Insulin resistance in penile arteries from a rat model of metabolic syndrome.
OBJECTIVE
Metabolic and cardiovascular abnormalities accompanying metabolic syndrome, such as obesity, insulin resistance and hypertension, are all associated with endothelial dysfunction and are independent risk factors for erectile dysfunction. The purpose of the present study was to investigate the vascular effects of insulin in penile arteries and whether these effects are impaired in a rat model of insulin resistance and metabolic syndrome.


METHODS
Penile arteries from obese Zucker rats (OZR) and their counterpart, lean Zucker rats (LZR), were mounted on microvascular myographs and the effects of insulin were assessed in the absence and presence of endothelium and of specific inhibitors of nitric oxide (NO) synthesis, phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK). Insulin-induced changes in intracellular Ca(2+) concentration [Ca(2+)](i) were also examined. KEY RESULTS OZR exhibited mild hyperglycaemia, hypercholesterolemia, hypertryglyceridemia and hyperinsulinemia. Insulin induced endothelium- and NO-dependent relaxations in LZR that were impaired in OZR. Inhibition of PI3K reduced relaxation induced by insulin and by the beta-adrenoceptor agonist isoprenaline, mainly in arteries from LZR. Antagonism of endothelin 1 (ET-1) receptors did not alter insulin-induced relaxation in either LZR or OZR, but MAPK blockade increased the responses in OZR. Insulin decreased [Ca(2+)](i), a response impaired in OZR.


CONCLUSIONS
Insulin-induced relaxation was impaired in penile arteries of OZR due to altered NO release through the PI3K pathway and unmasking of a MAPK-mediated vasoconstriction. This vascular insulin resistance is likely to contribute to the endothelial dysfunction and erectile dysfunction associated with insulin resistant states.
Contreras
Cristina
C
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Sánchez
Ana
A
Martínez
Pilar
P
Raposo
Rafaela
R
Climent
Belén
B
García-Sacristán
Albino
A
Benedito
Sara
S
Prieto
Dolores
D
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007172:Erectile Dysfunction / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009765:Obesity / Q000150:complications / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D010413:Penis / Q000098:blood supply* / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D011924:Rats, Zucker; D014664:Vasodilation / Q000187:drug effects
D007004:Hypoglycemic Agents; D007328:Insulin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium