Hypertension, Diabetes Mellitus, Hypercholesterolemia, and Endothelin B Receptor-Mediated Renal Nitric Oxide Release
Authors: Matthias Barton, Livius V. d’Uscio
Journal: Circulation (2000)

Kakoki et al 1 recently reported a reduced endothelin (ET) B receptor-mediated release of nitric oxide (NO) in renal perfusates of experimental models of hypertension, diabetes mellitus, and hypercholesterolemia, as measured by H 2 O 2 -based chemiluminescence.Reduced immunostaining for endothelial ET B receptors, as measured by semiquantitative immunohistochemistry, was observed in all experimental models, whereas staining for endothelial NO synthase (eNOS) was reduced in salt-sensitive Dahl rats but not spontaneously hypertensive (SHR) or hypercholesterolemic rats.Although interesting, these observations must be interpreted with caution.In SHR, the release of NO was not impaired, which contrasts with previously published data.eNOS activity is increased in SHR, but endothelial NO levels are reduced due to inactivation by the superoxide anion. 2 This discrepancy is not commented on by the authors, and the previously published work was not cited.In experimental diabetes and hypercholesterolemia, renal eNOS expression was unchanged, while ET B -mediated renal NO release was markedly reduced.The authors propose that the reduced expression of the ET B receptor accounts for the reduction in NO release without having investigated the effect of antioxidants such as superoxide dismutase, vitamin C, or N-acetylcysteine.Finally, the authors used whole, perfused kidneys to measure NO release in the renal vein, without assessing ET B receptor and NO synthase expression in nonvascular renal tissue, which also affects NO levels in the perfusate.Interestingly, an infusion of the ET B agonist BQ-3020 of Ͻ10 Ϫ10 mol/L reduced renal perfusion in salt-resistant Dahl rats, whereas renal perfusion in salt-sensitive animals was increased.The response to BQ-3020 was greater in salt-sensitive animals, despite their reduced NO release and eNOS immunostaining.These conflicting observations were not explained; nor did the authors investigate other potential mechanisms, such as ET B receptor-mediated prostacyclin release.With regard to ET-1 levels in Dahl rat plasma, these data were previously published in both salt-sensitive and salt-resistant strains in a study that included long-term treatment with an endothelin antagonist. 3T A receptors modulate ET-1-induced vasoconstriction and cell proliferation.ET B receptors mediate ET-1 clearance in rats, and ET B blockade increases peripheral vascular resistance in humans.In patients with chronic nitric oxide deficiency, ET A selective, but not combined ET blockade, improves NOmediated endothelial function (unpublished observation), as can be observed in mice with atherosclerosis.4 Finally, chronic antagonism of the ET B receptor worsens renovascular function and structure in salt-sensitive hypertension, 5 an effect that is also observed in dogs with congestive heart failure.On the basis of current knowledge regarding the ET system, the authors' statement that ET A /ET B receptor antagonists "are more useful than ET A receptor antagonists in improving peripheral circulatory disturbances" does not hold true.