title: Vasoconstrictor effect of aldosterone via angiotensin II type 1 (AT1) receptor: possible role of AT1 receptor dimerization.
abstract: OBJECTIVE
  We recently demonstrated that aldosterone induces a non-genomic vasoconstrictor effect on rat coronary arterioles and that this effect was blocked by angiotensin II type 1 receptor (AT1) blockers. Intracellular transglutaminase enhances AT1 signalling by cross-linking AT1 homodimers. The purpose of this study was to confirm the AT1-dependency of the vasoconstrictor effect of aldosterone using AT1a knockout (AT1aKO) mice and to investigate the role of intracellular transglutaminase and AT1 dimerization in this effect.
  
  
  RESULTS
  The mesenteric arterioles (60-160 microm) were isolated from C57BL/6J (wild-type, WT) and AT1aKO mice, and the internal diameter was measured by video microscopy. Aldosterone (10(-13) to 10(-6) M), but not hydrocortisone, produced a dose-dependent vasoconstriction in WT mice; the maximal diameter change was -8.6 +/- 0.3% from the baseline (P < 0.001). This vasoconstrictor effect was unaffected by the mineralocorticoid receptor antagonist spironolactone or eplerenone, the AT2 antagonist PD123319, the glucocorticoid receptor antagonist RU486, or endothelium denudation. Aldosterone's vasoconstrictor effect was negligible in AT1aKO mice. The AT1 blockers valsartan or candesartan suppressed aldosterone-induced vasoconstriction in WT mice. The transglutaminase inhibitors cystamine and monodansyl cadaverine also suppressed the vasoconstrictor effect of aldosterone, without affecting the vasoconstrictor effect of angiotensin II in WT mice. AT1 dimer protein levels were increased in WT mesenteric arterioles treated with 10(-7) M aldosterone, and the transglutaminase inhibitor and AT1 blocker blocked this aldosterone-induced formation of AT1 dimer. Treatment with 10(-7) M aldosterone for 10 min increased the transglutaminase activity by 2.5 +/- 0.2-fold in cultured vascular smooth muscle cells and by 1.2 +/- 0.1-fold in the mesenteric arterioles. These increases were abolished by transglutaminase inhibitors.
  
  
  CONCLUSIONS
  Aldosterone produces a non-genomic, endothelium-independent vasoconstrictor effect by enhancing intracellular transglutaminase activity and presumably inducing AT1 dimer formation in mesenteric arterioles.
authors.affiliation: Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamada
authors.forename: Motoi
authors.initials: M
authors.lastname: Kushibiki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Osanai
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomita
authors.forename: Ken
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000450:Aldosterone / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D019281:Dimerization; D000077545:Eplerenone; D008297:Male; D008643:Mesentery / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D011503:Transglutaminases / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D000451:Mineralocorticoid Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D000068756:Valsartan; D011503:Transglutaminases; D014633:Valine; C081643:candesartan