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

Abstract

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 α2-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.

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

“…Although several studies have shown a correlation between elevated endogenous cardiac glycosides and certain pathological conditions, the physiological function of endogenous cardiac glycoside-like compounds is still uncertain (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Plasma levels of endogenous cardiac glycosides are high in several animal models of hypertension, as well as in human essential hypertension and preeclampsia (10)(11)(12)(13)(14)(15)(16)(17).…”

“…Plasma levels of endogenous cardiac glycosides are high in several animal models of hypertension, as well as in human essential hypertension and preeclampsia (10)(11)(12)(13)(14)(15)(16)(17). In addition, marked increases in endogenous ouabain-like compounds occur in congestive heart failure, both in animal models and human patients (18)(19)(20). One concern raised with respect to endogenous cardiac glycoside-like compounds is that they occur in levels which may not significantly inhibit the Na,K-ATPase.…”

The sodium pump and hypertension: A physiological role for the cardiac glycoside binding site of the Na,K-ATPase

“…The identification of cardiac glycoside-like molecules in mammals has led to the proposal that these compounds are natural regulators of Na,K-ATPase in vivo (7)(8)(9)(10). Several studies have shown a correlation between these cardiac glycoside-like molecules and certain pathological conditions, such as hypertension and heart failure (11)(12)(13)(14)(15)(16)(17). Plasma levels of these putative ligands for the Na,KATPase are high in several animal hypertension models, as well as in human essential hypertension and preeclampsia (11-14, 18, 19).…”

“…Plasma levels of these putative ligands for the Na,KATPase are high in several animal hypertension models, as well as in human essential hypertension and preeclampsia (11-14, 18, 19). In addition, marked increases in peripheral and central endogenous ouabain-like compounds occur in animal models of congestive heart failure as well as in human patients (15)(16)(17). However, it is still difficult to draw definitive conclusions regarding the specific function of these molecules in pathophysiology.…”

Reduction of Vascular Noradrenaline Sensitivity by AT 1 Antagonists Depends on Functional Sympathetic Innervation

“…1 The mechanisms of the various interactions between the renin-angiotensin-aldosterone system and the sympathetic system have been established at different levels and have been shown to bear prominent pathophysiological implications. Angiotensin II (Ang II) stimulates the sympathetic system by activating central nervous tone and catecholamine release 2 and by facilitating the release of catecholamines from peripheral sympathetic neurons via ganglionic 3,4 and axonal presynaptic receptors. 5,6 Ang II has been shown to increase vascular sensitivity to noradrenaline in rats and isolated vessels, [7][8][9] so that Ang II and noradrenaline exert synergistic actions on vascular tone.…”