title: Influence of age on contractile response to insulin-like growth factor 1 in ventricular myocytes from spontaneously hypertensive rats.
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(2+) 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(2+) 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 (DeltaFFI) 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 DeltaFFI 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 DeltaFFI 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 micromol/L) and KCl (30 mmol/L). Pretreatment with nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/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(2+) channel opener Bay K8644 (1 micromol/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(2+) modulation may underlie, in part, the resistance to IGF-1 in hypertension and advanced age.
authors.affiliation: Department of Physiology, University of North Dakota, Grand Forks, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ren
authors.forename: L
authors.initials: L
authors.lastname: Jefferson
authors.forename: J R
authors.initials: JR
authors.lastname: Sowers
authors.forename: R A
authors.initials: RA
authors.lastname: Brown
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000503:physiopathology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009929:Organ Size / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018754:Ventricular Dysfunction / Q000503:physiopathology
chemical_list: D002120:Calcium Channel Agonists; D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester