Beta1-adrenergic receptor blockade attenuates angiotensin II-mediated catecholamine release into the cardiac interstitium in mitral regurgitation.
BACKGROUND
This study tested the hypothesis that beta1-adrenoreceptor blockade modulates the angiotensin II (Ang II)-evoked neural release of norepinephrine (NE) and epinephrine (Epi) into the cardiac interstitial fluid (ISF) space in experimentally induced mitral regurgitation (MR) in the dog.


RESULTS
Normal dogs (n=8) were compared with dogs with MR of 2 (n=8) and 4 (n=6) weeks' duration and with dogs with MR treated with beta1-receptor blockade (RB; extended-release metoprolol succinate, 100 mg QD; MR+beta1-RB) that was started 24 hours after MR induction for 2 (n=6) and 4 weeks (n=8). Left ventricular end-diastolic dimension increased 20% as plasma Ang II levels increased >5-fold in both MR and MR+beta1-RB dogs at 2 and 4 weeks. Ang II infusion into the left atrium produced increases in ISF NE and Epi in normal dogs, which were further increased in 2- and 4-week MR dogs but were restored to normal in 4-week MR+beta1-RB dogs. Ang II infusion produced 4-fold increases in circulating NE and Epi in 2- and 4-week MR dogs that returned to normal in 4-week+beta1-RB dogs. Left ventricular angiotensin-converting enzyme activity and ISF Ang II were increased in 4-week MR dogs but were decreased in 4-week MR+beta1-RB dogs.


CONCLUSIONS
beta1-RB decreases renin-angiotensin system sympathostimulation and activation by attenuating the Ang II-mediated NE and Epi release into the cardiac ISF and circulation and by decreasing left ventricular angiotensin-converting enzyme expression in the early phases of volume overload.
Tallaj
José
J
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Wei
Chih-Chang
CC
Hankes
Gerald H
GH
Holland
Merrilee
M
Rynders
Patricia
P
Dillon
A Ray
AR
Ardell
Jeffrey L
JL
Armour
J Andrew
JA
Lucchesi
Pamela A
PA
Dell'Italia
Louis J
LJ
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004333:Drug Administration Routes; D004837:Epinephrine / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000294:innervation / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008790:Metoprolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008944:Mitral Valve Insufficiency / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D000804:Angiotensin II; D003094:Collagen; D008790:Metoprolol; D009638:Norepinephrine; D004837:Epinephrine