Sulphate influx in the erythrocytes of normotensive,diabetic and hypertensive patients

This study aimed to show that modifications in intracellular metabolism are implicated in the pathophysiology of diabetes mellitus and essential hypertension. In fact, total magnesium, calcium, sodium and potassium concentrations, measured in the erythrocytes of normotensive, diabetic and hypertensive patients, have given the following results: a lower intracellular potassium concentration in the erythrocytes of diabetic and hypertensive patients than the erythrocytes of normotensive patients and a more elevated sodium, magnesium, calcium concentrations in the erythrocytes of diabetic and hypertensive patients than the normotensive.Because of the importance of Mg2+ and Ca2+ in metabolic enzyme regulation and their interaction with both Hb and band 3 protein, we examined SO4(2-) kinetic influx in the erythrocytes of normotensive, hypertensive and diabetic patients. The kinetic plots showed different profiles over the three groups and the fluxes were found to be 0.024, 0.061 and 0.072 mmol x (l cells x min)(-1) in normotensive, hypertensive and diabetic patients, respectively. We also found that the Vmax and Km of sulphate influx, obtained by Hofstee plots, increased in the erythrocytes of hypertensive and diabetic patients compared with control cells. In contrast, sulphate influx in the erythrocytes of diabetic and hypertensive patients in the presence of Nifedipine, a calcium antagonist, showed no difference either in the rate constants or in the kinetic profiles, compared to the normotensive control subjects.     

Dietary vitamin C supplementation decreases blood pressure in DOCA-salt hypertensive male Sprague Dawley rats and this is associated with increased liver oxidative stress

The effects of a vitamin C supplemented diet on blood pressure, body and liver weights, liver antioxidant status, iron and copper levels were investigated in DOCA-salt treated and untreated Sprague-Dawley (SD) male rats after 8 weeks of treatment. Vitamin C supplementation had no effect on blood pressure in SD rats but induced a significant decrease in blood pressure in DOCA-salt treated rats, the decrease being more efficient at 50 mg/kg of vitamin C than at 500 mg/kg. Hepatic lipid peroxidation and iron levels were significantly increased in DOCA-salt hypertensive rats whereas total hepatic antioxidant capacity (HAC), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were decreased. Vitamin C supplementation did not affect the overall antioxidant defences of control SD rat livers. In contrast, vitamin C supplementation accentuated the DOCA-salt induced accumulation of liver iron and lipid peroxidation. This occurred without any notable aggravation in the antioxidant deficiency of vitamin C supplemented DOCA-salt treated rat livers. Our data suggest that DOCA-salt treatment induces an accumulation of iron in rat livers which is responsible for the prooxidant effect of vitamin C. The normalization of blood pressure in DOCA-salt treated rats by vitamin C supplementation appears thus independent from liver antioxidant status.     

The role of heme oxygenase signaling in various disorders

Modern methods of cell and molecular biology, augmented by molecular technology, have great potential for helping to unravel the complex mechanisms of various diseases. They also have the potential to help us try to dissect the events which follow the altered physiological conditions. Thus, there is every reason to believe that some of the potential mechanisms will be translated sooner or later into the clinic. Heme oxygenase (HO)-related mechanisms play an important role in several aspects of different diseases. In the past several years, significant progress has been made in our understanding of the function and regulation of HO. The objective of this article is to review current knowledge relating to the importance of HO mechanism in various diseases including myocardial ischemia/reperfusion, hypertension, cardiomyopathy, organ transplantation, endotoxemia, lung diseases, and immunosuppression. The morbidity and mortality of these diseases remain high even with optimal medical management. Furthermore, in this review, we consider various factors influencing the HO system and finally assess current pharmacological approaches to their control.     

Fatty acid composition of brain hemispheres of spontaneously hypertensive rats suckled by female Wistar rats

Total lipid fatty acid composition was investigated in brain hemispheres of male Spontaneously Hypertensive Rats (SHR), compared with normotensive Wistar Kyoto rats (WKY) used as controls. Both strains were suckled by adoptive Wistar mothers, and then fed a standard diet after weaning. No difference was observed between the two hemispheres of WKY killed either at 10 or 30 days. In SHR killed at 10 days, the two hemispheres showed differences, SHR left hemispheres exhibiting greater fatty acid composition changes than those of WKY, phenomenon that toned down at 30 days. Hence, SHR pups showed a different total lipid fatty acid composition of their brain hemispheres when compared with their WKY controls, though the two strains received the same diet. Genetically programmed hypertension might be, directly or not, involved in these changes.     

Increased salt sensitivity secondary to leptin resistance in SHHF rats is mediated by endothelin

A link between leptin resistance, obesity, and salt sensitivity has been suggested. SHHF/Mcc-fa ^cp rats (SHHF) were used to study the effect of gene dosage of a null mutation of the leptin receptor (cp) on salt sensitivity and response to a combined endothelin A and B receptor antagonist (bosentan). Obese (cp/cp), heterozygous (+/cp), and homozygous lean (+/+) male SHHF were fed a low salt diet (0.3% NaCl) for 7 days, followed by a high salt diet (8.0% NaCl) for 7 days. There were no significant differences in systolic blood pressure between genotypes on low salt. In response to high salt, cp/cp had significantly greater systolic pressure than +/cp and +/+. On high salt diet, cp/cp showed a significant increase in 24 h urinary endothelin excretion and increased renal expression of preproendothelin mRNA. There was no effect of high salt diet on renal excretion of nitric oxide (NOx) or on gene expression of endothelial, neuronal, or cytokine-induced nitric oxide synthase isoforms (eNOS, nNOS, iNOS, respectively). Treatment with bosentan prevented the high salt-induced increment in systolic blood pressure in cp/cp. This was associated with a doubling of renal NOx excretion, but without changes in eNOS, nNOS, or iNOS expression. Endothelin receptor antagonism did not normalize systolic pressure in any of the genotypes. Our studies indicate that obesity secondary to leptin resistance (cp/cp) results in increased salt sensitivity that is mediated by endothelin in the SHHF rat.     

