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First identified as a powerful vasoconstrictor, endothelin has an extremely diverse set of actions that influence homeostatic mechanisms throughout the body. Two receptor subtypes, ET A and ET B , which usually have opposing actions, mediate the actions of endothelin. ET A receptors function to promote vasoconstriction, growth, and inflammation while ET B receptors produce vasodilation, increases in sodium excretion, and inhibit growth and inflammation. Potent and selective receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure and atherosclerosis. However, results are often contradictory and complicated because of the tissue-specific vasoconstrictor actions of ET B receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo. Considerable questions remain regarding whether ET A selective or non-selective ET A /ET B receptor antagonists would be useful in a range of clinical settings. Keywordsreceptor localization; pulmonary hypertension; heart failure; chronic kidney disease Shortly after it was discovered that the vascular endothelium releases a peptide capable of profound vasoconstriction, a considerable amount of attention was paid to the potential actions of endothelin in the pathogenesis of cardiovascular disease. We have since learned a great deal about how this paracrine factor influences function in an extremely wide range of areas including neurotransmission, cell growth and epithelial transport, just to name a few. This myriad of activities has allowed the endothelin system to garner a tremendous amount of attention from the pharmaceutical industry with the development of numerous receptor specific and non-specific antagonists as well as efforts to identify drugs that inhibit endothelin synthesis. This work has led to new therapeutic approaches to pulmonary arterial hypertension and most likely other diseases in the not too distant future. In addition to this enormous drug discovery effort, it has also become clear that endothelin plays an important physiological role in maintaining blood pressure homeostasis, for example, by facilitating the excretion of a high salt diet. Because of the almost bewildering range of actions of the endothelin peptides, we limit this review to focus on the receptor-specific cardiovascular actions of endothelin. ENDOTHELIN PEPTIDESEndothelin-1, a 21-amino-acid long peptide first isolated from the supernatant of cultured endothelial cells, is perhaps the most potent vasoconstrictor substance known (1). The human Address for Correspondence: David M. Pollock, Ph.D., Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912-2500, +1-706-721-8517 office, +1-706-721-9799 fax, dpollock@mcg.edu. NIH Public Access Author ManuscriptAnnu Rev Pharmacol Toxicol. Author manuscript; available in PMC 2010 February 22. P...

This analysis supports the concept of RAS inhibition as an emerging treatment for the primary and secondary prevention of AF but acknowledges the fact that some of the primary prevention trials were post-hoc analyses. Further areas of uncertainty include potential differences among specific RAS inhibitors and possible interactions or synergistic effects with antiarrhythmic drugs.

The pathogenesis of left ventricular hypertrophy in patients with CKD is incompletely understood. Sodium intake, which is usually assessed by measuring urinary sodium excretion, has been inconsistently linked with left ventricular hypertrophy. However, tissues such as skin and muscle may store sodium. Using sodium-magnetic resonance imaging, a technique recently developed for the assessment of tissue sodium content in humans, we determined skin sodium content at the level of the calf in 99 patients with mild to moderate CKD (42 women; median [range] age, 65 [23-78] years). We also assessed total body overhydration (bioimpedance spectroscopy), 24-hour BP, and left ventricular mass (cardiac magnetic resonance imaging). Skin sodium content, but not total body overhydration, correlated with systolic BP (=0.33, =0.002). Moreover, skin sodium content correlated more strongly than total body overhydration did with left ventricular mass (=0.56, <0.001 versus =0.35,<0.001; <0.01 between the two correlations). Linear regression analysis demonstrated that skin sodium content is a strong explanatory variable for left ventricular mass, unaffected by BP and total body overhydration. In conclusion, we found skin sodium content to be closely linked to left ventricular mass in patients with CKD. Interventions that reduce skin sodium content might improve cardiovascular outcomes in these patients.

