Received for publication March 1, 2006.
Revised May 31, 2006.
Accepted for publication June 1, 2006.

INTRAVENOUS IGF-I RECEPTOR ANTISENSE TREATMENT REDUCES ANGIOTENSIN RECEPTOR EXPRESSION AND FUNCTION IN SPONTANEOUSLY HYPERTENSIVE RATS

Abstract

The present study investigated the effects of a functional deficit in insulin-like growth factor-I signalling via chronic intravenous administration of IGF-I receptor antisense in the conscious spontaneously hypertensive rat cardiovascular system. 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 AS-treated SHR compared to untreated animals, whilst mismatch-treatment had no effect (ANOVA, n=3, P<0.01). Aortic and tail artery AT₁R expression was significantly reduced by IGF-IR antisense treatment; whilst AT₂R 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 to full-length mismatch treatment (Emax was reduced to 65 ± 7 mmHg compared to 99 ± 6 mmHg, p<0.05). Likewise, a reduction in pressor responses to noradrenaline was observed in hypertensive rats treated with IGF-IR antisense compared to full mismatch-treated rats (Emax was reduced to 60 ± 6 mmHg compared to 108 ± 5 mmHg, 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 whilst the proliferative and vasodilator effects of IGF-I are impaired in SHR, the effects on angiotensin receptor expression remain profound.

Key words: angiotensin II, antisense, hypertension, insulin-like growth factor-I, insulin-like growth factor-I receptor, spontaneously hypertensive rat