title: Beta1-adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog.
abstract: 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 beta-adrenergic receptors (ARs). However, activation of neuronal beta-ARs on cardiac neurons may lead to further catecholamine release, with an attendant risk of functional deterioration. We hypothesize that a beneficial effect of beta-AR blockade may therefore mitigate excessive catecholamine release from cardiac adrenergic neurons in dogs with MR. We measured the effects of chronic beta-receptor blockade (beta-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 + beta-RB dogs after 4 wk of MR. In MR + beta-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 + beta-RB dogs. In contrast, stellate-stimulated increases in ISF EP did not differ in control, MR, and MR + beta-RB dogs. This study demonstrates that beta-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 beta1-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.
authors.affiliation: Auburn University of Veterinary Medicine, Auburn, Alabama, USA.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Hankes
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Ardell
authors.forename: José
authors.initials: J
authors.lastname: Tallaj
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Wei
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Aban
authors.forename: Merrilee
authors.initials: M
authors.lastname: Holland
authors.forename: Patricia
authors.initials: P
authors.lastname: Rynders
authors.forename: Ray
authors.initials: R
authors.lastname: Dillon
authors.forename: Rene
authors.initials: R
authors.lastname: Cardinal
authors.forename: Donald B
authors.initials: DB
authors.lastname: Hoover
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Armour
authors.forename: Ahsan
authors.initials: A
authors.lastname: Husain
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000818:Animals; D004285:Dogs; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000031:analogs & derivatives; D008944:Mitral Valve Insufficiency / Q000378:metabolism* / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D008790:Metoprolol; D009638:Norepinephrine