Differential effects of angiotensin II versus endothelin-1 inhibitions in hypertrophic left ventricular myocardium during transition to heart failure

Background-In view of their mutual crosstalk, the roles of angiotensin II ( Ang II) and endothelin-1 (ET-1) in the myocardium are assumed to be synergi stic and supplemental. Methods and Results-In the phase of compensated left ventricular (LV) hyper trophy of Dahl salt-sensitive rats, Ang II peptide and the ACE mRNA in the LV were increased by 1.6- and 3.8-fold, respectively. In contrast, ET-1 pep tide and the preproET-1 mRNA remained unchanged. In subsequent congestive h eart failure (CBF), Ang II and ACE mRNA did not show further increases. But ET-1 and the mRNA were increased de novo by 5.3- and 4.1-fold, respectivel y. In ascending aorta-banded rats, the local activations of Ang II and ET-1 also showed a differential time course between LV hypertrophy and CHF. Lon g-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhib itor) and with bosentan (a mixed ET receptor blocker) equally improved long -term survival. Temocapril reduced the LV/body weight ratio and ameliorated LV fractional shortening. Conversely, although bosentan equally improved f ractional shortening, it did not reduce the increase in LV mass. Combined t reatment with these 2 drugs further ameliorated the animal's survival witho ut additional decreases in systolic pressure. Conclusions-The pathophysiological roles in the myocardium during the trans ition to CEF differ qualitatively between Ang II and ET-1. Thus, long-term therapy with a combination of ACE inhibition and ET antagonism may provide a new approach for heart failure in humans.