Vascular responses to IGF-I and insulin are impaired in aortae of hypertensive rats

OBJECTIVE: Insulin-like growth factor-I (IGF-I) and insulin are important vasoactive peptides but little is known about their effects in hypertension. DESIGN: We compared the responses of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rat aortae to IGF-I and insulin. METHODS: Aortae were removed from WKY and SHRSP, cut into 2-3 mm rings, and contractile responses to phenylephrine and endothelin-1 studied in organ chambers in the presence of vehicle, IGF-I (0.1 micromol/l) or insulin (0.1 micromol/l). In addition, the effects of nitric oxide synthase (NOS) inhibition, phosphatidylinositol 3-kinase (PI3-kinase) inhibition and superoxide scavenging on these responses were investigated. RESULTS: Incubation with IGF-I and insulin caused attenuation of phenylephrine-induced and endothelin-1-induced vasoconstriction in arteries from normotensive but not hypertensive animals. In the arteries from WKY rats, co-incubation with either wortmannin or LY294002, inhibitors of PI3-kinase, attenuated the effect of IGF-I. The vasorelaxant effect of IGF-I was also abolished by removal of the endothelium or addition of the NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME). Co-incubation with tiron, a superoxide scavenger, suggested that the attenuation of IGF-I vasodilation in SHRSP arteries was not due to excess superoxide production. CONCLUSION: In WKY, IGF-I/insulin attenuate phenylephrine-mediated constrictions via PI3-kinase/nitric oxide pathways. In contrast, in SHRSP these pathways are dysfunctional and IGF-I has little effect on vascular responses.