Influence of Age on Contractile Response to Insulin-Like Growth Factor 1 in Ventricular Myocytes From Spontaneously Hypertensive Rats

Abstract

Abstract-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 Ca 2ϩ 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 Ca 2ϩ 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 (⌬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 ⌬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 ⌬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 mol/L) and KCl (30 mmol/L). Pretreatment with nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME, 100 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 Ca 2ϩ channel opener Bay K8644 (1 mol/L) abolished IGF-1-induced cardiac depression in 36-week SHR myocytes. Collectively, these results suggest that the IGF-1-induced cardiac contractile response was reduced with advanced age as well as with hypertension. Alterations in nitric oxide and intracellular Ca 2ϩ modulation may underlie, in part, the resistance to IGF-1 in hypertension and advanced age.

Views From Within and Beyond: Narratives of Cardiac Contractile Dysfunction Under Senescence

“…Ventricular myocytes isolated from 36-wk-old but not 12-wk-old SHR rat hearts exhibit considerably larger dimension (either cell length or surface area) compared to those of the age-matched WKY rats (26,27). Advanced age alone has little effect on cell dimension.…”

“…The contraction and relaxation durations were not affected by early stage of hypertension and were reduced with advanced age (26). Moreover, myocytes from older SHR rats exhibit a prolonged contraction duration along with a normal relaxation duration as compared to the age-matched WKY rats (26,27). Alterations in nitric oxide modulation of IGF-1-induced contraction may underlie resistance to this inotropic peptide with advancing age and/or hypertension (26,27).…”

“…Interestingly, the myocyte shortening capacity decreases with advanced age (26,27). The contraction and relaxation durations were not affected by early stage of hypertension and were reduced with advanced age (26). Moreover, myocytes from older SHR rats exhibit a prolonged contraction duration along with a normal relaxation duration as compared to the age-matched WKY rats (26,27).…”

“…The shortened duration of contraction/relaxation in myocytes from older SHR rats exhibits increased maximal velocities of contraction and relaxation. Interestingly, the myocyte shortening capacity decreases with advanced age (26,27). The contraction and relaxation durations were not affected by early stage of hypertension and were reduced with advanced age (26).…”

“…Advanced age alone has little effect on cell dimension. Neither cell length nor surface area is affected by IGF-1 exposure (26,27). Myocytes isolated from 12-wk-old animals display similar extent of shortening capacity as indicated by peak contraction amplitude (26,27).…”