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1 Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
* To whom correspondence should be addressed. E-mail: fleenen{at}ottawaheart.ca.
In rats post-myocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoids receptors (MR). Stimulatory responses
to central infusion of aldosterone can be blocked by benzamil, and therefore appear to be mediated via Na+ channels, presumably ENaC, in the brain. To evaluate this concept for endogenous mineralocorticoids in Wistar rats post-MI, effects of blockade of MR and of
Na+ channels in the brain were examined. At 3 days after coronary artery ligation, intracerebroventricular (icv) infusions were started with spironolactone (400 ng/kg/h) or its vehicle, or benzamil (4 µg/kg/h) or its vehicle using osmotic minipumps. Rats with sham ligation served as control. After 4 weeks, in conscious rats, MAP, HR, renal sympathetic nerve activity (RSNA) were recorded at rest and in response to air-jet stress, icv injection of 
2-adrenoceptor agonist guanabenz, and iv infusion of phenyleprine and nitroprusside for baroreflex function. MI size was similar among the 4 groups of rats (~31%). In rats post-MI treated with vehicles, cardiac function was decreased (LVEDP up by 15 mmHg, LVPSP down by 32 mmHg, and LV dp/dtmax down by 2000 mmHg/sec), sympathetic reactivity enhanced (~120% increase in magnitudes of excitatory RSNA responses to air stress and inhibitory RSNA responses to guanabenz), and baroreflex function impaired (~35% decrease in maximal slope of reflex). Blockade of brain Na+ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function, and improved cardiac function (LVEDP only up by 5 mmHg, LVPSP only down by 12 mmHg, and LV dp/dtmax only down by 900 mmHg/sec). These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC in the brain and thereby leads to sympathetic hyperactivity and progressive LV dysfunction.
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