Brain "ouabain" and angiotensin II contribute to cardiac dysfunction aftermyocardial infarction

In chronic heart failure (CHF), sympathetic activity increases in parallel with the impairment of left ventricle (LV) function, and sympathetic hypera ctivity has been postulated to contribute to the progression of heart failu re. In the brain, compounds with ouabain-like activity ("ouabain," for brev ity) and the renin-angiotensin system contribute to sympathetic hyperactivi ty in rats with CHF after myocardial infarction (MI). In the present studie s, we assessed whether, in rats, chronic blockade of brain "ouabain" or the brain renin-angiotensin system inhibits the post-MI LV dysfunction. In rat s, 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 "ouabai n" or with losartan for blocking brain AT(1) receptors was started and cont inued until 8 wk post-MI using osmotic minipumps connected to intracerebrov entricular 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 a ffect these parameters. In contrast, chronic central blockade with either F ab 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 signifi cantly inhibited. These results indicate that chronic blockade of brain "ou abain" or brain AT(1) receptors substantially inhibits development of LV di lation and dysfunction in rats post-MI.