title: Mineralocorticoid action and sodium-hydrogen exchange: studies in experimental cardiac fibrosis.
abstract: There is increasing evidence that the trigger for cardiac fibrosis in response to mineralocorticoid/salt administration is coronary vasculitis and that effects can be seen within days of deoxycorticosterone acetate (DOCA) administration. Furthermore, rapid, nongenomic mineralocorticoid effects on the sodium-hydrogen exchanger (NHE-1) in vascular smooth muscle cells have recently been described. That this mechanism may act as an inflammatory or profibrotic signal was tested by comparing the specific NHE-1 antagonist cariporide and the mineralocorticoid receptor antagonist K canrenoate in the rat model of mineralocorticoid/salt perivascular fibrosis over 8 d of DOCA/salt administration. Interstitial collagen, inflammatory cell infiltration, and inflammatory markers were determined. DOCA elevated blood pressure above control, cariporide +DOCA, or K canrenoate +DOCA rats, without cardiac hypertrophy. At 8 d interstitial collagen was significantly elevated in the DOCA-alone group, with levels in cariporide- and K canrenoate-treated rats not different from control. Expression of osteopontin, cyclooxygenase-2, and ED-1 were elevated by DOCA treatment, blocked by potassium canrenoate, and (for ED-1 and osteopontin) partially reduced by cariporide. These results suggest mineralocorticoid/salt-induced cardiac fibrosis may involve coronary vascular smooth muscle cell NHE-1 activity as a possible contributor to the cascade of transcriptional events that produce the characteristic coronary vasculitis seen with excess mineralocorticoid and salt.
authors.affiliation: Endocrine Genetics, Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia. young@med.monash.edu.au
authors.forename: Morag
authors.initials: M
authors.lastname: Young
authors.forename: John
authors.initials: J
authors.lastname: Funder
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002191:Canrenoic Acid / Q000494:pharmacology; D003900:Desoxycorticosterone / Q000494:pharmacology*; D005355:Fibrosis; D006146:Guanidines / Q000494:pharmacology; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D006859:Hydrogen / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D014657:Vasculitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology
chemical_list: D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D000451:Mineralocorticoid Receptor Antagonists; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; D003900:Desoxycorticosterone; C093373:cariporide; D006859:Hydrogen; D002191:Canrenoic Acid; D012964:Sodium