Endothelin 1 Type A Receptor Antagonism Prevents Vascular Dysfunction and Hypertension Induced by 11β-Hydroxysteroid Dehydrogenase Inhibition: Role of Nitric Oxide
To the Editor:
The paper by Ruschitzka et al1 on 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and the regulation of vascular tone contains some important mistakes. The 11βHSD2 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 11βHSD2 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 (THF+5αTHF)/THE ratios are increased to 20 to 50, as compared with normal values of 0.75 to 1.25.3
Ruschitzka et al1 reported a decreased (THB+5αTHB)/THA ratio in GA treated rats, meaning that GA induces 11βHSD2 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 11βHSD2 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 14 in the paper by Ruschitzka et al is improper (11-hydroxylase/aldosterone synthase) and reference 5 is quoted incorrectly; Soro et al5 found increased, and not decreased (THF+5αTHF)/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.
- ↵Ruschitzka F, Quaschning T, Noll G, et al. Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11β-hydroxysteroid dehydrogenase inhibition: role of nitric oxide. Circulation. 2001; 103: 3129–3135.(Correction. 2001;104:1208).
- ↵Funder JW, Pearce PT, Smith R, et al. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science. 1988; 242: 583–585.
- ↵Soro A, Ingram MC, Tonolo G, et al. Evidence of 11beta-hydroxysteroid dehydrogenase and 5beta-reductase activity in subjects with untreated essential hypertension. Hypertension. 1995; 25: 67–70.
The figure relating to the steroid metabolite ratio is simply mislabeled and GAT-treated is, in fact, placebo. The correction was in press before Dr Ferrari’s letter was sent and was published several months ago.1 The changes we see after GAT treatment are exactly as expected and are in complete agreement with recent reports of liquorice-induced hypertension in man.2,3⇓
Regarding Dr Ferrari’s findings in a few apparent mineralocorticoid excess (AME) patients, we see nothing inconsistent with the idea that glycyrrhetinic acid-induced (GA) hypertension in rats may well involve components that are sensitive to verapamil and endothelin antagonists. Finally, in this paper, we do not claim to have analyzed the detailed mechanisms of GA-induced alterations in the endothelin system. A more informative experiment than the one suggested, evaluating effects of specific antagonists of mineralocorticoid (spironolactone) and glucocorticoid receptors (RU 486) in this model, has already been completed. These data will be presented in a separate forthcoming publication.