Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension.

Abstract

BACKGROUND:

The enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11-dehydro derivatives. Inhibition of 11beta-HSD2 by liquorice-derived glycyrrhizic acid (GA) therefore results in sodium retention and hypertension. The present study investigated the effect of the aldosterone receptor antagonist spironolactone in comparison with the endothelin ET(A) receptor antagonist darusentan on renovascular endothelial function in liquorice-induced hypertension.

METHODS:

GA, a recognized inhibitor of 11beta-HSD2 was supplemented to the drinking water (3 g/l) of Wistar Kyoto rats over a period of 21 days. From day 8 to 21, spironolactone (5.8+/-0.6 mg/kg/day), darusentan (45.2+/-6.5 mg/kg/day), or placebo was added to chow (n=7 per group). After the animals were killed, vascular function of isolated renal artery segments was assessed by isometric tension recording.

RESULTS:

Relaxation of pre-constricted renal artery segments in response to acetylcholine (10(-10) to 10(-5) mol/l) was impaired by GA as compared with controls (12+/-4% vs 98+/-5% of norepinephrine 3x10(-7) mol/l), whereas endothelium independent relaxations were unaffected. Endothelin receptor antagonism improved renovascular endothelium-dependent relaxation (32+/-4%, P<0.05 vs placebo) whereas endothelium-dependent relaxation was completely normalized by aldosterone receptor antagonism (85+/-4%, P<0.01 vs placebo).

CONCLUSIONS:

In GA-induced hypertension, both aldosterone receptor antagonism and endothelin receptor antagonism normalize blood pressure and improve renovascular function and, thus, may represent a new therapeutic approach in cardiovascular disease associated with impaired 11beta-HSD2 activity.

• Authors: T Quaschning, F Ruschitzka, B Niggli, C M Lunt, S Shaw, M Christ, M Wehling, T F Lüscher
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 16 Issue 11 Pg. 2146-51 (Nov 2001) ISSN: 0931-0509 [Print] England
• PMID: 11682659 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin Receptor Antagonists
• Mineralocorticoid Receptor Antagonists
• Vasoconstrictor Agents
• Spironolactone
• Potassium Chloride
• Glycyrrhizic Acid
• Norepinephrine

Topics

• Animals
• Blood Vessels (drug effects, physiopathology)
• Endothelin Receptor Antagonists
• Endothelium, Vascular (physiopathology)
• Glycyrrhiza (adverse effects)
• Glycyrrhizic Acid (pharmacology)
• Hypertension (etiology, physiopathology)
• Male
• Mineralocorticoid Receptor Antagonists
• Norepinephrine (pharmacology)
• Potassium Chloride (pharmacology)
• Rats
• Rats, Inbred WKY
• Renal Artery (drug effects)
• Renal Circulation (drug effects)
• Spironolactone (pharmacology)
• Vasoconstriction (drug effects)
• Vasoconstrictor Agents (pharmacology)
• Vasodilation (drug effects)