assessment-myofilament-ca2-sensitivity-underlying-cardiac-excitation

Assessment of Myofilament Ca<sup>2+</sup> Sensitivity Underlying Cardiac Excitation-contraction Coupling

Heart failure and cardiac arrhythmias are the leading causes of mortality and morbidity worldwide. However, the mechanism of pathogenesis and myocardial ...

Seoul National University College of Medicine

K(+) channels determine the plasma membrane potential of vascular myocytes, influencing arterial tone. In many types of arteries, a moderate increase in [K(+)]e induces vasorelaxation by augmenting the inwardly rectifying K(+) channel current (I Kir). K(+)-vasodilation matches regional tissue activity and O2 supply. In chronic hypertension (HT), small arteries and arterioles undergo various changes; however, ion channel remodeling is poorly understood. Here, we investigated whether K(+) channels and K(+)-induced vasodilation are affected in deep femoral (DFA) and cerebral artery (CA) myocytes of angiotensin II-induced hypertensive rats (Ang-HT). Additionally, we tested whether regular exercise training (ET) restores HT-associated changes in K(+) channel activity. In Ang-HT, both the voltage-gated K(+) channel current (I Kv) and I Kir were decreased in DFA and CA myocytes, and were effectively restored and further increased by combined ET for 2 weeks (HT-ET). Consistently, K(+)-vasodilation of the DFA was impaired in Ang-HT, and recovered in HT-ET. Interestingly, ET did not reverse the decreased K(+)-vasodilation of CA. CA myocytes from the Ang-HT and HT-ET groups demonstrated, apart from K(+) channel changes, an increase in nonselective cationic current (I NSC). In contrast, DFA myocytes exhibited decreased I NSC in both the Ang-HT and HT-ET groups. Taken together, the decreased K(+) conductance in Ang-HT rats and its recovery by ET suggest increased peripheral arterial resistance in HT and the anti-hypertensive effects of ET, respectively. In addition, the common upregulation of I NSC in the CA in the Ang-HT and HT-ET groups might imply a protective adaptation preventing excessive cerebral blood flow under HT and strenuous exercise.

Low K⁺ current in arterial myocytes with impaired K⁺-vasodilation and its recovery by exercise in hypertensive rats.

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.

Modulation of L-type Ca²⁺ channel activity by neuronal nitric oxide synthase and myofilament Ca²⁺ sensitivity in cardiac myocytes from hypertensive rat.

Zai Hao Zhao

Department of Physiology & Biomedical Sciences,
Ischemic/hypoxic Disease Institute,
Department of Physiology & Biomedical Sciences, Ischemic/hypoxic Disease Institute

Seoul National University College of Medicine

Assessment of Myofilament Ca²⁺ Sensitivity Underlying Cardiac Excitation-contraction Coupling

Zai Hao Zhao

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Physiology & Biomedical Sciences,Ischemic/hypoxic Disease Institute,Department of Physiology & Biomedical Sciences, Ischemic/hypoxic Disease Institute

Seoul National University College of Medicine

Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling

Department of Physiology & Biomedical Sciences,
Ischemic/hypoxic Disease Institute,
Department of Physiology & Biomedical Sciences, Ischemic/hypoxic Disease Institute

Assessment of Myofilament Ca²⁺ Sensitivity Underlying Cardiac Excitation-contraction Coupling