title: Steroidogenesis vs. steroid uptake in the heart: do corticosteroids mediate effects via cardiac mineralocorticoid receptors?
abstract: OBJECTIVE
  To test whether glucocorticoids act as the endogenous agonist of cardiac mineralocorticoid receptors, we evaluated the cardiac effects of aldosterone and corticosterone and cardiac steroidogenesis vs. steroid uptake from plasma.
  
  
  RESULTS
  Both corticosterone and aldosterone increased left ventricular pressure in the rat heart. Aldosterone decreased coronary flow, whereas corticosterone increased it. All corticosterone effects were blocked by the glucocorticoid receptor antagonist, RU486, and unaltered by the mineralocorticoid receptor antagonist, canrenoate, or the 11beta-hydroxysteroid dehydrogenase (HSD11B)2 inhibitor, carbenoxolone. Unlike mineralocorticoid receptor blockade, RU486 did not ameliorate postischemia infarct size and arrhythmias. Corticosterone, when added to the perfusion buffer, rapidly accumulated at cardiac tissue sites, reaching steady-state levels that were identical to those in coronary effluent, independently of the presence of aldosterone, RU486 or canrenoate. After stopping the perfusion, cardiac corticosterone fully washed away with a half-life of less than 1 min. Measurements of steroid-synthesizing enzyme gene expression levels in human ventricular and atrial tissue pieces from heart-beating organ donors, patients with end-stage heart failure and hypertrophic cardiomyopathy patients revealed that under no condition, the human heart was capable of synthesizing aldosterone or cortisol de novo. Yet, expression of HSD11B1, HSD11B2, mineralocorticoid receptors and glucocorticoid receptors was found, and HSD11B2 and mineralocorticoid receptors were upregulated in pathological conditions. Moreover, aldosterone reduced cardiac inotropy in a Na/K/2Cl cotransporter-dependent manner.
  
  
  CONCLUSIONS
  Both cortisol/corticosterone and aldosterone accumulate in the cardiac interstitium. The presence of HSD11B2 and mineralocorticoid receptors/glucocorticoid receptors at cardiac tissue sites allows both steroids to exert their effects via separate mechanisms.
authors.affiliation: Division of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Chai
authors.forename: Johannes
authors.initials: J
authors.lastname: Hofland
authors.forename: Pieter M
authors.initials: PM
authors.lastname: Jansen
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.forename: Antoon J
authors.initials: AJ
authors.lastname: van den Bogaerdt
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002191:Canrenoic Acid / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D017931:DNA Primers; D006727:Hormone Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013256:Steroids; D015735:Mifepristone; D000450:Aldosterone; D002191:Canrenoic Acid; D003345:Corticosterone