Leptin Attenuates Cardiac Contraction in Rat Ventricular Myocytes

Abstract

Abstract-Obesity is commonly associated with impaired myocardial contractile function. However, a direct link between these 2 states has not yet been established. There has been an indication that leptin, the product of the human obesity gene, may play a role in obesity-related metabolic and cardiovascular dysfunctions. The purpose of this study was to determine whether leptin exerts any direct cardiac contractile action that may contribute to altered myocardial function. Ventricular myocytes were isolated from adult male Sprague-Dawley rats. Contractile responses were evaluated by use of video-based edge detection. Contractile properties analyzed in cells electrically stimulated at 0.5 Hz included peak shortening, time to 90% peak shortening, time to 90% relengthening, and fluorescence intensity change. Leptin exhibited a dose-dependent inhibition in myocyte shortening and intracellular Ca 2ϩ change, with maximal inhibitions of 22.4% and 26.2%, respectively. Pretreatment with the NO synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME, 100 mol/L) blocked leptin-induced inhibition of both peak shortening and fluorescence intensity change. Leptin also stimulated NO synthase activity in a time-and concentration-dependent manner, as reflected in the dose-related increase in NO accumulation in these cells. Addition of an NO donor (S-nitroso-N-acetyl-penicillamine [SNAP]) to the medium mimicked the effects of leptin administration. In summary, this study demonstrated a direct action of leptin on cardiomyocyte contraction, possibly through an increased NO production. These data suggest that leptin may play a role in obesity-related cardiac contractile dysfunction. (Hypertension. 2000;36:501-505.)

Adipocyte-derived factors suppress heart contraction

“…17 The effect of leptin on cardiac physiology, however, is controversial. Although high doses of leptin (10-1000 nmol l À1 ) seem to directly suppress cardiac contraction in isolated cardiomyocytes, 16 physiologically relevant concentrations (25 ng ml À1 ) abolish the negative inotropic effect of IL-1b, 18 suggesting a potential role of leptin in modulating proinflammatory effects in the heart. A cardioprotective effect of leptin was shown in recent studies with isolated perfused hearts, in which leptin (10 nmol l À1 ) caused significant reductions in infarct size after reperfusion.…”

“…A comparison with previously published data reveals that leptin concentrations in our experiment were far below the effective threshold dose influencing heart contractility parameters. 16 …”

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

“…Cardiovascular regulation of the obese gene product leptin has attracted much attention because its deficiency or resistance leads to obesity and cardiovascular problems [3][4][5][6]. Leptin receptors exist in cardiomyocytes and are coupled to the signalling pathways regulating myocardial contractility [6,7] and cellular growth [5,8].…”

“…Cardiovascular regulation of the obese gene product leptin has attracted much attention because its deficiency or resistance leads to obesity and cardiovascular problems [3][4][5][6]. Leptin receptors exist in cardiomyocytes and are coupled to the signalling pathways regulating myocardial contractility [6,7] and cellular growth [5,8]. Mice lacking leptin (Lep/ Lep, formerly known as ob/ob) or its receptor (Lepr/Lepr, formerly known as db/db) develop cardiac hypertrophy and contractile dysfunction, consolidating a role for leptin in the maintenance of cardiac architecture and function [5,9,10].…”

Insulin resistance induces hyperleptinemia, cardiac contractile dysfunction but not cardiac leptin resistance in ventricular myocytes

“…2 Recent evidence has demonstrated an essential role of leptin in the regulation of cardiovascular function either via direct myogenic route or through autonomic nervous control indirectly. 1,3,4 Several signaling pathways have been confirmed in the cardiovascular regulation of leptin including Janus activated kinase (JAK), signal transducer and activators of transcription (STAT), mitogen activated protein (MAP) kinase and nitric oxide (NO). 4,5 However, little attempt has been made toward understanding the pathophysiological role of leptin in the onset of ventricular dysfunction under certain hyperleptinemic conditions such as obesity and hypertension.…”