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Eliot H Ohlstein - One of the best experts on this subject based on the ideXlab platform.
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In Vitro and In Vivo Characterization of Intrinsic Sympathomimetic Activity in Normal and Heart Failure Rats
2016Co-Authors: Robert N Willette, Nambi Aiyar, Eliot H Ohlstein, Tianli Yue, Marcus P Mitchell, Jyoti Disa, Barbara L Storer, Diane Naselsky, Jeffery M Stadel, Robert R RuffoloAbstract:Clinical studies conducted with carvedilol suggest that b-adre-noceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many b-adrenoceptor antagonists are weak partial agonists and possess significant Intrinsic Sympathomimetic Activity (ISA), which may be prob-lematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyo-cytes. At equieffective b1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffec-tive, and dose-related increase in heart rate in both pithed SD rats (ED50 5 5 and 40 mg/kg, respectively) and SHHF rats (ED5
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bucindolol displays Intrinsic Sympathomimetic Activity in human myocardium
Circulation, 2002Co-Authors: Peter Andreka, Nambi Aiyar, L Olson, Jian Qin Wei, Mark S Turner, Keith A Webster, Eliot H Ohlstein, Nanette H BishopricAbstract:Background— Most clinical studies have shown that β-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective β-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist Activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium. Methods and Results— Myocardial strips (≈1 mm3) obtained from rat and nonfailing human hearts were confirmed to be viable for ≥48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to β-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full β-adrenergic agonist isoproterenol raised cAMP levels by >2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP leve...
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in vitro and in vivo characterization of Intrinsic Sympathomimetic Activity in normal and heart failure rats
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Robert N Willette, Nambi Aiyar, Eliot H Ohlstein, Tianli Yue, Marcus P Mitchell, Jyoti Disa, Barbara L Storer, Diane Naselsky, Jeffery M Stadel, Robert R RuffoloAbstract:Clinical studies conducted with carvedilol suggest that β-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many β-adrenoceptor antagonists are weak partial agonists and possess significant Intrinsic Sympathomimetic Activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective β1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED50 = 5 and 40 μg/kg, respectively) and SHHF rats (ED50 = 6 and 30 μg/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast, carvedilol and bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by xamoterol and bucindolol was inhibited by treatment with propranolol, carvedilol, and betaxolol (β1-adrenoceptor antagonist) but not by ICI 118551 (β2-adrenoceptor antagonist) in neonatal rat. When the β-adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast, GTP-sensitive ligand binding and tissue adenylate cyclase Activity were not sensitive methods for detecting β-adrenoceptor partial agonist Activity in the heart. In summary, xamoterol and bucindolol, but not carvedilol and bisoprolol, exhibited direct β1-adrenoceptor-mediated ISA in normal and heart failure rats.
Nambi Aiyar - One of the best experts on this subject based on the ideXlab platform.
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In Vitro and In Vivo Characterization of Intrinsic Sympathomimetic Activity in Normal and Heart Failure Rats
2016Co-Authors: Robert N Willette, Nambi Aiyar, Eliot H Ohlstein, Tianli Yue, Marcus P Mitchell, Jyoti Disa, Barbara L Storer, Diane Naselsky, Jeffery M Stadel, Robert R RuffoloAbstract:Clinical studies conducted with carvedilol suggest that b-adre-noceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many b-adrenoceptor antagonists are weak partial agonists and possess significant Intrinsic Sympathomimetic Activity (ISA), which may be prob-lematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyo-cytes. At equieffective b1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffec-tive, and dose-related increase in heart rate in both pithed SD rats (ED50 5 5 and 40 mg/kg, respectively) and SHHF rats (ED5
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bucindolol displays Intrinsic Sympathomimetic Activity in human myocardium
Circulation, 2002Co-Authors: Peter Andreka, Nambi Aiyar, L Olson, Jian Qin Wei, Mark S Turner, Keith A Webster, Eliot H Ohlstein, Nanette H BishopricAbstract:Background— Most clinical studies have shown that β-adrenergic receptor antagonists improve long-term survival in heart failure patients. Bucindolol, a nonselective β-receptor blocker, however, failed to reduce heart failure mortality in a recent large clinical trial. The reasons for this failure are not known. Bucindolol has partial agonist properties in rat myocardium, but whether it has agonist Activity in human heart is controversial. To address this, we measured the ability of bucindolol to increase cAMP accumulation in human myocardium. Methods and Results— Myocardial strips (≈1 mm3) obtained from rat and nonfailing human hearts were confirmed to be viable for ≥48 hours in normoxic tissue culture by MTT assay and histology. Freshly isolated strips were exposed to β-adrenergic antagonists and agonists and assayed for cAMP. In both rat and human strips, the full β-adrenergic agonist isoproterenol raised cAMP levels by >2.5-fold at 15 minutes. Carvedilol and propranolol had no effect on basal cAMP leve...
