Chronic central versus systemic blockade of AT₁ receptors and cardiac dysfunction in rats post-myocardial infarction

Abstract

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 mg.kg(-1).day(-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.

Losartan prevents acquired epilepsy via TGF‐β signaling suppression

“…To test the efficacy of systemic losartan administration in the prevention of epilepsy, losartan was injected (IP, 100mg/kg) 40 minutes after treatment, and thereafter was continuously administered at therapeutic levels through drinking water (2gr/L) for 21 days (n=5) 41,42 . This time-course was chosen in order to ensure the presence of the drug throughout the entire duration of BBB dysfunction 10,32 .…”

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

“…These findings indicate that LV remodeling induced by MI was attenuated in GFAP/AT 1 RKO mice. Previous reports suggest that sympathetic hyperactivity after MI results from increases in cardiac sympathetic afferent activity and plasma angiotensin II, and the improvement of LV remodeling by blockade of brain AT 1 R leads to a persistent attenuation of these stimuli and therefore prevents sympathetic hyperactivity (19,20). In brief, sympathoinhibition induced by the blockade of brain AT 1 R attenuates LV remodeling after MI.…”

Remodeling in the ischemic heart: the stepwise progression for heart

“…Another proposed mechanism behind sympathetic hyperactivity after infarction is the activation of the brain RAAS (23). The role of central Ang II in post-myocardial remodeling was indicated by experimental studies showing that blockade of Ang II type 1 receptors (AT 1 ) in the central nervous system was more effective in preventing cardiac dysfunction than blockade of isolated peripheral AT 1 (24). Expression of aldosterone and its receptor increase in the hypothalamus after infarction, which stimulates the production of "ouabain-like" compounds and Ang II, two mechanisms that trigger and amplify the effects of sympathetic activation and predispose to HF.…”