PRECLINICAL STUDIES
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, MD,
Indu Poornima, MD,
Pratik Parikh, MD,
Megan Magovern,
You-Tang Shen, MD and
Richard P. Shannon, MD, FACC*
Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania
Manuscript received February 3, 2005;
revised manuscript received November 28, 2005,
accepted November 30, 2005.
* Reprint requests and correspondence: Dr. Richard P. Shannon, Department of Medicine, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, Pennsylvania 15212 (Email: rshannon{at}wpahs.org).
OBJECTIVES: Given that adverse effects of chronic sympathetic activation are mediated by all three adrenergic receptor subtypes (ß1, ß2,  1), 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.
BACKGROUND: Both ß1 selective 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.
METHODS: Thirty-three conscious, chronically instrumented dogs with pacing-induced (240 min–1 for 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.
RESULTS: 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.
CONCLUSIONS: 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.
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Abbreviations and Acronyms
| | ANOVA = analysis of variance | | cAMP = cyclic adenine monophosphate | | COMET = Carvedilol Or Metoprolol European Trial | | CR/XL = controlled release/extended release | | DCM = dilated cardiomyopathy | | dP/dt = derivative of pressure with time | | GTP/Iso = guanine triphosphate/isoproterenol | | LV = left ventricular | | LVEDP = left ventricular end-diastolic pressure | | MVO2 = myocardial oxygen consumption | | NE = norepinephrine | | NEFA = nonesterified fatty acids | | SVR = systemic vascular resistance |
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