Vascular and renal effects of vasopeptidase inhibition and angiotensin-converting enzyme blockade in spontaneously diabetic Goto-Kakizaki rats.
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.
Cheng
Zhong Jian
ZJ
Institute of Biomedicine, Pharmacology, University of Helsinki, FIN-00014 Helsinki, Finland.
Grönholm
Tina
T
Louhelainen
Marjut
M
Finckenberg
Piet
P
Merasto
Saara
S
Tikkanen
Ilkka
I
Mervaala
Eero
E
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
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