Effects of Angiotensin II Receptor Blockade on Hypoxia-induced Right Ventricular Hypertrophy in Rats

Abstract

It was the aim of the present study to characterize the hemodynamic, biochemical and morphologic effect of angiotensin II receptor blockade on hypoxia-induced right ventricular hypertrophy in rats. Isolated right ventricular hypertrophy was induced in female Sprague–Dawley rats by intermittent hypoxia (IH; 10% O2, 8 h/day, 5 days/week, 20 days of exposition,n=15). After completion of IH, left- (LV) and right-ventricular (RV) hemodynamic parameters were measured under room air conditions in the intact, thiopental-anesthetized animals with special Millar ultraminiature tipcatheter-manometers. Cardiac output was determined using the thermodilution method. Cell volume (CV) of isolated cardiomyocytes was measured with a Coulter Channellyzer after collagenase cell isolation. The specific activities of the myocardial pentose phosphate pathway enzymes glucose-6-phosphate-dehydrogenase (G-6-PD) and 6-phosphogluconate-dehydrogenase (6-PGD) were determined using a spectrophotometric assay. IH caused a rise in right ventricular systolic pressure (RVSP) from 38.1±0.83 to 58.1±1.42 mmHg and an increase in the RV weight/body weight ratio (RVW/BW) from 0.884±0.053 to 1.166±0.049 mg/g. The activities of G-6-PD and 6-PGD were significantly increased after IH in the RV, but not in the LV. CV was increased from 24 248±1193 to 29 541±1765μm3, myocardial cell length was unchanged. IH had no influence on the LV parameters or cardiac output. Co-infusion of the angiotensin II receptor antagonist losartan (LO; 12 mg/kg/d i.p.,n=14) during the IH period reduced the rises in RVSP (49.4±2.06 mmHg), RVW/BW (0.99±0.072 mg/g), G-6-PD and 6-PGD significantly, but not completely. The increase in CV, however, was prevented (24 524±2370μm3) entirely. We conclude from these data that the IH-induced RV-hypertrophy was primarily of the concentric type. LO attenuated the hypoxia-induced isolated RV hypertrophy and significantly reduced the metabolic response of the RV. The LO effect was most potent with regard to the increase in cardiomyocyte volume.