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₁-Adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog

¹Auburn University of Veterinary Medicine, Auburn, Alabama; ²Department of Pharmacology, East Tennessee State University, Johnson City, Tennessee; ³Center for Heart Failure Research, Departments of Medicine and Physiology and Biophysics, ⁴Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; and ⁵Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada

Submitted 6 September 2005 ; accepted in final form 25 January 2006

Mitral regurgitation (MR) is associated with increased neuronal release of norepinephrine (NE) and epinephrine (EP) into myocardial interstitial fluid (ISF) that may be necessary in sustaining left ventricular (LV) function via activation of cardiomyocyte -adrenergic receptors (ARs). However, activation of neuronal -ARs on cardiac neurons may lead to further catecholamine release, with an attendant risk of functional deterioration. We hypothesize that a beneficial effect of -AR blockade may therefore mitigate excessive catecholamine release from cardiac adrenergic neurons in dogs with MR. We measured the effects of chronic -receptor blockade (-RB) on ISF NE and EP release using in vivo microdialysis in open-chest anesthetized dogs after 4 wk of MR with or without extended release of metoprolol succinate (100 mg/day) as well as in control dogs. Fractional shortening increased by 30% in both MR and MR + -RB dogs after 4 wk of MR. In MR + -RB dogs, stellate-stimulated heart rate change was attenuated compared with control and MR dogs, whereas peak change of LV pressure over time (+dP/dt) increased equally in all groups. Stellate-stimulated ISF NE increased fivefold over baseline in MR versus twofold in control dogs (<0.05), but the NE release was significantly attenuated in MR + -RB dogs. In contrast, stellate-stimulated increases in ISF EP did not differ in control, MR, and MR + -RB dogs. This study demonstrates that -RB attenuates ISF NE release from cardiac neurons and that the LV functional response to MR is not dependent on an excess increase in ISF NE. Thus ₁-RB may exert a beneficial effect by attenuating untoward effects of excessive sympathetic efferent neural NE release while sustaining early LV functional adaptation to MR.

interstitial fluid; epinephrine

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