EFFECT OF CILAZAPRIL AND INDOMETHACIN ON ENDOTHELIAL DYSFUNCTION IN THE AORTAS OF SPONTANEOUSLY HYPERTENSIVE RATS

Chronic hypertension is associated with impaired endothelial function [i.e., reduced synthesis/release of endothelium-derived relaxing facto r (EDRF) and increased synthesis/release of endothelium-derived contra cting factor (EDCF)] in both animals and humans. Although it is not kn own whether endothelial dysfunction is the consequence and/or an impor tant pathogenetic cause of hypertension, the goal of effective antihyp ertensive therapy should include restoration of normal endothelial fun ction as well. Because angiotensin I-converting enzyme (ACE) inhibitor s are effectively used in the treatment of hypertension, the aim of th e present study was to test whether in vivo treatment of spontaneously hypertensive rats (SHRs) with the ACE inhibitor cilazapril improves e ndothelial function in the isolated thoracic aorta of SHRs. Treatment of SHRs with cilazapril (10 mg/kg/day orally for 2 weeks) resulted in a significant decrease in blood pressure and normalization of endothel ium-dependent relaxation evoked by acetylcholine (ACh) and adenosine d iphosphate (ADP). However, cilazapril treatment had no significant eff ect on endothelium-dependent contractions evoked by 5-hydroxytryptamin e (5-HT; serotonin) and prostaglandin F2alpha (PGF2alpha). In contrast , in vitro treatment of isolated thoracic aortas with indomethacin (10 (-5) M) normalized endothelium-dependent relaxations to ACh and ADP as well as inhibited endothelium-dependent contractions to 5-HT and PGF2 alpha. These results suggest that the ACE inhibitor cilazapril increas es the synthesis/release of EDRFs whereas indomethacin prevents the sy nthesis/release of cyclo-oxygenase-derived EDCFs in the endothelium of rat aorta. The exact mechanism of action of ACE inhibitors on endothe lial dysfunction remains to be determined.