been elucidated and correlated with their interaction with second messenger molecules. alpha 1-Adrenoceptors, beta-adrenoceptors, and alpha 2-adrenoceptors mediate their actions through stimulation of inositol phosphate release, stimulation of adenylate cyclase, and inhibition of adenylate cyclase, respectively. Site-directed mutagenesis and the preparation of chimeric receptors have located the site of receptor--second messenger interaction to the third intracellular loop for each of these adrenoceptors. While subtypes of each of these classes all interact with the same second messenger, studies with recombinant alpha 2-adrenoceptors show subtype-related differences in receptor--second messenger interaction. Multiple alpha-adrenoceptor subtypes are expressed in vascular smooth muscle and are involved in various aspects of blood vessel function, including contraction, cellular growth, and proliferation. Various physiological factors can selectively influence responses to a particular subtype, and the relative roles of each subtype can vary between vascular beds and along an individual blood vessel as its caliber changes. Functional studies in blood vessels suggest the presence of additional alpha-adrenoceptor subtypes not yet identified via molecular techniques. Optimization of the therapeutic profile of an alpha-adrenoceptor antagonist may be possible via enhancement of selectivity for a particular subtype or by design of a specific profile of affinity for the individual subtypes.

Animals↗
PubMed1995

Carvedilol, a new beta-adrenoreceptor blocker, vasodilator and free-radical scavenger, exerts an anti-shock and endothelial protective effect in rat splanchnic ischemia and reperfusion.

Splanchnic artery occlusion (SAO) followed by reperfusion results in circulatory shock in which oxygen-derived free radicals play an important role. Carvedilol, a novel beta adrenoceptor antagonist and a vasodilator, has been recently shown to exert potent antioxidant effects in multiple cell model systems. In the present experiment, we investigated the effect of carvedilol on SAO shock. Pentobarbital-anesthetized rats were subjected to 60 min of SAO followed by 120 min of reperfusion. Administration of 1 mg/kg carvedilol 10 min before reperfusion prolonged survival time (P < .05) and attenuated the increases in tissue myeloperoxidase activities (P < .01) and hematocrits (P < .001). Moreover, carvedilol significantly preserved superior mesenteric artery endothelial function (P < .01). Similar protection was seen in SAO shock rats treated with the superoxide free-radical scavenger superoxide dismutase. Except for a moderate attenuation of an increase in hematocrits, protective effects were not seen in SAO shock rats treated with the prototypic beta blocker propranolol. These results indicate that in murine SAO shock, carvedilol affords significant protection, which may be achieved through maintenance of tissue blood perfusion, quenching of oxygen free radicals, preservation of vascular endothelial function, and inhibition of neutrophil-endothelial interaction and its resultant increased microvascular permeability.

Adrenergic beta-Antagonists↗
PubMed1995

Electrophysiological effect of BRL-32872, a novel antiarrhythmic agent with potassium and calcium channel blocking properties, in guinea pig cardiac isolated preparations.

The effects of N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyl) ethyl] propyl]-4-nitrobenzamide hydrochloride (BRL-32872), a novel antiarrhythmic agent, were studied in guinea pig cardiac preparations using standard microelectrode and patch-clamp techniques. In papillary muscle, BRL-32872 did not change resting membrane potential and maximum rate of depolarization but prolonged action potential duration (APD) by 24% +/- 2% at 1.0 microM. When the concentration was increased to 3.0 and 10.0 microM, the effect on APD was not further enhanced, and a bell-shaped dose-response curve resulted. Patch-clamp experiments in isolated myocytes showed that BRL-32872 inhibited the rapidly activating component of the delayed rectifier potassium current (EC50 = 0.028 microM) and the L-type calcium current (EC50 = 2.8 microM) but had a limited effect on the inward rectifier potassium current. In papillary muscles stimulated at 300, 500, 1000 and 2000 msec, the effect of BRL-32872 in prolonging APD did not vary (P = .717). By contrast, N-(4-(1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl)- carbonyl]phenyl)methanesulfonamide dihydrochloride dihydrate (E-4031), a pure class III antiarrhythmic agent, increased APD more at slower than at faster stimulation rates (P = .001), which illustrated the reverse frequency-dependence of this agent. Among the 35 experiments performed with BRL-32872, only one fiber showed early afterdepolarizations (EADs), and these, which occurred at 1.0 microM, were suppressed at higher concentration (3.0 microM). Moreover, EADs induced by E-4031 were suppressed by BRL-32872 (3.0 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