Intravenous IGF-I receptor antisense reduces IGF-IR expression and diminishes pressor responses to angiotensin II in conscious normotensive rats.
Given the variety of cardiovascular effects of insulin-like growth factor-I (IGF-I), we investigated the effects of a functional deficit in IGF-I signalling in the conscious rat cardiovascular system using intravenous IGF-I receptor antisense (AS, 0.5 nmol) treatment.Insulin-like growth factor-I receptor (IGF-IR) immunoreactivity was reduced in IGF-IR AS-treated tail arteries. Western immunoblot analysis demonstrated a decrease in cardiac IGF-IR in IGF-IR AS-treated rats; treatment reduced the expression of IGF-IR to 83+/-6% of that in samples from vehicle-treated rats, compared to 99+/-3% for a control, full-mismatch oligonucleotide (MM-18) or 100% (vehicle).IGF-IR AS treatment had no effect on resting blood pressure during the 14-day treatment period. Pressor responses (as measured by increase in systolic arterial pressure) to angiotensin II (AngII) gradually decreased over 2 weeks treatment with IGF-IR AS (5 x 0.5 nmol per intravenous injection, 2 weeks), and were significantly reduced at treatment day 14 compared to day 7 (2.7-fold rightward shift). IGF-IR AS treatment caused a significant rightward shift in the angiotensin II (AngII) dose-response compared to both vehicle and full-mismatch treated rats (4.0-fold shift compared to vehicle, P<0.01, n=6-14). There was a significant decrease in cardiac angiotensin II type 1 receptor (AT(1)R) expression in AS-treated rats compared to vehicle-treated rats; cardiac AT(1)R was decreased to 80+/-6% in comparison to 100%. AT(1)R immunoreactivity was also reduced in IGF-IR AS-treated tail arteries.IGF-IR AS treatment resulted in structural changes in both the heart and aortae, with small but significant differences observed between left ventricle/bodyweight ratios of AS and both vehicle- and MM-18-treated rats (n=8, P<0.05). Aortic cross-sectional areas of AS-treated rats were significantly lower than MM-18- and vehicle-treated rats (27.4+/-5.7% reduction of vehicle-treated samples, n=8, P<0.01). The results of this study suggest that an induced loss of IGF-IR, while not affecting resting blood pressure, has a predominantly inhibitory effect on vascular response to vasoconstrictor agents including angiotensin II. This may occur through downstream effects on AT1R expression, via modulation of the expression of receptors for other vasoactive signalling molecules, or via changes in myocyte proliferation.
Nguyen
Tien Thuy
TT
Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia.
White
Paul James
PJ
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D005260:Female; D009638:Norepinephrine / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000037:antagonists & inhibitors*
D016376:Oligonucleotides, Antisense; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D017526:Receptor, IGF Type 1; D009638:Norepinephrine