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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/H968    most recent 00317.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Huang, B. S. Articles by Leenen, F. H. H. PubMed PubMed Citation Articles by Huang, B. S. Articles by Leenen, F. H. H.

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

Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

Submitted 31 March 2009 ; accepted in final form 13 July 2009

In rats, both central and systemic ANG II type 1 (AT₁) 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·kg^–1·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 (200 mg·kg^–1·day^–1) either via drinking water or by gavage similarly decreased AT₁ 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 AT₁ receptor blockade or the pharmacokinetic profile of subcutaneous versus oral dosing do not contribute to the different cardiac effects of central versus systemic AT₁ receptor blockade post-MI.

losartan; cardiac remodeling; echocardiography; Millar catheter; brain; ANG II type 1