angiotensinogen and temocapril-hydrochloride

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 synergistic and supplemental.. In the phase of compensated left ventricular (LV) hypertrophy 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 peptide and the preproET-1 mRNA remained unchanged. In subsequent congestive heart failure (CHF), 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, respectively. 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. Long-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhibitor) 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 fractional shortening, it did not reduce the increase in LV mass. Combined treatment with these 2 drugs further ameliorated the animal's survival without additional decreases in systolic pressure.. The pathophysiological roles in the myocardium during the transition to CHF 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.

Topics: Angiotensin II; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Disease Progression; Endothelin-1; Endothelins; Gene Expression Regulation; Heart Failure; Heart Ventricles; Hemodynamics; Hypertrophy, Left Ventricular; Male; Organ Size; Peptidyl-Dipeptidase A; Protein Precursors; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Survival Analysis; Thiazepines; Time Factors