Mechanical activity of the heart is adversely affected with metabolic syndrome (MetS) characterized with increased body-mass and marked insulin-resistance.Herein, we examined effects of high-carbohydrate intake on cardiac functional abnormalities via evaluating in situ heart-work, heart-rate and electrocardiograms (ECG) in rats. MetS is induced in Wistar male rats by adding 32% sucrose for 22-24 weeks and confirmed with insulin-resistance, increased body-weight, blood glucose and insulin, systolic and diastolic blood pressures besides significant left ventricular integrity-lost and increased connective-tissue around myofibrils. Analysis of in situ ECG-recordings showed markedly shorten QT-interval and depressed QRP with increased heart-rate. We also observed augmented oxidative stress and decreased antioxidant defense characterized with decreases in serum total thiol-level and attenuated paraoxonase and arylesterase activities. Our data clearly indicate that increased heart-rate and shortened QT-interval concomitant with higher left ventricular developed pressure responses to β-adrenoreceptor stimulation as a result of less cAMP-release could be regarded as natural compensation mechanisms in overweight MetS rats. Since MetS leads further to persistent insulin-resistance and obesity, one should get into consideration these important facts associated with onset of the depressed heart-work, the increased heart-rate and shorten QT-interval in highcarbohydrate intake, which will possible lead to more deleterious effects on mammalian heart.

β-Adrenoceptors (AR) stimulate cardiac Na/K pump in healthy hearts. β-ARs are upregulated by persistent sympathetic hyperactivity; however, their effect on Na/K ATPase activity and ventricular function in this condition is still unknown. Here, we investigate preventive effects of additional β-AR activation (BRL) on Na/K ATPase activity and in vivo hemodynamics in a model of noradrenaline-induced hypertrophy. Rats received NA or NA plus simultaneously administered BRL in vivo infusion for 14 days; their cardiac function was investigated by left ventricular pressure-volume analysis. Moreover, fibrosis and apoptosis were also assessed histologically. NA induced an hypertrophic pattern, as detected by morphological, histological, and biochemical markers. Additional BRL exposure reversed the hypertrophic pattern and restored Na/K ATPase activity. NA treatment increased systolic function and depressed diastolic function (slowed relaxation). Additional BRL treatment reversed most NA-induced hemodynamic changes. NA decreased Na/K pump α2 subunit expression selectively, a change also reversed by additional BRL treatment. Increasing β-AR stimulation may prevent the consequences of chronic NA exposure on Na/K pump and in vivo hemodynamics. β-AR agonism may thus represent a new therapeutic strategy for pharmacological modulation of hypertrophy under conditions of chronically enhanced sympathetic activity.

No abstract

G Protein-Coupled Receptor Kinase 2 (GRK2) is a culprit in the loss of cardiac contractile function in heart failure due to β-Adrenoceptor (AR) desensitization after its upregulation. Indeed, its inhibition has been demonstrated to improve cardiac function and increased GRK2 in the heart leads to larger injury after an ischemic insult. Nitric oxide (NO) via S-nitrosothiol (SNO) at residue Cys340 is a reported endogenous inhibitor of GRK2 activity. ß3ARs, on the other hand, are known to be resistant to desensitization by GRK2 and they are upregulated in cardiac pathologies. Activation of ß3ARs can be cardioprotective via NO signalling. Thus, in the present study, we aimed to investigate the interaction between ß3ARs and GRK2 through NO signaling to determine if ß3AR cardioprotection can occur via NO-mediated GRK2 inhibition. We used wild type C57BL/6 mice (WT), global β3AR knockout (KO) mice and GRK2-C340S knockin mice, which harbor a point mutation that changes Cys340 with a serine, meaning all endogenous GRK2 globally cannot be inhibited via NO-mediated S-nitrosylation. We exposed WT, GRK2-C340s KI and β3AR KO mice to ischemia/reperfusion (I/R) injury (40 min ischemia followed by 24 hrs reperfusion). We found that WT mice had significantly diminished cardiac function evaluated by echocardiography and Millar Catheterization, and this was rescued by treating these mice with CL316,243 (a selective β3AR agonist) at the time of reperfusion. On the other hand, GRK2-C340S KI mice did worse after I/R injury compared to WT mice and CL316,243 did not rescue this dysfunction as it did in WT mice. As expected, β3AR KO mice had worsened cardiac function compared to WT mice and CL316,243 had no functional benefit. Infarct size measurements after I/R revealed that β3AR KO mice had larger infarcts than WT mice supporting β3ARs as being protective. Indeed, CL316,243 induced robust cardioprotection in WT mice, reducing infarct size. GRK2-C340S mice had larger infarcts than WT mice and CL316,243 failed to offer any cardioprotection. Thus, β3AR-mediated cardioprotection clearly involves inhibition of GRK2 as part of its therapeutic mechanism and this appears to involve NO-mediated S-nitrosylation.