The altered balance between sympathetic nervous system and nitric oxide in salt hypertensive Dahl rats: ontogenetic and F2 hybrid studies.

OBJECTIVE: We have demonstrated earlier that the nitric oxide (NO) system is not able to counterbalance effectively the hyperactivity of the sympathetic nervous system (SNS) in salt hypertension of young Dahl rats in which augmented superoxide anion formation lowers NO bioavailability. The aim of the present study was to determine whether SNS hyperactivity and/or relative NO deficiency are also present in salt hypertension elicited in adult Dahl rats, and whether they are associated with blood pressure (BP) in the F2 population of Dahl rats. DESIGN AND METHODS: The contribution of major vasoactive systems [renin-angiotensin system (RAS), SNS and NO] and superoxide anions to BP maintenance was studied in SS/Jr rats in which salt hypertension was induced either in adulthood or in youth (8% NaCl diet from the age of 12 or 4 weeks). The contribution of particular vasoactive systems was also investigated in 122 young salt-loaded F2hybrids [derived from salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats] which were fed a high-salt diet (8% NaCl) for 6 weeks after weaning. Mean arterial pressure (MAP) was measured in conscious animals subjected to acute consecutive blockade of RAS (captopril 10 mg/kg i.v.), SNS (pentolinium 5 mg/kg i.v.) and NO synthase (l-NAME 30 mg/kg i.v.). RESULTS: Dahl rats with salt hypertension induced in adulthood were also characterized by enhanced pentolinium-induced BP fall (DeltaMAPpento), but their residual BP (recorded after the blockade of both RAS and SNS) was unaltered, in contrast to its elevation seen in young salt-hypertensive rats. The BP rise after NO synthase inhibition by l-NAME (DeltaMAPL-NAME), which was substantially greater in adult than in young hypertensive rats, was not enhanced by superoxide scavenging with tempol in adult hypertensive animals, in which this drug elicited a moderate BP reduction only. Basal MAP of young salt-loaded F2 hybrids was positively associated not only with DeltaMAPpento (P < 0.0001) and residual BP (P < 0.001) but also with DeltaMAPL-NAME (P < 0.001). The slope of the relationship between basal BP and pentolinium-induced BP changes was steeper than that between basal BP and BP changes elicited by l-NAME. The positive correlation of basal BP with DeltaMAPpento/DeltaMAPL-NAME ratio (P < 0.01) indicates that an altered balance between sympathetic vasoconstriction and NO-dependent vasodilation was associated with high blood pressure, even in the F2 population of Dahl rats. CONCLUSIONS: A comparison of young and adult salt-hypertensive Dahl rats stressed the importance of increased residual BP and relative NO deficiency for the severity of hypertension, because these two alterations were absent in a less-pronounced form of salt hypertension elicited in adulthood. The findings obtained in our young salt-loaded F2 population also confirm the major importance of both sympathetic hyperactivity and relative NO deficiency for the maintenance of salt hypertension in Dahl rats.

Effect of acute hyperglycemia on erythrocyte membrane ion transport in offspring of hypertensive parents.

OBJECTIVE: Patients with essential hypertension exhibit several red blood cell (RBC) ion transport abnormalities, insulin resistance (IR) and increased risk of developing type 2 diabetes. The aims of this study were to assess RBC ion transport activities under basal conditions and to test the in vivo effect of acute hyperglycemia on RBC ion transport in the offspring of hypertensive parents (OHP) and healthy controls (C). DESIGN AND METHODS: Activities of Na+-K+ pump, Na+-K+ cotransport, Na+-Li+ countertransport (SLC) and Na+, Rb+ and Li+ leaks were measured before and after a 5-h hyperglycemic (12 mmol/l) clamp (HGC) and compared to values found under euglycemic isovolumic conditions in OHP (n = 12) and C (n = 14). Insulin action was calculated as insulin sensitivity index (M/I) during HGC. RESULTS: The offspring of hypertensive parents were characterized by lower M/I (0.07 +/- 0.03 versus 0.12 +/- 0.07 mg/kg per min per microU per ml; P < 0.05) and elevated SLC (0.080 +/- 0.004 versus 0.068 +/- 0.003 mmol/h per litre; P < 0.05), as well as by higher Li+ (0.106 +/- 0.004 versus 0.093 +/- 0.003 mmol/h per litre; P < 0.05) and Rb+ leaks (0.160 +/- 0.014 versus 0.120 +/- 0.007 mmol/h per litre; P < 0.05) compared to controls. Acute hyperglycemia did not cause significant changes in any investigated RBC ion transport parameters. CONCLUSIONS: The offspring of hypertensive parents displayed higher insulin resistance, enhanced activity of SLC and formerly undocumented augmented Li+ and Rb+ leaks. Acute hyperglycemia did not modify any RBC ion transport activities in either offspring of hypertensive parents or controls.

