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Distinct roles of neuronal nitric oxide synthase in metabolic substrates‐induced abnormal Ca 2+ handling and cardiac arrhythmias in normal and hypertensive rats
Author(s) -
Zhao Zai Hao,
Zhang Yin Hua
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.952.9
Subject(s) - medicine , endocrinology , contraction (grammar) , enos , myocyte , insulin , nitric oxide , nitric oxide synthase , stimulation , angiotensin ii , chemistry , receptor
Background & Aim Metabolic syndrome is the precursor for ventricular arrhythmias. Here, we test metabolic syndromes' regulation of cardiac excitation‐contraction coupling (fatty acids, pyruvate, carnitine and 5 mM glucose, termed NF) and the role of neuronal nitric oxide syndrome, nNOS in left ventricular (LV) myocytes from sham and angiotensin (Ang II)‐induced hypertensive rats. Result: NF increased basal and beta‐adrenergic (ISO) stimulation of LV myocyte contraction in sham and hypertension. Notably, ISO induced delayed‐aftercontraction (DAC) in NF and the frequency of DAC was ~3 fold higher in hypertension. Insulin, which exerted anti‐adrenergic effect on myocyte contraction in normal tyrode (NT), did not affect basal and ISO‐stimulated myocyte contraction or DAC in NF in two groups. Furthermore, tyrosine phosphorylation of insulin receptor substrate (IRS‐Tyr 612 ) not insulin receptor (IRβ) or eNOS (eNOS‐Ser 1177 ) was significantly reduced by NF, suggesting impaired insulin signaling. Inhibition of nNOS with S‐methyl‐l‐thiocitrulline (SMTC) did not affect NF and ISO‐enhanced LV myocyte contraction in two groups. Unexpectedly, SMTC increased DAC in sham but reduced it in hypertension. Diastolic and peak [Ca 2+ ] i were elevated by NF and induced spontaneous Ca 2+ release. SMTC increased peak [Ca 2+ ] i in sham but reduced it in hypertension. KB‐R7943, an inhibitor of Na + ‐Ca 2+ exchanger, abolished ISO‐induced arrhythmias in NF. Conclusion NF impairs insulin‐dependent signaling, potentiates beta‐adrenergic stimulation of arrhythmias. nNOS prevents arrhythmias in normal heart but assists arrhythmogenesis in hypertension via its contrasting roles in [Ca 2+ ] i handling.