Cardioprotective Effects of the Novel Compound Vastiras in a Preclinical Model of End-Organ Damage.

Cardiac hypertrophy and renal damage associated with hypertension are independent predictors of morbidity and mortality. In a model of hypertensive heart disease and renal damage, we tested the actions of continuous administration of Vastiras, a novel compound derived from the linear fragment of ANP (atrial natriuretic peptide), namely pro-ANP31-67, on blood pressure and associated renal and cardiac function and remodeling. Of note, this peptide, unlike the ring structured forms, does not bind to the classic natriuretic peptide receptors. Dahl/Salt-Sensitive rats fed a 4% NaCl diet for 6 weeks developed hypertension, cardiac hypertrophy, and renal damage. Four weeks of treatment with 50 to 100 ng/kg per day of Vastiras exhibited positive effects on renal function, independent of blood pressure regulation. Treated rats had increased urine excretion, natriuresis, and enhanced glomerular filtration rate. Importantly, these favorable renal effects were accompanied by improved cardiac structure and function, including attenuated cardiac hypertrophy, as indicated by decreased heart weight to body weight ratio, relative wall thickness, and left atrial diameter, as well as reduced fibrosis and normalized ratio of the diastolic mitral inflow E wave to A wave. A renal subtherapeutic dose of Vastiras (25 ng/kg per day) induced similar protective effects on the heart. At the cellular level, cardiomyocyte size and t-tubule density were preserved in Vastiras-treated compared with untreated animals. In conclusion, these data demonstrate the cardiorenal protective actions of chronic supplementation of a first-in-class compound, Vastiras, in a preclinical model of maladaptive cardiac hypertrophy and renal damage induced by hypertension.

Cardiac hypertrophy in copper-deficient rats is not attenuated by angiotensin II receptor antagonist L-158,809.

We tested the hypothesis that cardiac hypertrophy which accompanies copper (Cu) deficiency was mediated by angiotensin II (Ang II). Thirty 17-day-old male Holtzman rats were offered a semipurified low-Cu diet (0.45 mg Cu/kg) for 39 days. Fifteen controls (Cu adequate) were given supplemental Cu (20 microgram/ml) in their drinking water, the other 15 (Cu deficient) were given deionized water. Five from each dietary treatment group were chronically infused by using osmotic pumps for 4 weeks with the Ang II receptor antagonist L-158,809, and five from each group were infused with propylene glycol vehicle. Five from each group were not implanted. Blood pressure (BP) changes to injection of Ang II, phenylephrine, and acetylcholine were monitored in cannulated rats. Cu-deficient rats had higher heart weight, left ventricular (LV)/body weight (BW), right ventricular (RV)/BW, lower mean BP, and coronary vascular resistance (CVR) than Cu-adequate rats. L-158-809 did not alter Cu levels or RV/BW in either dietary group, but did lower LV/BW, CVR, and mean BP in both dietary groups. Since Ang II blockage lowered HW/BW and LV/BW in both groups, the stimulus for cardiac hypertrophy in Cu-deficient rats remains unknown.