Omapatrilat-mediated vasorelaxation through nitric oxide pathway in aortic rings isolated from hypertensive rats

Omapatrilat is a recently developed vasopeptidase inhibitor (VPI) which displays equipotent, highly selective competitive activity against neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). Previous studies demonstrated that ACE inhibitors or NEP inhibitors increased nitric oxide (NO) production in coronary microvessels. To date, there is no information regarding the effect of VPI on vasorelaxation and NO production. We hypothesized that long-term treatment with omapatrilat will increase generation of nitric oxide and enhance NO-mediated vasorelaxation in hypertensive rat. To test this hypothesis, we performed the current study in spontaneously hypertensive rats (SHR, n=5). Vehicle (NaHCO3, 0.5 ml/day) or omapatrilat (100 nM/kg/day) were administered to SHR once daily by gavage for six months. Mean blood pressure (MBP) was determined by tail cuff method. Omapatrilat significantly decreased MBP from day 1 through end of study. At 6 months, SHR was sacrificed and aortic ring was isolated. The effect of omapatrilat on vasorelaxation in aortic ring was determined by organ chamber study. Omapatrilat caused concentration-dependent vasorelaxation (10-10 to 10-6 M) in aortic rings isolated from SHR which received long-term treatment of omapatrilat. The maximal relaxation to omapatrilat (10-6 M) was 68+/-8%. In contrast, L-NAME (10-4 M) completely blocked omapatrilat-mediated vasorelaxation in aortic rings. This study first time demonstrated that omapatrilat has potent vasorelaxation effect through NO-dependent pathway in hypertensive rats. Therefore, nitric oxide may play an important role on omapatrilat-mediated antihypertensive actions.