Brain "ouabain" and angiotensin II contribute to cardiac dysfunction after myocardial infarction. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H1786-H1792, 1999.-In chronic heart failure (CHF), sympathetic activity increases in parallel with the impairment of left ventricle (LV) function, and sympathetic hyperactivity has been postulated to contribute to the progression of heart failure. In the brain, compounds with ouabain-like activity ("ouabain," for brevity) and the renin-angiotensin

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... m contribute to sympathetic hyperactivity in rats with CHF after myocardial infarction (MI). In the present studies, we assessed whether, in rats, chronic blockade of brain "ouabain" or the brain renin-angiotensin system inhibits the post-MI LV dysfunction. In rats, an MI was induced by acute coronary artery ligation. At either 0.5 or 4 wk post-MI, chronic treatment with Fab fragments for blocking brain "ouabain" or with losartan for blocking brain AT 1 receptors was started and continued until 8 wk post-MI using osmotic minipumps connected to intracerebroventricular cannulas. At 8 wk post-MI, in conscious rats, LV pressures were measured at rest and in response to volume and pressure overload, followed by LV passive pressure-volume curves in vitro. At 8 wk post-MI, control MI rats exhibited clear increases in LV end-diastolic pressure (LVEDP) at rest and in response to pressure and volume overload. LV pressure-volume curves in vitro showed a marked shift to the right. Intravenous administration of the Fab fragments or losartan at rates used for central blockade did not affect these parameters. In contrast, chronic central blockade with either Fab fragments or losartan significantly lowered LVEDP at rest (only in 0.5-to 8-wk groups) and particularly in response to pressure or volume overload. LV dilation, as assessed from LV pressure-volume curves, was also significantly inhibited. These results indicate that chronic blockade of brain "ouabain" or brain AT 1 receptors substantially inhibits development of LV dilation and dysfunction in rats post-MI. heart; heart failure; left ventricle dilation; ouabain; reninangiotensin system IN BOTH ANIMALS AND HUMANS, the progressive remodeling of the left ventricle (LV) after a myocardial infarction (MI) leads to increases in LV end-diastolic and end-systolic volume and pressure and decreases in ejection fraction and cardiac output and clinical chronic heart failure (CHF), with the extent and time course of the changes depending on the size of the MI (11, 18, 24) . Stimuli for cardiac remodeling after a MI include increases in diastolic wall stress and (to a lesser extent) systolic wall stress (2). In addition, progressive in-creases in the activity of the circulatory and/or cardiac tissue renin-angiotensin system (RAS) and in sympathetic activity may further increase wall stress and may cause direct adverse effects on the heart. In CHF, parameters of sympathetic activity increase in parallel with the impairment of cardiac performance (5, 14, 20) , and sympathetic hyperactivity has been postulated to contribute to the progression of heart failure (15). Studies on the possible role of sympathetic hyperactivity in disease progression in CHF have used tools such as ␤-blockers (7, 10), and the results are consistent with the neurohormonal hypothesis (15). Recent studies in the putative central mechanisms mediating sympathetic hyperactivity in CHF suggest that, in the brain, both compounds with ouabain-like structure (in this paper called "ouabain") and the RAS play a major role. In the brain, inhibition of the Na ϩ -K ϩ -ATPase enzyme by steroids closely related to ouabain causes sympathoexcitation (8). In rats with post-MI LV dysfunction, ouabain-like activity increases about twofold in the hypothalamus (12), and blockade of brain "ouabain" prevents/reverses sympathetic hyperactivity (12) and the impairment of baroreflex function (9). The brain RAS is also involved in the regulation of sympathetic activity and baroreflex function (19). Recent studies indicate that the brain RAS plays a pivotal role in the sympathetic hyperactivity associated with salt-sensitive hypertension (23) and heart failure. In rats with post-MI LV dysfunction, blockade of the brain RAS reverses sympathetic hyperactivity (4, 25) and impairment of arterial baroreflex function (4, 25). In the present studies, we assessed whether chronic blockade of brain "ouabain" or the brain RAS can inhibit the progressive remodeling of the LV and the LV dysfunction in rats post-MI. Central infusion of antibody Fab fragments (Digibind) that bind in vivo and in vitro ouabain and related steroids, such as brain "ouabain," with high affinity (1, 12) was employed for chronic blockade of brain "ouabain." For blockade of the brain RAS, central infusions of the AT 1 receptor blocker losartan were employed. The results indicate that central blockade by the Fab fragments or losartan indeed can significantly blunt the LV dilation and decrease in cardiac function in rats post-MI. METHODS Male Wistar rats (Charles River Breeding Laboratories, Montreal, Canada), weighing 250-300 g, were housed on a 12:12-h light-dark cycle and were given regular rat chow and tap water. All procedures were carried out according to the guidelines of the University of Ottawa Animal Care Committee for the use and care of laboratory animals. After a 5-day acclimatization period, coronary artery ligation was performed as described by Pfeffer et al. (17). Briefly, after the animals were anesthetized with 1.0% halothane in oxygen The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.