Erythrocyte membrane ion transport in offspring of hypertensive parents: effect of acute hyperinsulinemia and relation to insulin action.

Some patients with essential hypertension exhibit insulin resistance (IR) and several red blood cell (RBC) ion transport abnormalities. The aims of the study were to assess RBC ion transport acitivities under basal conditions, to test in vivo the effect of acute hyperinsulinemia, and to evaluate the relationship to IR in the offspring of hypertensive parents (n = 12; OHP) and healthy controls (n = 14; C). Activities of the Na+-K+ pump, Na+-K+ cotransport, Na+-Li+ countertransport (SLC), and Na+, Rb+, and Li+ leaks (passive membrane permeability) were measured before and after a hyperinsulinemic (75 microU/mL) euglycemic clamp (HIC) and compared to those found under isoinsulinemic isovolumic conditions in OHP and C. An insulin action was calculated as glucose disposal and insulin sensitivity index (M/I) after HIC. OHP were characterized by lower M/I (0.12+/-0.07 vs. 0.20+/-0.09 mg/kg/min/microU/mL; p < 0.05) and elevated SLC and Li+ and Rb+ leaks (p < 0.05) compared with C. Although acute hyperinsulinemia did not modify significantly any ion transport parameter studied, negative correlation was observed between insulin action and membrane cation leaks. Glucose disposal correlated with an Li+ leak in C (r = -0.736; p < 0.01) and all subjects (r = -0.424; p < 0.05) after HIC and in OHP with an Na+ leak (r = -0.727; p < 0.05) before HIC. In conclusion, OHP displayed higher insulin resistance, enhanced activity of SLC, and augmented Li+ and Rb+ leaks. Acute hyperinsulinemia did not modify any ion transport parameter studied, although negative correlation was observed between insulin action and membrane leaks.

Membrane ion transport in erythrocytes of salt hypertensive Dahl rats and their F2 hybrids: the importance of cholesterol.

The possible association of salt hypertension and altered lipid metabolism with abnormalities of particular systems transporting sodium and potassium has been studied in erythrocytes of Dahl rats and their F2 hybrids fed a high-salt diet since weaning. Our attention was paid to the Na(+)-K+ pump, Na(+)-K+ cotransport and especially to passive membrane permeability for Na+ and Rb+ (Na+ and Rb+ leak), because the Na+ leak was found to be dependent on the genotype, age and salt intake of Dahl rats, whereas the Rb+ leak was suggested to be a potential marker of salt sensitivity in Dahl and Sabra rats. Young male Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats kept on a low-salt (0.3% NaCl) or high-salt diet (8% NaCl) were used for the progenitor study. The subsequent genetic study was based on 135 young male SS/Jr x SR/Jr F2 hybrids fed a high-salt diet since weaning. Ouabain (5 mmol/l) and bumetanide (10 micromol/l) were used to distinguish the contribution of the Na(+)-K+ pump, Na(+)-K+ cotransport and passive membrane permeability to measured net Na+ fluxes and unidirectional Rb+ (K+) movements. Compared to normotensive SR/Jr animals, salt-loaded SS/Jr rats had higher blood pressure (BP), elevated erythrocyte Na+ content, and increased Na+ and Rb+ leaks together with enhanced Na+ and Rb+ transport mediated by the Na(+)-K+ pump and Na(+)-K+ cotransport system. Salt hypertensive Dahl rats were also characterized by elevated plasma levels of total cholesterol and triglycerides, which were positively associated with BP of F2 hybrids (r=0.27 and 0.24, p< 0.01). In F2 hybrids, mean arterial pressure correlated significantly with erythrocyte Na+ content (r=0.24, p<0.01) and ouabain-sensitive Na+ extrusion, but not with the passive membrane permeability for Na+ or Rb+ (r=-0.02 and 0.06, not significant). Both of the above-mentioned significant associations could partially be ascribed to the dependence of erythrocyte Na+ content and ouabain-sensitive Na+ extrusion on plasma cholesterol (r=0.18 and 0.21, p<0.05). Our results support the idea that abnormal lipid metabolism and/or altered Na+,K(+)-ATPase function play an important role in the pathogenesis of salt hypertension in salt-sensitive Dahl rats.

