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CARDIOVASCULAR

Intravenous Insulin-like Growth Factor-I Receptor Antisense Treatment Reduces Angiotensin Receptor Expression and Function in Spontaneously Hypertensive Rats

Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia

The present study investigated the effects of a functional deficit in insulin-like growth factor-I signaling via chronic intravenous administration of insulin-like growth factor-I (IGF-I) receptor antisense in the conscious spontaneously hypertensive rat cardiovascular system. Insulin-like growth factor-I receptor (IGF-IR) antisense, but not full mismatch treatment, decreased IGF-IR expression in both conductance and resistance blood vessels. Aortic IGF-IR density was reduced by 67.4 ± 6.0% in antisense-treated spontaneously hypertensive rat (SHR) compared with untreated animals, whereas mismatch treatment had no effect (analysis of variance, n = 3, P < 0.01). Aortic and tail artery angiotensin II type 1 receptor expression was significantly reduced by IGF-IR antisense treatment, whereas angiotensin II type 2 receptor expression was unaffected by administration of antisense and mismatch oligonucleotides. IGF-I receptor antisense treatment caused a significant decrease in pressor responses to angiotensin II in comparison with full-length mismatch treatment (E_max was reduced to 65 ± 7 mm Hg compared with 99 ± 6 mm Hg, p < 0.05). Likewise, a reduction in pressor responses to noradrenaline was observed in hypertensive rats treated with IGF-IR antisense compared with full mismatch-treated rats (E_max was reduced to 60 ± 6 mm Hg compared with 108 ± 5 mm Hg, p < 0.01). There was no clear antisense effect on resting blood pressure and no effect at on aortic medial thickness. These results suggest that although the proliferative and vasodilator effects of IGF-I are impaired in SHR, the effects on angiotensin receptor expression remain profound.

Address correspondence to: Dr. Paul White, Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, 381 Royal Pde, Parkville, VIC, Australia 3052. E-mail: paul.white{at}vcp.monash.edu.au