In hypertensive subjects with LVH, regression of LVH was predicted much more closely by treatment-induced changes in ABP than in the clinic BP. This provides the first longitudinally controlled evidence that ABP may be clinically superior to traditional BP measurements.
In this study, we reveal that leptin evokes an acute hypotensive effect in 6-hydroxydopamine sympathectomized rats (response to maximal leptin dose, mean blood pressure: from 92 +/- 4 to 78 +/- 2 mmHg, P < 0.01). This hemodynamic effect is related to a direct action of the hormone on vascular tone, since in aortic and mesenteric rings increasing doses of leptin evoke a dose-dependent vasorelaxation (aorta: from 3 +/- 1 to 36 +/- 3, n = 15; mesenteric: from 6 +/- 1 to 30 +/- 5, n = 10), which is impaired by endothelial denudation. In particular, leptin-evoked vasorelaxation is impaired by nitric oxide synthase inhibition in aorta (delta% of maximal response: from 36 +/- 3 to 3 +/- 1, P < 0.01) and by endothelium-derived hyperpolarizing factor (EDHF) inhibition in mesenteric arteries (delta% of maximal response: from 30 +/- 5 to 7 +/- 2, P < 0.01), suggesting that vasorelaxation evoked by leptin is heterogeneous and related to the vascular bed. Finally, the inhibition of nitric oxide synthase by NG-nitro-L-arginine-methyl ester does not modify blood pressure response to leptin, suggesting a predominant role of the EDHF mechanism in the hypotensive effect of leptin.
Recent evidence suggests that besides its action on the central nervous system, leptin can modulate vascular tone through local mechanisms involving nitric oxide (NO) release. In this study, using a fluorescent probe for direct determination of NO, we demonstrated both in endothelial cells and in vessels that leptin is able to stimulate NO release. The effect of leptin on NO is abolished by erbstatin A, a Ca 2؉ -independent tyrosine kinase inhibitor, whereas it is not influenced by calcium removal or by other protein phosphorylation inhibitors, such as genistein (an ATP-dependent tyrosine-kinase inhibitor) or wortmannin and LY294002 (two different phosphatidylinositol [PI] 3-kinase inhibitors). Accordingly, leptin-induced vasorelaxation in aortic rings was abolished only by erbstatin A. Furthermore, immunoblotting studies revealed that leptin evokes Akt phosphorylation, with a comparable time course in both endothelial cells and vessels. Also in this experimental system, the effect of leptin was abolished by erbstatin A and not by other inhibitors. Finally, a considerable increase in endothelial NO synthase (eNOS) phosphorylation in Ser 1177 was found when vessels were treated with leptin. In conclusion, leptin induces NO production by activating a PI 3-kinase-independent Akt-eNOS phosphorylation pathway. Diabetes 51: 168 -173, 2002
These data suggest that in response to chronic pressure overload, cardiomyocyte-specific apoptosis contributed to the transition from LVH to LVD. LVH and LVD were accompanied by a dramatic cardiomyocyte upregulation of the proapoptotic gene bax and reduced bcl-2/bax ratio, predisposing cardiomyocytes to apoptosis.
IntroductionThe reason why hyperinsulinemia is associated with essential hypertension is not known. To test the hypothesis of a pathophysiologic link mediated by the sympathetic nervous system, we measured the changes in forearm norepinephrine release, by using the forearm perfusion technique in conjunction with the infusion of tritiated NE, in patients with essential hypertension and in normal subjects receiving insulin intravenously (1 mU/ kg per min) while maintaining euglycemia.Hyperinsulinemia (50-60 jsU/ml in the deep forearm vein) evoked a significant increase in forearm NE release in both groups of subjects. However, the response of hypertensives was threefold greater compared to that of normotensives (2.28±45 ng. liter-' * min' in hypertensives and 0.80±0.27 ng. liter-' in normals; P < 0.01). Forearm Although the coexistence ofhyperinsulinemia and essential hypertension has long been recognized (1-3), the nature and the significance of this association are far from being completely elucidated. A critical question is whether hyperinsulinemia is causally related to the development of hypertension and, if so, what mechanism underlies insulin action on blood pressure regulation. The question is under active investigation but the data available so far are not entirely consistent. Substantial evidence favoring a causal role of insulin comes essentially from the studies in fructose-fed rats (4-6). In this model, insulin resistance, hyperinsulinemia, and hypertension develop and this sequence may be interrupted by preventing either insulin resistance with physical exercise or hyperinsulinemia with somatostatin (5, 6).The relationship between insulin and human hypertension has been extensively investigated on epidemiological ground, less so from a mechanistic standpoint. The available clinical data, however, tend to support the concept that the two factors must be linked by pathophysiologic mechanisms. Particularly relevant is the observation that a program of physical activity or body weight control leads to a parallel reduction of hyperinsulinemia and blood pressure levels (7). Of interest is also the recent observation that in the offspring of essential hypertensive parents insulin resistance and hyperinsulinemia are demonstrable before the development of high blood pressure (8).Among the various factors considered as potential links between insulin and blood pressure, the sympathetic nervous system is indicated as a prime candidate for a number of reasons: (a) in hypertensive patients, glucose intolerance and insulin resistance with attendant hyperinsulinemia have been amply demonstrated (3, 9, 10); (b) in normal individuals, insulin evokes sympathetic overactivity (1 1, 12); (c) increased sympathetic activity in essential hypertension, particularly in the mild form of young hypertensives, has been documented by a variety of approaches (13,14); and (d) sympathetic overactivity may be potentially responsible for elevated blood pressure (15) and may antagonize insulin action (16)(17)(18)(19)(20). Ba...
