Published online before print February 5, 2004, doi: 10.1161/01.RES.0000120864.21172.5A
© 2004 American Heart Association, Inc.
Integrative Physiology |
Prevention of Sympathetic and Cardiac Dysfunction After Myocardial Infarction in Transgenic Rats Deficient in Brain Angiotensinogen
From the Hypertension Unit (H.W., B.S.H., F.H.H.L.), University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Max-Delbruck Centre for Molecular Medicine (D.G.), Berlin-Buch, Germany.
Correspondence to Frans H.H. Leenen, MD, PhD, Hypertension Unit, University of Ottawa Heart Institute, H360, 40 Ruskin St, Ottawa, Ontario, Canada K1Y 4W7. E-mail fleenen{at}ottawaheart.ca
To provide evidence for the role of angiotensin II locally produced in the brain in the development of sympathetic hyperactivity and heart failure after myocardial infarction (MI), transgenic rats (TGR) were used, which express an antisense RNA against angiotensinogen. In TGR and control Sprague-Dawley (SD) rats, an MI was induced by acute coronary artery ligation. At 8 weeks after MI, MI sizes were similar in TGR and SD rats. In the groups with MI 
25% of left ventricle (LV), LV peak systolic pressure decreased in SD rats but not in TGR. LV end-diastolic pressure increased substantially more in SD-MI than TGR-MI rats (from 2±1 to 15±2 mm Hg, and 2±1 to 8±1 mm Hg, respectively; P<0.05). LV dP/dtmax decreased from 
5400 to 3573±187 in SD-MI rats, but only to 4353±180 mm Hg/sec in TGR-MI (P<0.05). LV pressure volume curves in vitro showed a marked shift to the right in SD-MI rats. This shift was significantly attenuated by –70% in TGR versus SD rats with MI. Both RV weight and interstitial fibrosis in the LV increased clearly in the SD-MI rats, but not or significantly less in the TGR-MI rats. In SD-MI rats, arterial baroreflex control of heart rate and renal sympathetic nerve activity was markedly impaired but was not affected in the TGR-MI. Plasma angiotensin II levels tended to be higher in SD versus TGR rats, both in sham and MI-groups. This study provides the major new finding that in rats after MI, angiotensin II locally produced in the brain plays a dominant role in the development of LV dysfunction after MI, possibly through its effects on sympathetic function and on circulatory/cardiac renin-angiotensin system.
Key Words: angiotensin • brain • cardiac remodeling • left ventricular dysfunction • arterial baroreflex
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