title: Modulation of L-type Ca²⁺ channel activity by neuronal nitric oxide synthase and myofilament Ca²⁺ sensitivity in cardiac myocytes from hypertensive rat.
abstract: Neuronal nitric oxide synthase (nNOS) is important in cardiac protection in diseased heart. Recently, we have reported that nNOS is associated with myofilament Ca(2+) desensitization in cardiac myocytes from hypertensive rats. So far, the effect of myofilament Ca(2+) desensitization or nNOS on L-type Ca(2+) channel activity (I(Ca)) in cardiac myocyte is unclear. Here, we examined nNOS regulation of I(Ca) in left ventricular (LV) myocytes from sham and angiotensin II (Ang II)-induced hypertensive rats. Our results showed that basal I(Ca) was not different between sham and hypertension (from -60 to +40 mV, 0.1 Hz). S-methyl-L-thiocitrulline (SMTC), a selective nNOS inhibitor, increased peak I(Ca) similarly in both groups. However, chelation of intracellular Ca(2+) [Ca(2+)]i with BAPTA increased I(Ca) and abolished SMTC-augmentation of I(Ca) only in hypertension. Myofilament Ca(2+) desensitization with butanedione monoxime (BDM), a myosin ATPase inhibitor, decreased I(Ca) in both groups but to a greater extent in hypertension. Intracellular BAPTA or nNOS inhibition reinstated I(Ca) in the presence of BDM to the basal level, suggesting Ca(2+)-dependent inactivation of I(Ca) by nNOS and greater vulnerability in hypertension. Increasing stimulation frequencies (2, 4 and 8 Hz) attenuated myofilament Ca(2+) sensitivity in sham and reduced peak ICa in both groups. Nevertheless, SMTC or BAPTA exerted no effect on I(Ca) at high frequencies in either group. These results suggest that nNOS attenuates I(Ca) via Ca(2+)-dependent mechanism and the vulnerability is greater in hypertension subject to myofilament Ca(2+) desensitization. nNOS or [Ca(2+)]i does not affect I(Ca) at high stimulation frequencies. The results were recapitulated with computer simulation.
authors.affiliation: Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, South Korea.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiology, Inje University, College of Medicine, Busan, South Korea.
authors.forename: Jae Boum
authors.initials: JB
authors.lastname: Youm
authors.affiliation: Yanbian University Hospital, Yanji, Jilin Province, China.
authors.forename: Chun Zi
authors.initials: CZ
authors.lastname: Jin
authors.affiliation: Department of Premedical Program, College of Medicine, Chosun University, Gwangju, South Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, South Korea.
authors.forename: Zai Hao
authors.initials: ZH
authors.lastname: Zhao
authors.affiliation: Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, South Korea.
authors.forename: Eun Yeong
authors.initials: EY
authors.lastname: Seo
authors.affiliation: Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, South Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, South Korea.
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Yanbian University Hospital, Yanji, Jilin Province, China. Electronic address: jinzh_621@163.com.
authors.forename: Zhe Hu
authors.initials: ZH
authors.lastname: Jin
authors.affiliation: Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, South Korea; Yanbian University Hospital, Yanji, Jilin Province, China; Institute of Cardiovascular Sciences, University of Manchester, UK. Electronic address: yinzhang@snu.ac.kr.
authors.forename: Yin Hua
authors.initials: YH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015220:Calcium Channels; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling; D006352:Heart Ventricles / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D052248:Nitric Oxide Synthase Type I
keywords: Ca(2+)-dependent inactivation; Hypertension; L-type calcium channel; Myofilament Ca(2+) sensitivity; Rate-dependency; nNOS