title: Cardiac inotropy, lusitropy, and Ca2+handling with major metabolic substrates in rat heart.
abstract: Fatty acid (FA)-dependent oxidation is the predominant process for energy supply in normal heart. Impaired FA metabolism and metabolic insufficiency underlie the failing of the myocardium. So far, FA metabolism in normal cardiac physiology and heart failure remains undetermined. Here, we evaluate the mechanisms of FA and major metabolic substrates (termed NF) on the contraction, relaxation, and Ca2+handling in rat left ventricular (LV) myocytes. Our results showed that NF significantly increased myocyte contraction and facilitated relaxation. Moreover, NF increased the amplitudes of diastolic and systolic Ca2+transients ([Ca2+]i), abbreviated time constant of [Ca2+]idecay (tau), and prolonged the peak duration of [Ca2+]i. Whole-cell patch-clamp experiments revealed that NF increased Ca2+influx via L-type Ca2+channels (LTCC, ICa-integral) and prolonged the action potential duration (APD). Further analysis revealed that NF shifted the relaxation phase of sarcomere lengthening vs. [Ca2+]itrajectory to the right and increased [Ca2+]ifor 50 % of sarcomere relengthening (EC50), suggesting myofilament Ca2+desensitization. Butanedione monoxime (BDM), a myosin ATPase inhibitor that reduces myofilament Ca2+sensitivity, abolished the NF-induced enhancement of [Ca2+]iamplitude and the tau of [Ca2+]idecay, indicating the association of myofilament Ca2+desensitization with the changes in [Ca2+]iprofile in NF. NF reduced intracellular pH ([pHi]). Increasing [pH]ibuffer capacity with HCO3/CO2attenuated Δ [pH]iand reversed myofilament Ca2+desensitization and Ca2+handling in NF. Collectively, greater Ca2+influx through LTCCs and myofilament Ca2+desensitization, via reducing [pH]i, are likely responsible for the positive inotropic and lusitropic effects of NF. Computer simulation recapitulated the effects of NF.
authors: Department of Physiology & Biomedical Sciences, Ischemic/hypoxic disease institute, Seoul National University, College of Medicine, 103 Dae Hak Ro, Jongno Gu,, Seoul, 110-799, South Korea.
authors: Zai Hao
authors: ZH
authors: Zhao
authors: Department of Physiology, College of Medicine, Inje University, Busan, South Korea.
authors: Jae Boum
authors: JB
authors: Youm
authors: Department of Physiology & Biomedical Sciences, Ischemic/hypoxic disease institute, Seoul National University, College of Medicine, 103 Dae Hak Ro, Jongno Gu,, Seoul, 110-799, South Korea.
authors: Yue
authors: Y
authors: Wang
authors: College of Medicine/Asan Medical Center, University of Ulsan, Ulsan, South Korea.
authors: Jeong Hoon
authors: JH
authors: Lee
authors: Department of Physiology & Biomedical Sciences, Ischemic/hypoxic disease institute, Seoul National University, College of Medicine, 103 Dae Hak Ro, Jongno Gu,, Seoul, 110-799, South Korea.
authors: Jae Hwi
authors: JH
authors: Sung
authors: College of Pharmacy, Chungnam National University, Daejeon, South Korea.
authors: Joon-Chul
authors: JC
authors: Kim
authors: College of Pharmacy, Chungnam National University, Daejeon, South Korea.
authors: Sun Hee
authors: SH
authors: Woo
authors: College of Medicine/Asan Medical Center, University of Ulsan, Ulsan, South Korea.
authors: Chae Hun
authors: CH
authors: Leem
authors: Department of Physiology & Biomedical Sciences, Ischemic/hypoxic disease institute, Seoul National University, College of Medicine, 103 Dae Hak Ro, Jongno Gu,, Seoul, 110-799, South Korea.
authors: Sung Joon
authors: SJ
authors: Kim
authors: Yan Bian University Hospital, Yanji, Ji Lin, China. lancui@ybu.edu.cn.
authors: Lan
authors: L
authors: Cui
authors: Department of Physiology & Biomedical Sciences, Ischemic/hypoxic disease institute, Seoul National University, College of Medicine, 103 Dae Hak Ro, Jongno Gu,, Seoul, 110-799, South Korea. yinzhang87@gmail.com.|Yan Bian University Hospital, Yanji, Ji Lin, China. yinzhang87@gmail.com.|Division of Cardiovascular Sciences, Manchester University, Manchester, UK. yinzhang87@gmail.com.
authors: Yin Hua
authors: YH
authors: Zhang
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001639:Bicarbonates; D020746:Calcium Channels, L-Type; D005227:Fatty Acids
keywords: Cardiac myocyte; Contraction; Intracellular Ca2+ transient; Metabolic substrates; Myofilament Ca2+ sensitivity; Relaxation; pH