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in vitro and in vivo characterization of Intrinsic Sympathomimetic Activity in normal and heart failure rats
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Robert N Willette, Nambi Aiyar, Eliot H Ohlstein, Tianli Yue, Marcus P Mitchell, Jyoti Disa, Barbara L Storer, Diane Naselsky, Jeffery M Stadel, Robert R RuffoloAbstract:Clinical studies conducted with carvedilol suggest that β-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many β-adrenoceptor antagonists are weak partial agonists and possess significant Intrinsic Sympathomimetic Activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective β1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED50 = 5 and 40 μg/kg, respectively) and SHHF rats (ED50 = 6 and 30 μg/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast, carvedilol and bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by xamoterol and bucindolol was inhibited by treatment with propranolol, carvedilol, and betaxolol (β1-adrenoceptor antagonist) but not by ICI 118551 (β2-adrenoceptor antagonist) in neonatal rat. When the β-adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast, GTP-sensitive ligand binding and tissue adenylate cyclase Activity were not sensitive methods for detecting β-adrenoceptor partial agonist Activity in the heart. In summary, xamoterol and bucindolol, but not carvedilol and bisoprolol, exhibited direct β1-adrenoceptor-mediated ISA in normal and heart failure rats.
Robert H. G. Schwinger - One of the best experts on this subject based on the ideXlab platform.
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Bucindolol exerts agonistic Activity on the propranolol-insensitive state of β-adrenoceptors in human myocardium
2002Co-Authors: Andreas Bundkirchen, Klara Brixius, Robert H. G. SchwingerAbstract:In congestive heart failure patients, treatment with -adreno-ceptor antagonists improves symptoms and decreases mortal-ity. However, Intrinsic Sympathomimetic Activity of -adreno-ceptor antagonists might be disadvantageous in chronic heart failure. The nonselective 1- and 2-adrenoceptor antagonist bucindolol has failed to decrease mortality in clinical trials. A putative 4-adrenoceptor, which mediates positive inotropic effects by activation of the adenylate cyclase has been de-scribed. Recently, this putative 4-adrenoceptor has been identified to be a propranolol-insensitive state of the 1-adre-noceptor. The present study aimed to characterize whether bucindolol exhibits agonistic Activity on this atypical 1-adre-noceptor state as one possible reason for clinical inefficiency. For comparison (S)-4-(3-t-butylamino-1-hydroxypropoxy)
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nebivolol bucindolol metoprolol and carvedilol are devoid of Intrinsic Sympathomimetic Activity in human myocardium
British Journal of Pharmacology, 2001Co-Authors: Klara Brixius, Andreas Bundkirchen, Birgit Bolck, Uwe Mehlhorn, Robert H. G. SchwingerAbstract:1. The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly beta(1)-selective adrenoceptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisoprolol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n=9). 2. The rank order of beta(1)-selectivity as judged by competition experiments to (3)H-CGP 12.1777 in the presence of CGP 207.12 A (300 nmol l(-1), K(i)beta(2)) or ICI 118.551 (50 nmol l(-1), K(i)beta(1)) were NEB(K(i)beta(2)/K(i)beta(1): 40.7) > BIS(15.6) > MET(4.23) > CAR(0.73) > BUC(0.49). 3. The rank order of the negative inotropic potency of the beta-adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 micromol l(-1))-stimulated force (IC(50)) was: MET (0.6 micromol l(-1)) > CAR (4.1 micromol l(-1)) > NEB (7.0 micromol l(-1)). 4. NEB, BUC, MET and CAR did not not exert an Intrinsic Sympathomimetic Activity (ISA) as determined by measurements of force development in forskolin (0.3 micromol l(-1)) pre-treated left ventricular trabeculae, nor by measuring adenylate cyclase Activity in forskolin (0.3 micromol l(-1))-stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl-5'-yl imidodiphosphate (Gpp(NH)p). 5. Although all studied beta-adrenoceptor antagonists lack Intrinsic Sympathomimetic Activity (ISA), they differ in the beta(1)-selectivity as well as in their direct negative inotropic action. These differences as well as the mode of extracardiac action may have an impact on outcome of patients treated with beta-adrenoceptor antagonists.
Robert R Ruffolo - One of the best experts on this subject based on the ideXlab platform.