Background and aimsSodium tissue content by 23Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes characterized by sodium retention leads to decreased tissue sodium content due to its pharmacological action.Materials and methodsIn a prospective double blind, placebo controlled, cross-over trial 59 patients (61 ± 7.6 years) with type 2 diabetes were randomized to either dapagliflozin 10 mg or placebo once daily for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analysed the sodium content in the skin and muscles of the lower leg by Na-MRI.ResultsCompared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132 ± 28 vs. 114 ± 19 mg/dl, p < 0.001), postprandial blood glucose (178 ± 66 mg/dl vs. 153 ± 46 mg/dl, p < 0.001), body weight (87.6 vs. 86.6 kg, p < 0.001) and systolic (129 ± 12 vs. 126 ± 11 mmHg, p = 0.010), and diastolic (77.4 ± 9 vs. 75.6 ± 8 mmHg, p = 0.024), 24-h ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline [24.1 ± 6.6 vs. 22.7 ± 6.4 A.U.(arbitrary unit) p = 0.013]. No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5 ± 3.5 vs. 20.4 ± 3.7 A.U. p = 0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline.ConclusionSGLT-2 inhibition with dapagliflozin resulted in a significant decrease in tissue sodium content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition.Trial registration The study was registered at http://www.clinicaltrials.gov (NCT02383238) retrospectively registered

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Levels of ADMA were reduced with enalapril and eprosartan therapy. Our results suggest a specific action of these drugs on ADMA levels that is independent of BP.

Abstract-Mice with a collecting duct-specific deletion of endothelin-1 are hypertensive and have impaired Na excretion.Because endothelin-1 activates NO synthase (NOS) in the collecting duct, we hypothesized that impaired renal NO production in knockout mice exacerbates the hypertensive state. Control and knockout mice were treated chronically with N G -nitro-Larginine methyl ester, and blood pressure (BP) and urinary nitrate/nitrite excretion were assessed. On a normal Na diet, knockout systolic BP was 18 mm Hg greater than in controls. N G -nitro-L-arginine methyl ester increased BP in control mice by 30 mm Hg and 10 mm Hg in collecting duct-specific deletion of endothelin-1 knockout mice, thereby abolishing the difference in systolic BP between the groups. A high-Na diet increased BP similarly in both groups. Urinary nitrate/nitrite excretion was lower in knockout mice than in controls on normal or high Na intake. In separate experiments, renal perfusion pressure was adjusted in anesthetized mice, and urinary nitrate/nitrite and Na excretion were determined. Similar elevations of BP increased urinary Na and nitrate/nitrite excretion in control mice but to a significantly lesser extent in knockout mice. Isoform-specific NOS activity and expression were determined in renal inner medulla homogenates from control and knockout mice. NOS1 and NOS3 activities were lower in knockout than in control mice given normal or high-Na diets. However, NOS1 or NOS3 protein expressions were similar in both groups on normal or high-Na intake. These data demonstrate that collecting duct-derived endothelin-1 is important in the following: (1) Key Words: ET-1 Ⅲ NO Ⅲ Na Ⅲ natriuresis Ⅲ diuresis Ⅲ blood pressure C ollecting duct (CD)-derived endothelin-1 (ET-1) is an important regulator of blood pressure (BP) and renal Na excretion. 1 ET-1 inhibits distal nephron Na/K ATPase and epithelial Na channel activity, 2,3 whereas CD-specific knockout of ET-1 causes hypertension and impaired Na excretion. 1 The natriuretic effect of ET-1 is attributable, at least partially, to activation of CD endothelin B (ET B ) receptors, because CDspecific deletion of ET B receptors causes hypertension and reduced Na excretion. 4 How ET-1 modulates renal Na excretion and BP is unknown; however, the NO pathway may be involved. ET-1 stimulates NO production in inner medullary CD via the ET B receptor and NO synthase (NOS) 1 (also known as nNOS). 5 Inner medullary NOS1 and NOS3 (latter also known as eNOS) activity are reduced in rats with dysfunctional ET B receptors. 6,7 In thick-ascending limbs, ET-1 enhances NO production through increased NOS3 activity with resultant inhibition of chloride transport. 8,9 NO also inhibits Na transport in isolated cortical CD. 10 Taken together, these studies suggest that NO is an important mediator of the natriuretic and antihypertensive effects of CD-derived ET-1.One condition under which the CD ET-1/NO pathway may be of particular importance is increased Na excretion in response to elevations of renal perfusion pressur...