Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction.
OBJECTIVE
Vasopeptidase inhibitors are drugs that inhibit angiotensin-converting enzyme and neutral endopeptidase (NEP). The latter is a protease that degrades vasoactive peptides and is increased in diabetes. We have previously shown that treating streptozotocin-induced diabetic rats, an animal model of type 1 diabetes, with AVE7688, a vasopeptidase inhibitor, improves neurovascular and neural function. In this study, we determined the effect of treating Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes, with AVE7688 on vascular and neural function.


METHODS
ZDF rats at 12 weeks of age were treated for 12 weeks with AVE7688 (500 mg/kg diet). Afterwards, vascular reactivity of epineurial arterioles of the sciatic nerve and nerve conduction velocity and blood flow was determined.


RESULTS
Vascular and neural function was significantly impaired in ZDF rats compared with age-matched lean (control) rats. Treating ZDF rats with AVE7688 improved vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles. Motor and sensory nerve conduction velocity, endoneurial blood flow and thermal nociception end-points were also improved by treatment compared with untreated ZDF rats. Superoxide and expression of NEP were increased in epineurial arterioles from ZDF rats and attenuated by treatment with AVE7688.


CONCLUSIONS
AVE7688 is an effective treatment for microvascular and neural disease in ZDF rats. Thus, vasopeptidase inhibitors may be an effective treatment for diabetic microvascular and neural complication in type 2 diabetes.
Veteran Affairs Medical Center, Iowa City, IA 52246, USA.
C L
CL
Oltman
E P
EP
Davidson
L J
LJ
Coppey
T L
TL
Kleinschmidt
M A
MA
Yorek
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006575:Heterocyclic Compounds, 3-Ring / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011924:Rats, Zucker; D012584:Sciatic Nerve / Q000187:drug effects / Q000503:physiopathology
C479877:AVE 7688; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D007004:Hypoglycemic Agents; D015260:Neprilysin