Vasopeptidase inhibition restores renovascular endothelial dysfunction in salt-induced hypertension.
Renovascular hemodynamics plays a pivotal role in the regulation of BP. The effect of the vasopeptidase inhibitor omapatrilat (O) and the ACE-inhibitor captopril (C) on endothelial function in the renal circulation in salt-induced hypertension were investigated. Dahl salt-sensitive rats (n = 6 per group) on standard or salt-enriched chow were treated for 8 wk with O (36 +/- 4 mg/kg per d), C (94 +/- 2 mg/kg per d), or placebo. Renal arteries were suspended in organ chambers for isometric tension recording. Vascular hypertrophy was assessed by determination of standardized heart weight and aortic weight, and morphologic analysis of glomerular injury was performed. Systolic BP of salt-fed, placebo-treated animals increased to 196 +/- 6 mmHg, which was reduced by O (162 +/- 5 mmHg; P < 0.05) and C (164 +/- 7 mmHg; P < 0.05) to a comparable degree. In salt-induced hypertension, endothelium-dependent relaxations in renal arteries (56 +/- 6 versus 100 +/- 6%; P < 0.05) as well as contractions to endothelin-1 (ET-1) (98 +/- 5% versus 128 +/- 5%; P < 0.05) and big ET-1 (47 +/- 6% versus 116 +/- 7%; P < 0.05) were markedly reduced as compared with control animals, whereas standardized aortic weight and heart weight (4.9 +/- 0.4 versus 3.2 +/- 0.3 g/kg; P < 0.05) increased. Treatment with O restored endothelium-dependent relaxations (88 +/- 6%; P < 0.05 versus C) and contractions to ET-1 (120 +/- 6%) and big ET-1 (98 +/- 9%). O prevented vascular hypertrophy (0.23 +/- 0.019 mg/mm(2) versus 0.31 +/- 0.018 mg/mm(2) in high-salt diet; P < 0.05), but, in contrast to C, it only had a modest effect on glomerular injury. In conclusion, O restored renovascular endothelial function and prevented vascular hypertrophy in salt-induced hypertension and therefore may advance as a beneficial approach in the therapy of various forms of hypertension.
Quaschning
Thomas
T
Cardiovascular Research, Institute of Physiology, University of Zürich, Zürich, Switzerland.
D'Uscio
Livius V
LV
Cardiovascular Research, Institute of Physiology, University of Zürich, Zürich, Switzerland.
Shaw
Sidney
S
Clinical Research, Inselspital, University of Bern, Bern, Switzerland.
Gröne
Hermann-Josef
HJ
Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Ruschitzka
Frank
F
Cardiovascular Center and Cardiology, University of Zürich, Zürich, Switzerland.
Lüscher
Thomas F
TF
Cardiovascular Center and Cardiology, University of Zürich, Zürich, Switzerland.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001808:Blood Vessels / Q000473:pathology; D002216:Captopril / Q000494:pharmacology; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006973:Hypertension / Q000139:chemically induced* / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D012079:Renal Circulation / Q000187:drug effects*; D012965:Sodium Chloride; D013841:Thiazepines / Q000494:pharmacology*; D014661:Vasoconstriction; D014664:Vasodilation
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D012965:Sodium Chloride; D002216:Captopril; D015260:Neprilysin