title: Vascular and renal effects of vasopeptidase inhibition and angiotensin-converting enzyme blockade in spontaneously diabetic Goto-Kakizaki rats.
abstract: BACKGROUND
  The renin-angiotensin system plays an important role in the pathogenesis of diabetes-induced vascular and renal complications. Vasopeptidase inhibitors simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase.
  
  
  OBJECTIVE
  To compare the effectiveness of vasopeptidase inhibition and ACE inhibition in preventing hypertension, endothelial dysfunction and diabetic nephropathy in spontaneously diabetic Goto-Kakizaki (GK) rats.
  
  
  METHODS
  Eight-week-old GK rats received omapatrilat (40 mg/kg) or enalapril (30 mg/kg) for 12 weeks, either during a normal-sodium or high-sodium diet (7% w/w). Blood pressure, arterial functions and renal morphology were determined.
  
  
  RESULTS
  Blood pressure and albuminuria were increased in GK rats compared to non-diabetic Wistar controls. Endothelium-dependent vascular relaxation in response to acetylcholine (ACh) and endothelium-independent vascular relaxation in response to sodium nitroprusside (SNP) were impaired in GK rats. Experiments with N-nitro-L-arginine methyl ester (L-NAME), diclofenac, and L-NAME + diclofenac suggested that cyclooxygenase and endothelium-derived hyperpolarizing factor components of endothelium-dependent vascular relaxation were also impaired. A high-sodium diet aggravated hypertension and diabetes-induced vascular and renal complications. Omapatrilat and enalapril normalized blood pressure and albuminuria during the normal-sodium diet, and effectively ameliorated diabetes-induced renal complications also during the high-sodium diet. However, omapatrilat improved endothelium-dependent relaxation to ACh to a greater extent (85 +/- 5%) than enalapril (68 +/- 6%, P < 0.05). Diclofenac pre-incubation eliminated this difference between omapatrilat and enalapril in ACh-induced vascular relaxation, suggesting that it was mediated, at least in part, via the cyclooxygenase pathway.
  
  
  CONCLUSIONS
  Despite comparable blood pressure-lowering and renoprotective properties, omapatrilat may be more effective in preventing vascular dysfunction during diabetes compared to enalapril in GK rats.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, FIN-00014 Helsinki, Finland.
authors.forename: Zhong Jian
authors.initials: ZJ
authors.lastname: Cheng
authors.forename: Tina
authors.initials: T
authors.lastname: Grönholm
authors.forename: Marjut
authors.initials: M
authors.lastname: Louhelainen
authors.forename: Piet
authors.initials: P
authors.lastname: Finckenberg
authors.forename: Saara
authors.initials: S
authors.lastname: Merasto
authors.forename: Ilkka
authors.initials: I
authors.lastname: Tikkanen
authors.forename: Eero
authors.initials: E
authors.lastname: Mervaala
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000419:Albuminuria / Q000188:drug therapy; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004008:Diclofenac / Q000494:pharmacology; D004656:Enalapril / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015260:Neprilysin / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012982:Sodium, Dietary / Q000008:administration & dosage; D013841:Thiazepines / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011725:Pyridines; D012982:Sodium, Dietary; D013841:Thiazepines; D014665:Vasodilator Agents; D004008:Diclofenac; D009599:Nitroprusside; C106266:omapatrilat; D004656:Enalapril; D045726:Metalloproteases; D015260:Neprilysin; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester