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Am J Physiol Heart Circ Physiol (February 12, 2004). doi:10.1152/ajpheart.01045.2003
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Submitted on November 18, 2003
Accepted on February 6, 2004

Endogenous {beta}3-Adrenoceptor Activation Contributes to Left Ventricular and Cardiomyocyte Dysfunction in Heart Failure

Atsushi Morimoto1, Hiroshi Hasegawa1, Heng-Jie Cheng1, William C. Little1, and Che-Ping Cheng1*

1 Internal Medicine-Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, NC, USA

* To whom correspondence should be addressed. E-mail: ccheng{at}wfubmc.edu.

Objective: Test the hypothesis that endogenous {beta}3-adrenoreceptor (AR) activation contributes to left ventricular (LV) and cardiomyocyte dysfunction in heart failure (CHF). Background: Stimulation of {beta}3-AR inhibits cardiac contraction. In the failing myocardium, {beta}3-ARs are upregulated, suggesting that stimulation of {beta}3-ARs may contribute to depressed cardiac performance in CHF. Methods and Results: We assessed the functional significance of endogenous {beta}3-AR activation in 10 conscious dogs, before and after pacing-induced CHF. Under normal conditions, L-748,337, a specific {beta}3-AR antagonist, produced a mild increase in LV contractile performance assessed by the slope (EES) of LV pressure (P)-volume (V) relation (18%, 6.2±0.9 vs 7.3±1.2 mm Hg/ml, p<0.05) and improved LV relaxation time constant ({tau}) (28.4±1.9 vs 26.8±1.0 ms, p<0.05). After CHF, plasma norepinephrine concentration increased 8 fold, and L-748,337 produced larger increase in EES (34%, 3.8±0.7 vs 5.1±0.8 mm Hg/ml, p<0.05) and greater decrease in {tau}(46.4±4.2 vs 41.0±3.9 ms, p<0.05). Similar responses were observed in isolated myocytes harvested from LV biopsies before and after CHF. In the normal myocyte, L-748,337 did not cause significant changes in contraction or relengthening. In contrast, in CHF myocytes, L-748,337 produced significant increases in contraction (5.8±0.9 vs 6.8±0.9%, p<0.05) and relengthening (33.5±4.2 vs 39.7±4.0 µm/s, p<0.05). The L-748,337-induced myocyte response was associated with improved [Ca2+]i regulation. In the CHF myocytes, nadolol caused a decrease in contraction and relengthening, and adding isoproterenol to nadolol caused a further depression of myocyte function.




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