Effects of cariporide and losartan on hypertrophy, calcium transients, contractility, and gene expression in congestive heart failure

Abstract

Background - The purpose of this study was to compare long-term effects of cariporide with those of losartan in postinfarction heart failure. Methods and Results - Female Sprague-Dawley rats with large myocardial infarctions and sham controls were randomized to losartan, cariporide, or placebo after 7 days and treated for 49 days. Cardiac function was assessed by echocardiography and measurement of left ventricular pressures, and gene expression was assessed by competitive reverse transcription-polymerase chain reaction. Cell dimensions, shortening, and relaxation were determined by videomicroscopy and calcium transients by fura 2. Losartan reduced postinfarction systolic and diastolic left ventricular dilation (by 24% and 31%, respectively), left and right ventricular weight (by 22% and 26%, respectively), and cardiomyocyte hypertrophy length and width (by 62% and 54%, respectively). Induction of myocardial atrial natriuretic peptide decreased 66%. Cariporide did not affect postinfarction hypertrophy or atrial natriuretic peptide. Losartan and cariporide respectively improved reduced cellular contractility (55% and 30%) and reduced elevated systolic (86% and 27%) and diastolic (49% and 43%) calcium. Losartan and cariporide respectively reduced prolonged time to 50% relaxation (66% and 25%) and time to 50% calcium reduction (55% and 53%). Conclusions - Losartan and cariporide improve cardiomyocyte contractility and calcium regulation in chronic heart failure. Losartan has salutary effects on postinfarction remodeling and gene expression, whereas cariporide is neutral.