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

Abstract

Background— This study tested the hypothesis that β 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 β 1 -receptor blockade (RB; extended-release metoprolol succinate, 100 mg QD; MR+β 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+β 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+β 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+β 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+β 1 -RB dogs. Conclusions— β 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.