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In Vitro and In Vivo Characterization of Intrinsic Sympathomimetic Activity in Normal and Heart Failure Rats
2016Co-Authors: Robert N Willette, Nambi Aiyar, Eliot H Ohlstein, Tianli Yue, Marcus P Mitchell, Jyoti Disa, Barbara L Storer, Diane Naselsky, Jeffery M Stadel, Robert R RuffoloAbstract:Clinical studies conducted with carvedilol suggest that b-adre-noceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many b-adrenoceptor antagonists are weak partial agonists and possess significant Intrinsic Sympathomimetic Activity (ISA), which may be prob-lematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyo-cytes. At equieffective b1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffec-tive, and dose-related increase in heart rate in both pithed SD rats (ED50 5 5 and 40 mg/kg, respectively) and SHHF rats (ED5
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in vitro and in vivo characterization of Intrinsic Sympathomimetic Activity in normal and heart failure rats
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Robert N Willette, Nambi Aiyar, Eliot H Ohlstein, Tianli Yue, Marcus P Mitchell, Jyoti Disa, Barbara L Storer, Diane Naselsky, Jeffery M Stadel, Robert R RuffoloAbstract:Clinical studies conducted with carvedilol suggest that β-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many β-adrenoceptor antagonists are weak partial agonists and possess significant Intrinsic Sympathomimetic Activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective β1-adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED50 = 5 and 40 μg/kg, respectively) and SHHF rats (ED50 = 6 and 30 μg/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast, carvedilol and bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by xamoterol and bucindolol was inhibited by treatment with propranolol, carvedilol, and betaxolol (β1-adrenoceptor antagonist) but not by ICI 118551 (β2-adrenoceptor antagonist) in neonatal rat. When the β-adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast, GTP-sensitive ligand binding and tissue adenylate cyclase Activity were not sensitive methods for detecting β-adrenoceptor partial agonist Activity in the heart. In summary, xamoterol and bucindolol, but not carvedilol and bisoprolol, exhibited direct β1-adrenoceptor-mediated ISA in normal and heart failure rats.
P Dorigo - One of the best experts on this subject based on the ideXlab platform.
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characterization of Intrinsic Sympathomimetic Activity of carteolol in rat cardiovascular preparations
Journal of Pharmacological Sciences, 2004Co-Authors: Maura Floreani, Guglielmina Froldi, Katia Varani, Maria Teresa Dorigo, Maurizio Cavalli, Maria Cecilia Giron, Stefania Gessi, Pier Andrea Borea, Sergio Bova, P DorigoAbstract:Abstract We evaluated in vitro, in myocardial and vascular preparations isolated from reserpine-treated rats, the Intrinsic Sympathomimetic Activity (ISA) of carteolol, a β1/β2-adrenoceptor blocking agent used in cardiovascular and non-cardiovascular diseases. In spontaneously beating atria, carteolol, at low concentrations (0.01 and 0.1 μM), antagonized the positive inotropic effect of isoprenaline, whereas at higher concentrations (1 μM to 1 mM), it caused an increase in the force of contraction (EC50: 4.6 ± 0.1 μM, Emax: 17.1 ± 1.1%, with respect to the maximum isoprenaline response) and a slight increase (7.8 ± 1.9% over basal values) in the heart rate. The positive inotropic effect of carteolol was abolished by concentrations of propranolol or timolol (10 μM) much higher than those blocking isoprenaline effects in the same preparations. A similar positive inotropic effect was also observed in electrically driven left atrium and in Langendorff perfused hearts. Functional and biochemical evidences supported the involvement of cAMP in the cardiac action of carteolol. In peripheral arteries (femoral and tail) pre-contracted with phenylephrine, carteolol exerted ISA-related relaxing effects, independent of the presence of endothelium and sensitive to high concentrations (10 μM) of conventional β-blockers. On the basis of these results, we propose to categorize carteolol as a non-conventional partial agonist of both cardiac and vascular β-adrenoceptors.
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Characterization of Intrinsic Sympathomimetic Activity of Carteolol in Rat Cardiovascular Preparations
'Japanese Pharmacological Society', 2004Co-Authors: Maura Floreani, Guglielmina Froldi, Katia Varani, Maurizio Cavalli, Stefania Gessi, Pier Andrea Borea, Bova Sergio, Giron, Maria Cecilia, Dorigo, Maria Teresa, P DorigoAbstract:Abstract: We evaluated in vitro, in myocardial and vascular preparations isolated from reserpine-treated rats, the Intrinsic Sympathomimetic Activity (ISA) of carteolol, a beta1/beta2-adrenoceptor blocking agent used in cardiovascular and non-cardiovascular diseases. In spontaneously beating atria, carteolol, at low concentrations (0.01 and 0.1 muM), antagonized the positive inotropic effect of isoprenaline, whereas at higher concentrations (1 muM to 1 mM), it caused an increase in the force of contraction (EC50: 4.6 +/- 0.1 muM, E-max: 17.1 +/- 1.1%, with respect to the maximum isoprenaline response) and a slight increase (7.8 +/- 1.9% over basal values) in the heart rate. The positive inotropic effect of carteolol was abolished by concentrations of propranolol or timolol (10 muM) much higher than those blocking isoprenaline effects in the same preparations. A similar positive inotropic effect was also observed in electrically driven left atrium and in Langendorff perfused hearts. Functional and biochemical evidences supported the involvement of cAMP in the cardiac action of carteolol. In peripheral arteries (femoral and tail) pre-contracted with phenylephrine, carteolol exerted ISA-related relaxing effects, independent of the presence of endothelium and sensitive to high concentrations (10 muM) of conventional beta-blockers. On the basis of these results, we propose to categorize carteolol as a non-conventional partial agonist of both cardiac and vascular beta-adrenoceptors
