Endothelin 1 Type A Receptor Antagonism Prevents Vascular Dysfunction and Hypertension Induced by 11β-Hydroxysteroid Dehydrogenase Inhibition: Role of Nitric Oxide

Abstract

The paper by Ruschitzka et al 1 on 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) and the regulation of vascular tone contains some important mistakes. The 11␤HSD2 converts cortisol (F) in humans and corticosterone (B) in rodents to their inactive ketoform cortisone (E) and 11-dehydrocorticosterone (A), respectively, thus protecting the nonselective mineralocorticoid receptor from overactivation by glucocorticoids. 2 This prevents blood pressure (BP) increases associated with excess renal sodium reabsorption. 2,3 With reduced 11␤HSD2 activity, as observed with the genetic defect called apparent mineralocorticoid excess (AME) syndrome or with inhibition by glycyrrhetinic acid (GA), the active liquorice component is signaled by a relative deficiency of 11-ketoglucocorticoids. This is detected by an increased urinary ratio of active to inactive tetrahydro-(TH-) glucocorticoids. 3 In AME syndrome, the (THFϩ5␣THF)/THE ratios are increased to 20 to 50, as compared with normal values of 0.75 to 1.25. 3 Ruschitzka et al 1 reported a decreased (THBϩ5␣THB)/THA ratio in GA treated rats, meaning that GA induces 11␤HSD2 activity rather than inhibits it. Because these measurements were incorrect, an experimental error can be assumed and therefore, the observed results are possibly also incorrect. Moreover, I have treated a few patients with AME, and it has proved impossible to normalize BP with antihypertensive agents other than the mineralocorticoid receptor antagonist spironolactone. 3 However, verapamil and LU135252 normalized BP in GA-treated rats in this study. 1 Considering the mechanism of BP elevation associated with inhibited 11␤HSD2 activity, these results are questionable.Moreover, to assess whether alterations in the endothelin system after GA were directly or indirectly dependent on GA, a control group of adrenalectomized rats would have been necessary. Also, reference 1 4 in the paper by Ruschitzka et al is inappropriate because it is dealing with a totally different genetic condition (11-hydroxylase/aldosterone synthase) and reference 5 is quoted incorrectly; Soro et al 5 found increased, and not decreased (THFϩ5␣THF)/THE ratios in hypertensive subjects.Considering the few faulty aspects mentioned, it is justifiable to cast some major doubts on the quality and accuracy of the paper by Ruschitzka et al.