Mineralocorticoids, salt, hypertension: effects on the heart.
In uninephrectomized rats on 1% NaCl solution to drink, aldosterone (0.75 micrograms/h subcutaneously for 8 weeks) raises blood pressure and causes marked interstitial and perivascular cardiac fibrosis, effects not seen in animals on a low salt intake. In extending these initial findings, we have shown that cardiac fibrosis (i) is not reversed by correction of mineralocorticoid-induced hypokalemia; (ii) appears not to involve the plasma or tissue renin-angiotensin systems, as fibrosis is largely unaffected by concurrent administration of Losartan or Perindopril; (iii) is independent of cardiac hypertrophy, in that it is equally seen in right and left ventricles, and in rats rendered hypertensive without cardiac hypertrophy by the administration of 9 alpha-fluorocortisol; (iv) is independent of elevated blood pressure, in that it is found in normotensive animals infused peripherally with aldosterone and intracerebroventricularly with the mineralocorticoid receptor (MR) antagonist RU28318; (v) is via classical MR, in that it is blocked by concurrent administration of the MR antagonist potassium canrenoate; and (vi) may or may not be a direct cardiac effect, inasmuch as data for in vivo effects on collagen formation by cardiac fibroblasts are conflicting. Although there is a high probability that the action of aldosterone to cause cardiac fibrosis in this experimental model is an effect via non-epithelial MR, the locus of aldosterone action remains to be established, as do the molecular mechanisms linking MR occupancy by aldosterone and collagen deposition. In addition, and in particular, the mechanisms underlying the crucial contribution of high salt intake in this model of mineralocorticoid excess await exploration.
Young
M J
MJ
Baker Medical Research Institute, Melbourne, Australia.
Funder
J W
JW
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy; D005355:Fibrosis; D006321:Heart / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy; D007008:Hypokalemia / Q000139:chemically induced; D008901:Mineralocorticoids / Q000378:metabolism / Q000494:pharmacology*; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D012084:Renin-Angiotensin System; D012492:Salts / Q000378:metabolism / Q000494:pharmacology*
D008901:Mineralocorticoids; D012492:Salts; D000450:Aldosterone