SAR340835, a Novel Selective Na/Ca Exchanger Inhibitor, Improves Cardiac Function and Restores Sympathovagal Balance in Heart Failure.

In failing hearts, Na/Ca exchanger (NCX) overactivity contributes to Ca depletion, leading to contractile dysfunction. Inhibition of NCX is expected to normalize Ca mishandling, to limit afterdepolarization-related arrhythmias, and to improve cardiac function in heart failure (HF). SAR340835/SAR296968 is a selective NCX inhibitor for all NCX isoforms across species, including human, with no effect on the native voltage-dependent calcium and sodium currents in vitro.

Control of blood pressure variability in caveolin-1-deficient mice: role of nitric oxide identified in vivo through spectral analysis.

Aims: In endothelial cells, caveolin-1 (cav-1) is known to negatively modulate the activation of endothelial nitric oxide synthase, a key regulator of blood pressure (BP). However, the impact of genetic alteration of cav-1 on vascular nitric oxide (NO) production and BP homeostasis in vivo is unknown.

Methods And Results: We used spectral analysis of systolic blood pressure (SBP) variability in mice chronically equipped with telemetry implants to identify frequency ranges (0.

Rosuvastatin increases vascular endothelial PPARgamma expression and corrects blood pressure variability in obese dyslipidaemic mice.

Aims: Statins improve atherosclerotic diseases through cholesterol-reducing effects. Whether the latter exclusively mediate similar benefits, e.g.

H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart.

Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia.

Protein turnover in cardiac cell growth and survival.

Protein turnover represents the balance between protein synthesis and degradation. It can be controlled quantitatively, for instance by an activation of protein synthesis during cardiac hypertrophy or by activating protein degradation during ventricular unloading. It can also be regulated qualitatively by changing the steady state concentration of specific proteins and enzymes.

Regulation of the mammalian heart function by nitric oxide.

The mammalian heart expresses all three isoforms of nitric oxide synthases (NOS) in diverse cell types of the myocardium. Despite their apparent promiscuity, the NOS isoforms support specific signaling because of their subcellular compartmentation with colocalized effectors and limited diffusibility of NO in muscle cells. eNOS and nNOS sustain normal EC coupling and contribute to the early and late phases of the Frank-Starling mechanism of the heart.

Statins and hypertension.

Hypertension and dyslipidemia are frequently associated as risk factors for cardiovascular diseases. Statins are among the most potent drugs to correct hypercholesterolemia, and their use across a wide range of cardiovascular risk levels significantly reduced morbidity and mortality in large intervention trials. Aside from (or in addition to) reducing plasma cholesterol, statins also reduce blood pressure, another effect associated with cardiovascular risk reduction by other antihypertensive drugs.

Weight-loss-associated induction of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma correlate with reduced atherosclerosis and improved cardiovascular function in obese insulin-resistant mice.

Background: Weight loss in obese insulin-resistant but not in insulin-sensitive persons reduces coronary heart disease risk. To what extent changes in gene expression are related to atherosclerosis and cardiovascular function is unknown.

Methods And Results: We studied the effect of diet restriction-induced weight loss on gene expression in the adipose tissue, the heart, and the aortic arch and on atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency.

Cardiomyocyte-restricted overexpression of endothelial nitric oxide synthase (NOS3) attenuates beta-adrenergic stimulation and reinforces vagal inhibition of cardiac contraction.

Background: In the heart, nitric oxide synthases (NOS) modulate cardiac contraction in an isoform-specific manner, which is critically dependent on their cellular and subcellular localization. Defective NO production by NOS3 (endothelial NOS [eNOS]) in the failing heart may precipitate cardiac failure, which could be reversed by overexpression of NOS3 in the myocardium.

Methods And Results: We studied the influence of NOS3 in relation to its subcellular localization on the function of cardiomyocytes isolated from transgenic mice overexpressing NOS3 under the alpha-myosin heavy chain promoter (NOS3-TG).

Caveolin-1 expression is critical for vascular endothelial growth factor-induced ischemic hindlimb collateralization and nitric oxide-mediated angiogenesis.

Nitric oxide (NO) is a powerful angiogenic mediator acting downstream of vascular endothelial growth factor (VEGF). Both the endothelial NO synthase (eNOS) and the VEGFR-2 receptor colocalize in caveolae. Because the structural protein of these signaling platforms, caveolin, also represses eNOS activity, changes in its abundance are likely to influence the angiogenic process in various ways.

Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E-/- mice in vivo.

Background: Decreased heart rate variability (HRV) and increased blood pressure variability (BPV), determined in part by nitric oxide (NO)-dependent endothelial dysfunction, are correlated with adverse prognosis in cardiovascular diseases. We examined potential alterations in BPV and HRV in genetically dyslipidemic, apolipoprotein (apo) E-/-, and control mice and the effect of chronic statin treatment on these parameters in relation to their NO synthase (NOS)-modifying properties.

Methods And Results: BP and HR were recorded in unrestrained, nonanesthetized mice with implanted telemetry devices with or without rosuvastatin.

Cardiac transcriptome analysis in obesity-related hypertension.

Obesity is associated with volumetric arterial hypertension and with early increase in heart rate and decreased heart rate variability. The consequences of obesity-related hypertension on heart gene regulation are poorly known and were investigated in a model of obesity-related hypertension induced by high fat diet in dogs. When compared with control animals (n=6), a 9-week high fat diet (n=6) provoked significant weight gain and increased blood pressure load and heart rate but failed to significantly change left ventricular mass assessed by echocardiography.

High isoproterenol doses are required to activate beta3-adrenoceptor-mediated functions in dogs.

The "in vivo" conditions for beta3-adrenoceptors (beta-AR) activation by isoproterenol were investigated in dog. Experiments were carried out in anesthetized dogs using isoproterenol as a nonselective beta-AR agonist. Intravenous infusion of isoproterenol (0.

Alpha2 -adrenoceptor function in arterial hypertension associated with obesity in dogs fed a high-fat diet.

Objective: To investigate the status of alpha2-adrenoceptors in a model of obesity-related arterial hypertension.

Design: A parallel study in dogs randomly assigned to a high-fat diet (HFD group, n = 6) or normal canine food (controls, n = 6) for 9 weeks.

Methods: Postsynaptic vascular alpha2-adrenoceptors were assessed through analysis of dose-pressor responses to clonidine [2.