The Effects of Combined Versus Selective Adrenergic Blockade on Left Ventricular and Systemic Hemodynamics, Myocardial Substrate Preference, and Regional Perfusion in Conscious Dogs With Dilated Cardiomyopathy

• Published in: Journal of the American College of Cardiology Vol. 47; no. 9; pp. 1871 - 1881
• Main Authors: Nikolaidis, Lazaros A., Poornima, Indu, Parikh, Pratik, Magovern, Megan, Shen, You-Tang, Shannon, Richard P.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 02.05.2006; Elsevier Science; Elsevier Limited
• Subjects: Adrenergic Antagonists - therapeutic use; Adrenergic beta-Agonists - pharmacology; Animals; Biological and medical sciences; Carbazoles - therapeutic use; Cardiology; Cardiology. Vascular system; Cardiomyopathy; Cardiomyopathy, Dilated - drug therapy; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - physiopathology; Dogs; Fatty acids; Heart; Heart rate; Heart Rate - drug effects; Hemodynamics - drug effects; Isoproterenol - pharmacology; Laboratory animals; Medical sciences; Metoprolol - analogs & derivatives; Metoprolol - therapeutic use; Mortality; Myocarditis. Cardiomyopathies; Myocardium - metabolism; Plasma; Propanolamines - therapeutic use; Regional Blood Flow - drug effects; Rodents; Ventricular Function, Left - drug effects; CR/XL; COMET; Mvo2; LV; cAMP; SVR; DCM; LVEDP; ANOVA; dP/dt; GTP/Iso; NEFA; NE; Regional perfusion; Fissipedia; Carnivora; Cardiovascular disease; Systemic; Myocardial disease; Phlebology; Left ventricle; Substrate; Vertebrata; Mammalia; Congestive hypertrophic cardiomyopathy; Preference; Heart disease; Animal; Circulatory system; Disseminated; Hemodynamics; Cardiology; Dog; Comparative study
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2005.11.082

The Effects of Combined Versus Selective Adrenergic Blockade on Left Ventricular and Systemic Hemodynamics, Myocardial Substrate Preference, and Regional Perfusion in Conscious Dogs With Dilated Cardiomyopathy Lazaros A. Nikolaidis, Indu Poornima, Pratik Parikh, Megan Magovern, You-Tang Shen, Richard P. Shannon We investigated the effects of therapeutic doses of carvedilol versus metoprolol succinate controlled release/extended release in conscious dogs with severe dilated cardiomyopathy. Carvedilol showed more pronounced salutary effects on left ventricular hemodynamics and systemic flow to the kidneys, liver, and skeletal muscle. In addition, carvedilol attenuated neurohormonal activation and improved myocardial glucose uptake and substrate metabolism to a greater extent than metoprolol succinate. The metabolic differences were attributable to the β2- and α1-blocking properties of carvedilol. These mechanisms might provide plausible explanations for the advantages of combined versus selective adrenergic inhibition detected in the Carvedilol Or Metoprolol European Trial (COMET). Given that adverse effects of chronic sympathetic activation are mediated by all three adrenergic receptor subtypes (β1, β2, α1), we examined the effects of standard doses of carvedilol and metoprolol succinate (metoprolol controlled release/extended release [CR/XL]) on hemodynamics, myocardial metabolism, and regional organ perfusion. Both β1selective and combined adrenergic blockade reduce morbidity and mortality in heart failure. Whether there are advantages of one class over the other remains controversial, even in the wake of the Carvedilol Or Metoprolol European Trial (COMET). Similarly, the mechanistic basis for the relative differences is incompletely understood. Thirty-three conscious, chronically instrumented dogs with pacing-induced (240 min−1for 4 weeks) dilated cardiomyopathy (DCM) were randomized to carvedilol (25 mg twice daily, Coreg, Glaxo Smith Kline, Research Triangle, North Carolina) or metoprolol succinate (100 mg qd, Toprol XL, Astra Zeneca, Wilmington, Delaware). Left ventricular and systemic hemodynamics, myocardial substrate uptake, and norepinephrine spillover were measured before and after three days of treatment. Regional (renal, hepatic, skeletal muscle) blood flows were measured using neutron-activated microspheres. Both agents had comparable heart rate effects. However, carvedilol-treated dogs showed significantly greater increases in stroke volume and cardiac output and decreases in left ventricular end-diastolic pressure and systemic vascular resistance. Carvedilol increased renal, hepatic, and skeletal muscle blood flow. Carvedilol increased myocardial glucose uptake and suppressed norepinephrine and glucagon. Carvedilol antagonized the response to exogenous norepinephrine to a greater extent than metoprolol CR/XL. At doses inducing comparable heart rate reductions, short-term treatment with carvedilol had superior hemodynamic and metabolic effects compared with metoprolol CR/XL. These data suggest important advantages of blocking all three adrenergic receptor subtypes in DCM.