Chronic central versus systemic blockade of AT(1) receptors and cardiac dysfunction in rats post-myocardial infarction

Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 08/2009; 297(3):H968-75. DOI: 10.1152/ajpheart.00317.2009
Source: PubMed


In rats, both central and systemic ANG II type 1 (AT(1)) receptor blockade attenuate sympathetic hyperactivity, but central blockade more effectively attenuates left ventricular (LV) dysfunction post-myocardial infarction (MI). In protocol I, we examined whether functional effects on cardiac load may play a role and different cardiac effects disappear after withdrawal of the blockade. Wistar rats were infused for 4 wk post-MI intracerebroventricularly (1 or injected subcutaneously daily (100 mg x kg(-1) x day(-1)) with losartan. LV dimensions and function were assessed at 4 wk and at 6 wk post-MI, i.e., 2 wk after discontinuing treatments. At 4 and 6 wk post-MI, LV dimensions were increased and ejection fraction was decreased. Intracerebroventricular but not subcutaneous losartan significantly improved these parameters. At 6 wk, LV peak systolic pressure (LVPSP) and maximal or minimal first derivative of change in pressure over time (dP/dt(max/min)) were decreased and LV end-diastolic pressure (LVEDP) was increased. All four indexes were improved by previous intracerebroventricular losartan, whereas subcutaneous losartan improved LVEDP only. In protocol II, we evaluated effects of oral instead of subcutaneous administration of losartan for 4 wk post-MI. Losartan ( approximately 200 mg x kg(-1) x day(-1)) either via drinking water or by gavage similarly decreased AT(1) receptor binding densities in brain nuclei and improved LVEDP but further decreased LVPSP and dP/dt(max). These results indicate that effects on cardiac load by peripheral AT(1) receptor blockade or the pharmacokinetic profile of subcutaneous versus oral dosing do not contribute to the different cardiac effects of central versus systemic AT(1) receptor blockade post-MI.

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    • "In a preliminary experiment, we confirmed that 100 ng kg À1 min À1 SC angiotensin II infusion for 2 weeks increased plasma angiotensin II levels comparable to those in heart failure model rats, which was consistent with previous studies (Leenen et al. 1999a, b; Kang et al. 2008, 2009; Huang et al. 2010; ). The doses of losartan and hydralazine were determined according to previous studies (Zhang et al. 1999; Kang et al. 2008; Huang et al. 2009; Nishihara et al. 2012a,b). The systemic and peripheral infusion of losartan at the present dose has already been reported not to alter hemodynamics (Zhang et al. 1999). "
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    ABSTRACT: Sympathoexcitation contributes to the progression of heart failure. Activation of brain angiotensin II type 1 receptors (AT1R) causes central sympathoexcitation. Thus, we assessed the hypothesis that the increase in circulating angiotensin II comparable to that reported in heart failure model affects cardiac function through the central sympathoexcitation via activating AT1R in the brain. In Sprague-Dawley rats, the subcutaneous infusion of angiotensin II for 14 days increased the circulating angiotensin II level comparable to that reported in heart failure model rats after myocardial infarction. In comparison with the control, angiotensin II infusion increased 24 hours urinary norepinephrine excretion, and systolic blood pressure. Angiotensin II infusion hypertrophied left ventricular (LV) without changing chamber dimensions while increased end-diastolic pressure. The LV pressure -: volume relationship indicated that angiotensin II did not impact on the end-systolic elastance, whereas significantly increased end-diastolic elastance. Chronic intracerebroventricular infusion of AT1R blocker, losartan, attenuated these angiotensin II-induced changes. In conclusion, circulating angiotensin II in heart failure is capable of inducing sympathoexcitation via in part AT1R in the brain, subsequently leading to LV diastolic dysfunction. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    08/2015; 3(8). DOI:10.14814/phy2.12514
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    ABSTRACT: Coronary artery disease is the leading cause of death in the developed world and in developing countries. Acute mortality from acute myocardial infarction (MI) has decreased in the last decades. However, the incidence of heart failure (HF) in patients with healed infarcted areas is increasing. Therefore, HF prevention is a major challenge to the health system in order to reduce healthcare costs and to provide a better quality of life. Animal models of ischemia and infarction have been essential in providing precise information regarding cardiac remodeling. Several of these changes are maladaptive, and they progressively lead to ventricular dilatation and predispose to the development of arrhythmias, HF and death. These events depend on cell death due to necrosis and apoptosis and on activation of the inflammatory response soon after MI. Systemic and local neurohumoral activation has also been associated with maladaptive cardiac remodeling, predisposing to HF. In this review, we provide a timely description of the cardiovascular alterations that occur after MI at the cellular, neurohumoral and electrical level and discuss the repercussions of these alterations on electrical, mechanical and structural dysfunction of the heart. We also identify several areas where insufficient knowledge limits the adoption of better strategies to prevent HF development in chronically infarcted individuals.
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