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

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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 (AT 1 -R) blockade has an inhibitory effect on CAD, we evaluated the effects of TCV-116, an AT 1 -R antagonist, in a murine model of cardiac transplantation. Methods and Results Hearts of DBA/2 mice (H-2 d ) were transplanted heterotopically to B10.D2 mice (H-2 d ). 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 AT 1 -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.