Salt-induced hypertension in WKY rats: Prevention by α-lipoic acid supplementation

There is strong evidence that points to excess dietary salt as a major factor contributing to the development of hypertension. Salt sensitivity is associated with glucose intolerance and insulin resistance in both animal models and humans. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes which bind to vascular calcium channels, increasing cytosolic [Ca²⁺]_i and blood pressure. In an insulin resistant animal model of hypertension, spontaneously hypertensive rats (SHRs), dietary supplementation with lipoic acid lowers tissue aldehydes and plasma insulin levels and normalizes blood pressure. The objective of this study is to examine the effects of a high salt diet on tissue aldehydes, cytosolic [Ca²⁺]_i and blood pressure in WKY rats and to investigate whether dietary supplementation with lipoic acid can prevent a salt induced increase in blood pressure. Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each and treated for 10 weeks with diets as follows: WKY-normal salt (0.7% NaCl); WKY-high salt (8% NaCl); WKY-high salt + lipoic acid (8% NaCl diet + lipoic acid 500 mg/Kg feed). At completion, animals in the high salt group had elevated systolic blood pressure, platelet [Ca²⁺]_i, and tissue aldehyde conjugates compared with the normal salt group and showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary -lipoic acid supplementation in high salt-treated WKY rats normalized systolic blood pressure and cytosolic [Ca²⁺]_i and aldehydes in liver and aorta. Kidney aldehydes and renal vascular changes were attenuated, but not normalized.     

Control of cardiomyocyte gene expression as drug target

Pressure overload of the heart is associated with a perturbed gene expression of the cardiomyocyte leading to an impaired pump function. The ensuing neuro-endocrine activation results in disordered influences of angiotensin II and catecholamines on gene expression. To assess whether angiotensin II type 1 receptor inhibition can also counteract a raised sympathetic nervous system activity, spontaneously hypertensive rats fed a hypercaloric diet were treated with eprosartan (daily 90 mg/kg body wt) and cardiovascular parameters were monitored with implanted radiotelemetry pressure transducers. Both, blood pressure and heart rate were increased (p < 0.05) by the hypercaloric diet. Although eprosartan reduced (p < 0.05) the raised systolic and diastolic blood pressure, the diet-induced rise in heart rate was blunted only partially. In addition to drugs interfering with the enhanced catecholamine influence, compounds should be considered that selectively affect cardiomyocyte gene expression via 'metabolic' signals.     

Molecular Cloning and Chromosomal Localization of Human Salt-Tolerant Protein

We have isolated a novel human cDNA coding for human salt-tolerant protein (HSTP), that is a homologue of the rat salt-tolerant protein (STP) and may contribute to salt-induced hypertension by modulating renal cation transport. The nucleotide sequence (1988 bp) of the HSTP cDNA contains an open reading frame encoding a polypeptide comprising 545 amino acids, two residues fewer than the rat STP cDNA. The predicted amino acid sequence exhibits 92% identity to that of the rat protein. HSTP contains predicted coiled-coil domains and Src Homology 3 domain, and shows a high degree of identity to CIP4 (Cdc42 target protein) and human Trip 10 (thyroid-hormone receptor interacting protein). We have mapped the HSTPgene to human chromosome 19 by fluorescence in situhybridization. This revised version was published online in July 2006 with corrections to the Cover Date.     

The long-term costs of traumatic stress: intertwined physical and psychological consequences

The gradual emergence of symptoms following exposure to traumatic events has presented a major conceptual challenge to psychiatry. The mechanism that causes the progressive escalation of symptoms with the passage of time leading to delayed onset post-traumatic stress disorder (PTSD) involves the process of sensitization and kindling. The development of traumatic memories at the time of stress exposure represents a major vulnerability through repeated environmental triggering of the increasing dysregulation of an individual’s neurobiology. An increasing body of evidence demonstrates how the increased allostatic load associated with PTSD is associated with a significant body of physical morbidity in the form of chronic musculoskeletal pain, hypertension, hyperlipidaemia, obesity and cardiovascular disease. This increasing body of literature suggests that the effects of traumatic stress need to be considered as a major environmental challenge that places individual’s physical and psychological health equally at risk. This broader perspective has important implications for developing treatments that address the underlying dysregulation of cortical arousal and neurohormonal abnormalities following exposure to traumatic stress.     

Chronopharmacology of cardiovascular medications

The cardiovascular system is well organized in time. Mechanisms of regulation and pathophysiological events are not evenly distributed over the 24-h scale. Moreover, certain diseases may even alter the physiological circadian pattern in the cardiovascular system. This observation bares implications for drug treatment, e.g. regarding drug formulations and dosing time intervals. Pitfalls may arise from neglecting circadian phase-dependency in pharmacokinetics and in the concentration-dependent effect relationship. Moreover, different types of drugs may be superior to others when circadian time-related symptoms are concerned. There is sound evidence that “time-of-day” has to be included in our diagnostic and therapeutic strategies.