Angiotensin II Receptor Antagonist TCV-116 Reduces Graft Coronary Artery Disease and Preserves Graft Status in a Murine Model

Abstract

BACKGROUND: Despite the current progress in immunosuppressive regimens, the incidence of graft coronary artery disease (CAD) after cardiac transplantation has not decreased. Recent study has revealed that angiotensin-converting enzyme (ACE) inhibition decreases CAD in rats; however, it is not clear whether this beneficial effect of ACE inhibition is due to a decrease in production of angiotensin II (Ang II) or inhibition of bradykinin degradation. To determine whether Ang II type 1 receptor (AT1-R) blockade has an inhibitory effect on CAD, we evaluated the effects of TCV-116, an AT1-R antagonist, in a murine model of cardiac transplantation. METHODS AND RESULTS: Hearts of DBA/2 mice (H-2d) were transplanted heterotopically to B10.D2 mice (H-2d). Recipients were treated orally with TCV-116 (10 mg/kg per day), captopril (100 mg/kg per day), or vehicle only. Graft status, as assessed by palpation and inspection at laparotomy 70 days after transplantation, was preserved better in the TCV-116-treated group (P < .005) and in the captopril-treated group (P < .05) than in the vehicle-treated group. Intimal area in the graft coronary arterial wall decreased to 31% in the TCV-116-treated group (P < .001 versus vehicle-treated group) and to 34% (P < .005) in the captopril-treated group but was 45% in the vehicle-treated group. Fibrotic lesions of the left ventricle were less prominent in the TCV-116-treated (31%; P < .01 versus vehicle-treated group) and captopril-treated groups (33%; P < .05) than in the vehicle-treated group (54%). CONCLUSIONS: These findings show that AT1-R blockade is at least as effective as ACE inhibition in management of chronic allograft rejection and suggest that Ang II may play an important role in chronic allograft rejection.