11 beta-hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids.
The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in the rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. We have previously demonstrated that cortisol-induced cutaneous vasoconstriction in man is potentiated by the 11 beta-OHSD inhibitor glycyrrhetinic acid, suggesting that 11 beta-OHSD may protect vascular corticosteroid receptors. In this study we report quantitation of 11 beta-OHSD bioactivity in homogenates of rat aorta, mesenteric artery, caudal artery, and heart, expressed as the percent in vitro conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone. Nicotinamide adenine dinucleotide phosphate (NADP+)-dependent 11 beta-OHSD activity was found in all of these tissues and was significantly higher in resistance vessels than aorta (P less than 0.05) [without NADP+: caudal artery (4.2 +/- 0.2%) greater than mesenteric artery (2.5 +/- 0.7%) = heart (1.67 +/- 0.2%) greater than aorta (0.79 +/- 0.2%); with 200 microM NADP+: caudal artery (43.9 +/- 2.1%) greater than heart (20.6 +/- 1.0%) = mesenteric artery (17.7 +/- 3.1%) = aorta (11.4 +/- 0.4%); heart greater than aorta]. All of these were lower than renal cortex (29.4 +/- 1.8% without NADP+; 82.4 +/- 0.4% with NADP+; P less than 0.001). 3H-11-dehydrocorticosterone was the major metabolite of 3H-corticosterone (greater than 97% of 3H-corticosterone metabolized). Reduction of 3H-11-dehydrocorticosterone to 3H-corticosterone was not detected in these experiments. We also report localization of 11 beta-OHSD-like immunoreactivity by immunohistochemistry using antisera raised against rat liver 11 beta-OHSD, and of 11 beta-OHSD messenger RNA expression by in situ hybridization using complementary RNA probes transcribed from complementary DNA encoding rat liver 11 beta-OHSD. We found 11 beta-OHSD immunoreactivity and messenger RNA expression in vascular and cardiac smooth muscle cytoplasm but not in endothelium. Thus, 11 beta-OHSD is appropriately sited to modulate access of corticosterone to vascular receptors and could influence vascular resistance, cardiac output and thereby blood pressure.
Walker
B R
BR
University of Edinburgh, Department of Medicine, Western General Hospital, United Kingdom.
Yau
J L
JL
Brett
L P
LP
Seckl
J R
JR
Monder
C
C
Williams
B C
BC
Edwards
C R
CR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D001011:Aorta / Q000201:enzymology; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000187:drug effects*; D003345:Corticosterone / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008638:Mesenteric Arteries / Q000201:enzymology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology*; D009249:NADP / Q000494:pharmacology; D009693:Nucleic Acid Hybridization; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D005938:Glucocorticoids; D012333:RNA, Messenger; D009249:NADP; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; C003552:11-dehydrocorticosterone; D003345:Corticosterone