Published Online
on July 7, 2003

A more recent version of this article appeared on July 15, 2003

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Submitted on February 6, 2003
Revised on March 20, 2003
Accepted on March 26, 2003

₁-Adrenergic Receptor Blockade Attenuates Angiotensin II-Mediated Catecholamine Release Into the Cardiac Interstitium in Mitral Regurgitation

José Tallaj MD, Chih-Chang Wei PhD, Gerald H. Hankes DVM, PhD, Merrilee Holland DVM, Patricia Rynders DVM, A. Ray Dillon DVM, Jeffrey L. Ardell PhD, J. Andrew Armour MD, PhD, Pamela A. Lucchesi PhD, and Louis J. Dell'Italia MD^*

From the Department of Medicine (J.T., C.-C.W., P.A.L., L.J.D.), Division of Cardiovascular Disease, Department of Veterans Affairs (L.J.D.), University of Alabama at Birmingham; College of Veterinary Medicine (G.H.H., M.H., P.R., A.R.D.), Auburn University, Auburn, Ala; the Department of Pharmacology (J.L.A.), East Tennessee State University, Johnson City, Tenn; and the Department of Pharmacology (J.A.A.), University of Montreal, Montreal, Quebec, Canada.

^* To whom correspondence should be addressed. E-mail: dell'italia{at}physiology.uab.edu.

Background--This study tested the hypothesis that ₁-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.

Methods and 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 ₁-receptor blockade (RB; extended-release metoprolol succinate, 100 mg QD; MR+₁-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+₁-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+₁-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+₁-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+₁-RB dogs.

Conclusions--₁-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.

Key words: angiotensin • nervous system, autonomic • receptors, adrenergic, beta • heart failure • renin

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