Vasopeptidase inhibition prevents endothelial dysfunction of resistance arteries in salt-sensitive hypertension in comparison with single ACE inhibition

To determine whether natriuretic peptides in addition to the renin-angiotensin system are involved in functional and structural vascular changes in salt-sensitive hypertension, we compared equipotent hypotensive treatment with the dual neutral endopeptidase/ACE inhibitor omapatrilat (35 mg . kg(-1) . d(-1)) or the ACE inhibitor captopril (100 mg . kg(-1) . d(-1)). The reactivity and geometry of mesenteric resistance arteries from Dahl salt-sensitive rats were studied in vitro under perfused and pressurized conditions. Chronic salt administration increased systolic blood pressure by 57+/-4 mm Hg, whereas concentrations of atrial natriuretic peptide were reduced in heart and in plasma (P<0.05). In addition, the medial cross-sectional area of small mesenteric arteries was increased and endothelium-dependent relaxation in response to acetylcholine and contraction in response to endothelin-l were impaired in the mesenteric arteries of salt-sensitive rats on a high-salt diet (P<0.05). Concomitant treatment with either omapatrilat or captopril reduced the increase in systolic blood pressure and hypertrophic remodeling to a similar degree (P<0.05) but affected plasma and cardiac atrial natriuretic peptide levels differently (P<0.05). In addition, omapatrilat normalized endothelium-dependent relaxations to a greater extent than captopril (P<0.05). Furthermore, vasopeptidase inhibition increased cGMP levels compared with captopril (P<0.05). Contractions to endothelin-l were normalized by either antihypertensive drug. These results suggest that in the Dahl rat, with similar reductions in systolic blood pressure, omapatrilat is superior to captopril in preventing impaired endothelial function in small resistance arteries. Thus, vasopeptidase inhibition may have therapeutic advantages of the prevention of changes in vascular function and structure in salt-sensitive forms of hypertension.