Vasopeptidase inhibition exhibits endothelial protection in salt-induced hypertension.
Omapatrilat represents a new class of drugs capable of inhibiting both ACE and neutral endopeptidase 24.11, the so-called vasopeptidase inhibitors. It therefore contributes to neurohumoral modulation, which might improve endothelial function in cardiovascular diseases. This study investigated the effect of omapatrilat in comparison to the ACE inhibitor captopril on systolic blood pressure and endothelial function in salt-induced hypertension. Dahl salt-sensitive rats (n=6/group) on standard or salt-enriched (4% NaCl) chow were treated for 8 weeks with either omapatrilat (36+/-4 mg/kg per day), captopril (94+/-2 mg/kg per day), or placebo. Aortic rings were then isolated and suspended in organ chambers for isometric tension recording. Systolic blood pressure of salt-fed, placebo-treated animals increased to 196+/-6 mm Hg, which was prevented by omapatrilat (162+/-5 mm Hg, P<0.05) and captopril (164+/-7 mm Hg, P<0.05) to a comparable degree. In control rats, acetylcholine (10(-10) to 10(-5) mol/L) induced endothelium-dependent relaxation (97+/-4%), which was reduced by high-salt diet to 30+/-5% (P<0.005; n=6). Omapatrilat improved relaxation to a greater extent (86+/-5%) than did captopril (57+/-6%; P<0.05). eNOS protein expression and aortic nitrite/nitrate content were reduced in hypertensive rats and improved by both omapatrilat and captopril. Aortic endothelin-1 levels were increased in salt-fed animals and unaffected by omapatrilat or captopril. These data suggest that despite comparable blood pressure, omapatrilat is superior to captopril in improving endothelium-dependent relaxation in salt-sensitive hypertension.
Quaschning
T
T
Cardiovascular Research, Institute of Physiology, University of Zürich, Switzerland.
d'Uscio
L V
LV
Shaw
S
S
Lüscher
T F
TF
D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D012044:Regression Analysis; D012077:Renal Artery / Q000187:drug effects; D012982:Sodium, Dietary; D018709:Statistics, Nonparametric; D013841:Thiazepines / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D011725:Pyridines; D012982:Sodium, Dietary; D013841:Thiazepines; C106266:omapatrilat; D002216:Captopril; D019001:Nitric Oxide Synthase; D015260:Neprilysin