Effects of vasopeptidase inhibition on renal function and tubuloglomerular feedback in spontaneously hypertensive rats.
Vasopeptidase inhibitors are a novel class of antihypertensive agents that concomitantly inhibit angiotensin converting enzyme and neutral endopeptidase. Our purpose was to investigate the effects of omapatrilat, a vasopeptidase inhibitor, on renal function and tubuloglomerular feedback (TGF) response in anesthetized 9-10-week-old spontaneously hypertensive rats (SHR). Intravenous injection of omapatrilat at 10 micromol/kg decreased systemic blood pressure and renal vascular resistance. Renal plasma flow was unchanged, whereas glomerular filtration rate (GFR) and filtration fraction (FF) were reduced. Increased urinary sodium excretion of tubular origin was observed. These parameters remained unaltered with vehicle treatment. Micropuncture study revealed that the maximal reduction of early proximal flow rate (EPFR) induced by orthograde perfusion of Henle's loop with artificial tubular fluid (ATF) was significantly reduced by omapatrilat treatment (28.5+/-3.1% vs. 72.0+/-2.8% of control) and was not significantly changed in the vehicle-treated group (vehicle 70.8+/-1.7% vs. control 71.0+/-2.1%). EPFR at zero perfusion was comparable between omapatrilat and vehicle treatment (29.7+/-2.2 vs. 31.3+/-2.1 nl/min, respectively). Luminal perfusion of 10(-4) mol/l 7-nitroindazole in ATF abrogated the blunting of TGF response by omapatrilat but elicited no change in the vehicle-treated group. The suppression of the TGF mechanism and the reduction in FF suggest that omapatrilat respectively dilates the afferent and efferent arterioles. Under such conditions, reduction of GFR may indicate a fall in intraglomerular pressure. The restoration of nitric oxide signaling in the juxtaglomerular apparatus of SHR seems to participate in the inhibition of TGF by omapatrilat. These findings suggest that omapatrilat may provide a novel approach to the treatment of systemic and glomerular hypertension.
Wang
Tao
T
Fourth Department of Internal Medicine, Shimane University School of Medicine, Izumo, Japan. wangtao@med.shimane-u.ac.jp
Takabatake
Toshikazu
T
D000818:Animals; D025461:Feedback, Physiological / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000502:physiology; D007684:Kidney Tubules / Q000187:drug effects* / Q000502:physiology; D008138:Loop of Henle / Q000187:drug effects / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013841:Thiazepines / Q000494:pharmacology*
D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; D009569:Nitric Oxide; C106266:omapatrilat