Losartan and acute myocardial infarction in insulin-resistant Zucker fatty rats: reduced ventricular arrhythmias and improved survival

• Published in: Canadian journal of physiology and pharmacology 2005-11, Vol.83 (11), p.989-998
• Main Authors: Pourdjabbar, Ali, Parker, Thomas G, Desjardins, Jean-François, Nguyen, Quang Trinh, Tsoporis, James N, Lapointe, Nathalie, Rouleau, Jean-Lucien
• Format: Article
• Language: English
• Subjects: Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Antihypertensive agents; Arrhythmias, Cardiac - prevention & control; Biological and medical sciences; Blood Pressure - drug effects; Cardiac arrhythmia; Cardiovascular system; Chemical reactions; Diabetes; Gene Expression Regulation - drug effects; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; Heart attacks; Heart failure; Heart Ventricles - drug effects; Hypertrophy, Left Ventricular - drug therapy; Losartan - pharmacology; Male; Medical sciences; Myocardial Infarction - drug therapy; Pharmacology; Pharmacology. Drug treatments; Rats; Rats, Zucker; RNA, Messenger - metabolism; Survival Analysis; Ventricular Function; Ventricular Remodeling - drug effects
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/y05-072

Insulin resistance (IR) and diabetes increase the risk of acute myocardial infarction (MI). Angiotensin receptor blockers (ARBs) have been shown to reduce the risk of cardiovascular events in patients with hypertension and diabetes, and to be beneficial after a large MI. Whether pretreatment with ARBs is beneficial in acute MI is unknown. We evaluated whether pre-, peri-, and post-MI treatment with the ARB losartan improved the outcome in the IR Zucker fatty rat (ZFR). ZFR (n = 264) received either losartan (3 mg/kg daily) or vehicle for 7 d prior to MI. Early (24 h) protocol (n = 31): ventricular arrhythmias were evaluated post-MI using continuous ambulatory ECG monitoring. Late (38 d) protocol (n = 233): losartan was increased to 10 mg/kg daily 10 d post-MI and to 30 mg/kg daily 20 d post-MI. Blood glucose, cardiac hemodynamics and remodeling, GLUT-4, fetal gene expression, and survival were evaluated. In large-MI rats, losartan improved early survival (43% vs. 27% in controls, p = 0.01) and late survival (23% vs.15% in controls, p = 0.02). Improved early survival was associated with a reduction in ventricular arrhythmias. Losartan reduced pulmonary congestion, cardiac hypertrophy, and fetal gene expression in the absence of statistically significant changes in ventricular dilatation and hemodynamics. Blood glucose and cardiac GLUT-4 expression did not change with losartan. In IR ZFR, losartan improves post-MI survival, likely as a result of an early reduction in ventricular arrhythmias. There was also an associated reduction in pulmonary congestion, hypertrophy, and fetal gene expression.Key words: diabetes, heart failure, myocardial infarction, remodeling, renin-angiotensin system, ventricular arrhythmias.