Erythrocyte ion transport and membrane lipid composition in young and adult rats with NO-deficient hypertension.

The aim of our study was to search for abnormalities of sodium and potassium transport in erythrocytes of male Wistar rats subjected to chronic L-NAME treatment (40 mg/kg/day) for 4 weeks either from weaning (4-week-old) or in adulthood (12-week-old). Sodium content, Na(+),K(+)-pump and Na(+),K(+)-cotransport activity, cation leaks as well as membrane cholesterol and phospholipid contents were determined in fresh erythrocytes. Chronic inhibition of NO synthase elicited similar blood pressure rise in both age groups which did not differ in the degree of NO synthase inhibition. No significant ion transport abnormalities were disclosed in erythrocytes of young NO-deficient rats, whereas erythrocyte Na(+) content, outward Na(+),K(+)-cotransport and inward Na(+) leak were significantly reduced in adult hypertensive animals compared to age-matched controls. It should be noted that the erythrocytes of adult control rats were characterized by higher activity of Na(+),K(+)-pump and Na(+),K(+)-cotransport, increased Na(+) and Rb(+) leaks and elevated membrane cholesterol content compared to those of young normotensive controls. Increased Na(+) leak and elevated membrane cholesterol content but reduced membrane phospholipid content were revealed in erythrocytes of adult hypertensive rats when compared to young hypertensive rats. It can be concluded that young and adult Wistar rats did not differ in the extent of NO synthase inhibition and blood pressure rise elicited by chronic L-NAME treatment. Our results exclude the important participation of classical sodium transport abnormalities in the pathogenesis of this NO-deficient form of experimental hypertension.

Hypertensive response to chronic NG-nitro-L-arginine methyl ester (L-NAME) treatment is similar in immature and adult Wistar rats.

The aim of our study was to evaluate whether the blood pressure (BP) response to chronic inhibition of NO synthase (NOS) is exaggerated in young rats, which were reported to develop a more pronounced salt hypertension than the adult ones. The enhanced BP rise in immature rats subjected to excess salt intake might be due either to a generally increased reactivity in immature organisms to these stimuli or to a greater impairment of NO bioavailability that accompanies the development of salt hypertension. To determine between the two alternatives, we have compared the hypertensive response and the extent of NOS inhibition in immature (4-week-old) and adult (12-week-old) male Wistar rats which were treated with NG-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg of body mass per day) for 4 weeks. BP and NOS activity in the aorta, left ventricle and kidney were determined at the end of the experiment. It should be noted that chronic L-NAME treatment caused a similar degree of NOS inhibition in both age groups (irrespective of tissue examined). There was no significant difference in BP elevation between young and adult animals chronically treated with L-NAME. A strong negative correlation between NOS activity and BP level was observed in separate groups of normotensive controls and L-NAME hypertensive rats. Thus the BP of both normotensive and hypertensive animals seems to be inversely proportional to the production of NO. It can be concluded that there was the same BP rise in both age groups of L-NAME-treated rats in which a similar degree of NOS inhibition was disclosed. This suggests that the altered NO bioavailability (but not the generally exaggerated reactivity to hypertensive stimuli) is the cause of exaggerated hypertensive response observed in immature rats exposed to excess salt intake.