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Increased sympathoexcitation and renal sodium retention during high salt intake are hallmarks of the salt sensitivity of blood pressure. The mechanism(s) by which excessive sympathetic nervous system release of norepinephrine influences renal sodium reabsorption is unclear. However, studies demonstrate that norepinephrine can stimulate the activity of the NCC (sodium chloride cotransporter) and promote the development of SSH (salt-sensitive hypertension). The adrenergic signaling pathways governing NCC activity remain a significant source of controversy with opposing studies suggesting a central role of upstream α1- and β-adrenoceptors in the canonical regulatory pathway involving WNKs (with-no-lysine kinases), SPAK (STE20/SPS1-related proline alanine-rich kinase), and OxSR1 (oxidative stress response 1). In our previous study, α1-adrenoceptor antagonism in norepinephrine-infused male Sprague-Dawley rats prevented the development of norepinephrine-evoked SSH in part by suppressing NCC activity and expression. In these studies, we used selective adrenoceptor antagonism in male Dahl salt-sensitive rats to test the hypothesis that norepinephrine-mediated activation of the NCC in Dahl SSH occurs via an α1-adrenoceptor dependent pathway. A high-salt diet evoked significant increases in NCC activity, expression, and phosphorylation in Dahl salt-sensitive rats that developed SSH. Increases were associated with a dysfunctional WNK1/4 dynamic and a failure to suppress SPAK/OxSR1 activity. α1-adrenoceptor antagonism initiated before high-salt intake or following the establishment of SSH attenuated blood pressure in part by suppressing NCC activity, expression, and phosphorylation. Collectively, our findings support the existence of a norepinephrine-activated α1-adrenoceptor gated pathway that relies on WNK/SPAK/OxSR1 signaling to regulate NCC activity in SSH.Iron overload has been recently shown to be associated with a hyperadrenergic state in genetic hemochromatosis. Whether this is also the case in essential hypertension, characterized by sympathetic activation and frequently by body iron overload, is unknown. In 17 healthy normotensive controls (age 52.3±3.2 years, mean±SE), in 21 age-matched patients with hypertension with iron overload (HT+), defined by serum ferritin levels, and in 28 hypertensives without this condition, we measured efferent postganglionic muscle sympathetic nerve traffic (microneurography), heart rate and blood pressure variability (power spectral analysis), serum ferritin, and metabolic variables. Muscle sympathetic nerve traffic was significantly (P less then 0.02 at least) greater in HT+ than in patients with hypertension without iron overload and normotensive subjects both when expressed as bursts incidence over time (41.8±1.4 versus 31.5±1.4 and 23.6±0.9 bursts/min) and as bursts corrected for heart rate (55.3±1.8 versus 42.3±1.2 and 31.7±1.2 bursts/100 heartbeats). In HT+, low-frequency systolic blood pressure variability was significantly reduced. In HT+, but not in the other 2 groups, muscle sympathetic nerve traffic was significantly related to serum ferritin (r=0.51, P less then 0.03), transferrin saturation (r=0.47, P less then 0.03), and hepatic iron load (r=0.76, P less then 0.0001, magnetic resonance imaging), as well as to homeostatic model assessment index values (r=0.46, P less then 0.05). find more These data provide the first evidence that in HT+ elevated serum ferritin is associated with a hyperadrenergic state of greater magnitude than the one seen in patients with hypertension without iron overload. They also show that the potentiation of the sympathetic activation detected in HT+ is related to elevated serum ferritin and to the associated metabolic alterations, possibly participating in the increased cardiovascular risk characterizing iron overload.The carotid body is implicated as an important mediator and potential treatment target for hypertension. The mechanisms driving increased carotid body tonicity in hypertension are incompletely understood. Using a large preclinical animal model, which is crucial for translation, we hypothesized that carotid sinus nerve denervation would chronically decrease blood pressure in a renovascular ovine model of hypertension in which hypertonicity of the carotid body is associated with reduced common carotid artery blood flow. Adult ewes underwent either unilateral renal artery clipping or sham surgery. Two weeks later, flow probes were placed around the contralateral renal and common carotid arteries. Hypertension was accompanied by a significant reduction in common carotid blood flow but no change in renal blood flow. Carotid sinus nerve denervation significantly reduced blood pressure compared with sham. In both hypertensive and normotensive animals, carotid body stimulation using potassium cyanide caused dose-dependent increases in mean arterial pressure and common carotid conductance but a reduction in renal vascular conductance. These responses were not different between the animal groups. Taken together, our findings indicate that (1) the carotid body is activated in renovascular hypertension, and this is associated with reduced blood flow (decreased vascular conductance) in the common carotid artery and (2) the carotid body can differentially regulate blood flow to the common carotid and renal arteries. We suggest that in the ovine renovascular model, carotid body hypertonicity may be a product of reduced common carotid artery blood flow and plays an amplifying role with the kidney in the development of hypertension.Although relatively rare in childhood, primary hypertension (PH) is thought to have originated in childhood and may be even determined perinatally. PH prevalence increases in school-age children and affects 11% of 18-year-old adolescents. Associated with metabolic risk factors, elevated blood pressure in childhood is carried into adulthood. Analysis of the phenotype of hypertensive children has revealed that PH is a complex of anthropometric and neuro-immuno-metabolic abnormalities, typically found in hypertensive adults. Children with elevated blood pressure have shown signs of accelerated biological development, which are closely associated with further development of PH, metabolic syndrome, and cardiovascular disease in adulthood. find more At the time of diagnosis, hypertensive children were reported to have significant arterial remodelling expressed as significantly increased carotid intima-media thickness, increased stiffness of large arteries, lower area of microcirculation, and decreased endothelial function. These changes indicate that their biological age is 4 to 5 years older than their normotensive peers.
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