Influence of age on contractile response to insulin-like growth factor 1 in ventricular myocytes from spontaneously hypertensive rats

Evidence suggests a pathophysiological role of insulin-like growth factor 1 (IGF-1) in hypertension. Cardiac function is altered with advanced age, similar to hypertension. Accordingly, the effects of IGF-1 on cardiac myocyte shortening and intracellular Ca2+ were evaluated in hypertension at different ages. Ventricular myocytes were isolated from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), aged 12 and 36 weeks. Mechanical and intracellular Ca2+ properties were examined by edge-detection and fluorescence microscopy. At 12 weeks, IGF-1 (1 to 500 ng/mL) increased peak twitch amplitude (PTA) and FFI changes (Delta FFI) in a dose-dependent manner in WKY myocytes, with maximal increases of 27.5% and 35.2%, respectively, However, IGF-1 failed to exert any action on PTA and Delta FFI in the age-matched SHR myocytes. Interestingly, at 36 weeks, IGF-1 failed to exert any response in WKY myocytes but depressed both PTA and Delta FFI in a dose-dependent manner in SHR myocytes, with maximal inhibitions of 40.5% and 16.1%, respectively. Myocytes from SHR or 36-week WKY were less sensitive to norepinephrine (1 mu mol/L) and KCl (30 mmol/L). Pretreatment with nitric oxide synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME, 100 mu mol/L) did not alter the IGF-1-induced response in 12-week WKY myocytes but unmasked a positive action in 12-week SHR and 36-week WKY myocytes. L-NAME also significantly attenuated IGF-1-induced depression in 36-week SHR myocytes. In addition, the Ca2+ channel opener Bay K8644 (1 mu mol/L) abolished IGF-l-induced cardiac depression in 36-week SHR myocytes. Collectively, these results suggest that the IGF-l-induced cardiac contractile response was reduced with advanced age as well as with hypertension. Alterations in nitric oxide and intracellular Ca2+ modulation may underlie, in part, the resistance to IGF-1 in hypertension and advanced age.