Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction

Blockade of brain "ouabain" prevents the sympathetic hyperactivity and impairment of baroreflex function in rats with congestive heart failure (CHF). Because brain "ouabain" may act by activating the brain renin-angiotensin system (RAS), the aim of the present study was to assess whether chronic treatment with the AT1-receptor blocker losartan given centrally normalizes the sympathetic hyperactivity and impairment of baroreflex function in Wistar rats with CHF postmyocardial infarction (MI). After left coronary artery ligation (2 or 6 wk), rats received either intracerebroventricular losartan (1 mg. kg-1. day-1, CHF-Los) or vehicle (CHF-Veh) by osmotic minipumps. To assess possible peripheral effects of intracerebroventricular losartan, one set of CHF rats received the same rate of losartan subcutaneously. Sham-operated rats served as control. After 2 wk of treatment, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) at rest and in response to air-jet stress and intracerebroventricular injection of the alpha2-adrenoceptor-agonist guanabenz were measured in conscious animals. Arterial baroreflex function was evaluated by ramp changes in MAP. Compared with sham groups, CHF-Veh groups showed impaired arterial baroreflex control of HR and RSNA, increased sympathoexcitatory and pressor responses to air-jet stress, and increased sympathoinhibitory and hypotensive responses to guanabenz. The latter is consistent with decreased activity in sympathoinhibitory pathways. Chronic intracerebroventricular infusion of losartan largely normalized these abnormalities. In CHF rats, the same rate of infusion of losartan subcutaneously was ineffective. In sham-operated rats, losartan intracerebroventricularly or subcutaneously did not affect sympathetic activity. We conclude that the chronic increase in sympathoexcitation, decrease in sympathoinhibition, and desensitized baroreflex function in CHF all appear to depend on the brain RAS, since this whole pattern of changes can be normalized by chronic central AT1-receptor blockade with losartan.