Endothelins are a family of peptides, which comprises endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), each containing 21 amino-acids. ET-1 is a peptide secreted mostly by vascular endothelial cells, the predominant isoform expressed in vasculature and the most potent vasoconstrictor currently known. ET-1 also has inotropic, chemotactic and mitogenic properties. In addition, it influences salt and water homeostasis through its effects on the renin-angiotensin-aldosterone system (RAAS), vasopressin and atrial natriuretic peptide and stimulates the sympathetic nervous system.

Obesity increases the risk of hypertension and its cardiovascular complications. This has been partly attributed to increased sympathetic nerve activity, as assessed by microneurography and catecholamine assays. However, increased vasoconstriction in response to obesity-induced sympathoactivation has not been unequivocally demonstrated in obese subjects without hypertension. We evaluated sympathetic α-adrenergic vascular tone in the forearm by brachial arterial infusion of the α-adrenoreceptor antagonist phentolamine (120 µg/min) in normotensive obese (daytime ambulatory arterial pressure: 123 ± 1/77 ± 1 mm Hg; body mass index: 35 ± 1 kg/m2) and lean (daytime ambulatory arterial pressure: 123 ± 2/77 ± 2 mm Hg; body mass index: 22 ± 1 kg/m2) subjects (n = 25 per group) matched by blood pressure, age, and gender. Microneurographic sympathetic nerve activity to skeletal muscle was significantly higher in obese subjects (30 ± 3 versus 22 ± 1 bursts per minute; P = 0.02). Surprisingly, complete α-adrenergic receptor blockade by phentolamine (at concentrations sufficient to completely inhibit norepinephrine and phenylephrine-induced vasoconstriction) caused equivalent vasodilatation in obese (−57 ± 2%) and lean subjects (−57 ± 3%; P = 0.9). In conclusion, sympathetic vascular tone in the forearm circulation is not increased in obese normotensive subjects despite increased sympathetic outflow. Vasodilator factors or mechanisms occurring in obese normotensive subjects could oppose the vasoconstrictor actions of increased sympathoactivation. Our findings may help to explain why some obese subjects are protected from the development of hypertension.

Normotensive obese individuals exhibit markedly impaired muscle and skin microcirculatory responses to mental stress. The increased propensity of obese individuals to develop hypertension under conditions of chronic psychosocial stress may underlie obesity-related hypertension and cardiovascular disease.

Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil.

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Evidence from experimental studies suggest that renalase, a soluble FAD-dependent protein, is involved in blood pressure regulation, possibly via degradation of catecholamines including noradrenaline. To investigate whether renalase is associated with blood pressure levels and/or indices of noradrenaline disposition in humans we studied a cohort of 22 patients with resistant hypertension (at least 3 antihypertensive drugs including a diuretic) and 4 healthy, normotensive control subjects. Radiotracer dilution methodology and arterial blood sampling was applied to measure whole body noradrenaline (NA) spillover. Arterial plasma levels of renalase were measured by Western blot analysis using a monoclonal anti-renalase antibody and quantified using a gel documentation system (Bio-Rad Quantity One Software). Split half analysis of the hypertensive cohort according to systolic blood pressure levels (mean: 186 AE 22 vs 156 AE 9mmHg; p < 0.001) revealed that mean arterial renalase levels were substantially lower in the group with higher systolic blood pressure (62 AE 31 vs 125 AE 82 arbitrary units; p < 0.05), whereas whole body NA spillover tended to be higher in the group with higher systolic blood pressure without reaching statistical significance (645 AE 445 vs 407 AE 195ng/min; p = 0.12). Arterial renalase levels were higher (238 AE 174 arbitrary units) and whole body NA spillover was lower (168 AE 78ng/min) in the normotensive control subjects (mean systolic blood pressure: 123 AE 7mmHg)(all p < 0.05). Correlation analysis revealed an inverse relationship between arterial renalase plasma levels and systolic blood pressure for the entire cohort (r = -0.52; p < 0.05). These data suggest that arterial plasma levels of renalase are inversely associated with systolic blood pressure in a cohort of patients with resistant hypertension. Whether this relation can in part be explained by alleviated degradation of noradrenaline or whether alternative pathways are involved requires further investigation.Objective: Essential hypertension is characterized by a marked sympathetic activation, which is coupled with an impairment of baroreceptor-heart rate control. Whether the behaviour of sympathetic and baroreceptor function is peculiar of the established hypertensive state or it does also characterize the so-called high-normal blood pressure (BP) state is unknown, however.Design and Methods: In 12 subjects with optimal BP (O, age: 38.1 AE 2.1 years, mean AE SEM), 10 with normal BP (N) and 9 with high-normal BP (HN, ESH guidelines classification), all age-matched with O, we measured beat-to-beat arterial BP (Finapres), heart rate (HR, EKG), plasma norepinephrine (NE, venous sample, HPLC) and muscle sympathetic nerve traffic (MSNA, microneurography peroneal nerve) at rest and during baroreceptor stimulation and deactivation (vasoactive drug infusion technique). Measurements also included anthropometric as well as metabolic parameters, such as HOMA index.Results: Body mass index,waist circumference and HOMA index were slightly, alt...

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