Abstract-Upregulation of the sympathetic nervous system plays a key role in the pathogenesis of insulin resistance.Although the heart is a target organ of insulin, few studies have examined the mechanisms by which -adrenergic stimulation affects insulin sensitivity in cardiac muscle. In this study, we explored the molecular mechanisms involved in the regulation of the cross-talk between  adrenergic and insulin receptors in neonatal rat cardiomyocytes and in transgenic mice with cardiac overexpression of a constitutively active mutant of Akt (E40K Tg). The results of this study show that -adrenergic receptor stimulation has a biphasic effect on insulin-stimulated glucose uptake. Short-term stimulation induces an additive effect on insulin-induced glucose uptake, and this effect is mediated by phosphorylation of Akt in threonine 308 through PKA/Ca 2ϩ -dependent and PI3K-independent pathway, whereas insulin-evoked threonine phosphorylation of Akt is exclusively PI3K-dependent. On the other hand, long-term stimulation of -adrenergic receptors inhibits both insulin-stimulated glucose uptake and insulin-induced autophosphorylation of the insulin receptor, and at the same time promotes threonine phosphorylation of the insulin receptor. This is mediated by serine 473 phosphorylation of Akt through PKA/Ca 2ϩ and PI3K-dependent pathways. Under basal conditions, E40K Tg mice show increased levels of threonine phosphorylation of the  subunit of the insulin receptor and blunted tyrosine autophosphorylation of the -subunit of the insulin receptor after insulin stimulation. These results indicate that, in cardiomyocytes, -adrenergic receptor stimulation impairs insulin signaling transduction machinery through an Akt-dependent pathway, suggesting that Akt is critically involved in the regulation of insulin sensitivity.
A simple estimate of low myocardial mechano-energetic efficiency is associated with altered metabolic profile, LVH, concentric left ventricular geometry, and diastolic dysfunction and predicts cardiovascular end-points, independently of age, sex, LVH antihypertensive therapy, and cardiovascular risk factors.
Background and Purpose-Endothelium-derived NO is formed from L-arginine by endothelial NO synthase (eNOS) encoded by the NOS 3 gene on chromosome 7. Because several studies have indicated that NO plays a key role in the development of the atherosclerotic process, we investigated whether common variants in the eNOS gene are associated with an increased risk of plaque on carotid arteries. Methods-We studied 375 subjects attending the hypertension center of our institution to be screened for arterial hypertension. The examined subjects were classified according to the presence of carotid plaques (intima-media thickness Ն1.5 mm), and 2 intronic (CA and 27-bp repeats) polymorphisms and 1 exonic (Glu298Asp) polymorphism of the eNOS gene were explored. Results-Only the Glu298Asp polymorphism of eNOS was associated with the presence of carotid plaques (PϽ0.05). In particular, there was an excess of homozygotes for the Asp298 variant among subjects with carotid plaques, whereas the number of subjects who had the Glu298 allele in exon 7 of the eNOS gene was equally distributed in both study groups. Interestingly, the risk of having carotid plaques was increased Ϸ3 times in subjects who were homozygotic for the Asp298 variant compared with subjects who were homozygotic for the Glu298 variant and was independent of the other common risk factors (age, blood pressure, and smoking). Conclusions-Homozygosity for Asp298, a common variant of the eNOS gene, is an independent risk factor for carotid atherosclerosis in this study population.
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