Leptin has been proposed to modulate cardiac electrical properties via ␤-adrenergic receptor activation. The presence of leptin receptors and adipocytes in myocardium raised a question as to whether leptin can directly modulate cardiac electrical properties such as heart rate and QT interval via its receptor. In this work, the role of local direct actions of leptin on heart rate and ventricular repolarization was investigated. We identified the protein expression of leptin receptors at cell surface of sinus node, atrial, and ventricular myocytes isolated from rat heart. Leptin at low doses (0.1-30 g/kg) decreased resting heart rate; at high doses (150 -300 g/kg), leptin induced a biphasic effect (decrease and then increase) on heart rate. In the presence of high-dose propranolol (30 mg/kg), high-dose leptin only reduced heart rate and sometimes caused sinus pauses and ventricular tachycardia. The leptin-induced inhibition of resting heart rate was fully reversed by leptin antagonist. Leptin also increased heart rate-corrected QT interval (QTc), and leptin antagonist did not. In isolated ventricular myocytes, leptin (0.03-0.3 g/ml) reversibly increased the action potential duration. These results supported our hypothesis that in addition to indirect pathway via sympathetic tone, leptin can directly decrease heart rate and increase QT interval via its receptor independent of ␤-adrenergic receptor stimulation. During inhibition of ␤-adrenergic receptor activity, high concentration of leptin in myocardium can cause deep bradycardia, prolonged QT interval, and ventricular arrhythmias.leptin; leptin receptor; resting heart rate; QT interval NEW & NOTEWORTHYLeptin is believed to increase heart rate via adrenergic receptor stimulation. We found evidence that leptin can exert local direct inhibition of heart rate and prolongation of QTc interval via its receptor. The findings offer better understanding of higher incidence of prolonged QT and sudden cardiac death in obesity.LEPTIN IS A 16-KDA ADIPOKINE released from adipocytes acting via its receptor. Detection of adipocytes in obese human heart (21, 30) and leptin receptors in human cardiac ventricles (19) has suggested that leptin can have autocrine and paracrine effects on cardiac functions.Leptin has been demonstrated to play an important role in cardiac contractility (19, 37), development of hypertrophy (12,19,37,39), and apoptosis (20). However, studies of leptin on cardiac electrical properties are rare and limited to indirect effects via adrenergic receptor stimulation. It has been widely accepted that leptin increases the heart rate through increasing sympathetic activity (5, 9, 10). Leptin-mediated increase in sympathetic activity can explain obese subjects with higher heart rate to meet the increased metabolic demands (25), but it cannot explain why many of them exhibit unchanged or decreased resting heart rate (2, 7).In heart failure patients, fatty infiltration of cardiomyocytes has been demonstrated. The percentage of fat in myocardium is positively correlat...

Increasing evidence has demonstrated the potential risks of cardiac arrhythmias (such as prolonged QT interval) using tyrosine kinase inhibitors for cancer therapy. We report here that a widely used selective inhibitor of Src tyrosine kinases, PP2, can inhibit and prevent isoproterenol stimulation of cardiac pacemaker activity. In dissected rat sinus node PP2 inhibited and prevented isoproterenol stimulation of spontaneous beating rate. In isolated sinus node myocytes PP2 suppressed the hyperpolarization-activated “funny” current (If) by negatively shifting the activation curve and decelerating activation kinetics, associated with decreased cell surface expression and reduced tyrosine phosphorylation of hyperpolarization-activated, cyclic nucleotide-modulated channel 4 (HCN4) channel proteins. In human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed isoproterenol stimulation of HCN4 and inhibited HCN4-573x, a cAMP insensitive human HCN4 mutant. Isoprotenrenol had little effects on HCN4-573x. These results demonstrated that inhibition of presumably tyrosine Src kinase activity in heart by PP2 decreased and prevented the potential β-adrenergic stimulation of cardiac pacemaker activity. These effects are mediated, at least partially, by a cAMP-independent attenuation of channel activity and cell surface expression of HCN4, the key channel protein that controls the heart rate.

In peripubertal sheep, a decrease in inhibition by estradiol leads to an increase in gonadotropin releasing hormone (GnRH), and thus luteinizing hormone (LH), secretion, causing the onset of puberty. The neural mechanisms governing this process remain largely unknown. Kisspeptin is expressed in the arcuate nucleus of the hypothalamus of sheep and stimulates GnRH/LH secretion. We hypothesized that kisspeptin expression would be greater in postpubertal sheep and that its expression would be increased in the absence of steroid negative feedback. Four groups of females were used: prepubertal intact, prepubertal ovariectomized, postpubertal ewes in the early follicular phase, and postpubertal ovariectomized. LH was measured to confirm the endocrine state of each animal. Kisspeptin expression was greater in postpubertal ewes as compared to prepubertal ewes, and was increased by ovariectomy only in the prepubertal group. The increase in kisspeptin cell numbers in postpubertal females is consistent with a role for kisspeptin in puberty onset in the sheep. Further, the increase in kisspeptin expression with ovariectomy in prepubertal females indicates that decreased kisspeptin cell numbers in intact prepubertal females is due to the negative feedback effects of estradiol. NIH Grant 5P20RR016477 to the West Virginia IDeA Network for Biomedical Research Excellence

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