title: Eplerenone inhibits the intracrine and extracellular actions of angiotensin II on the inward calcium current in the failing heart. On the presence of an intracrine renin angiotensin aldosterone system.
abstract: The influence of chronic administration of eplerenone on the intracrine as well as on the extracellular action of angiotensin II (Ang II) on L-type inward calcium current was investigated in the failing heart of cardiomyopathic hamsters (TO-2).For this, eplerenone (200 mg/kg/day) was administered orally to 2 month-old cardiomyopathic hamsters for a period of 3 months. Measurements of the peak inward calcium current (I(Ca)) was performed in single cells under voltage clamp using the whole cell configuration. The results indicated that eplerenone suppressed the intracrine action of Ang II (10(-)(8) M) on peak I(Ca) density. Moreover, the intracellular dialysis of the peptide did not change the time course of I(Ca) inactivation in animals treated chronically with eplerenone. The extracellular administration of Ang II (10(-)(8) M) incremented the peak I(Ca) density by only 20+/-8% (n=30) compared with 38+/-4% (n=35) (P<0.05) obtained in age-matched cardiomyopathic hamsters not exposed to eplerenone. Interestingly, the inhibitory of eplerenone (10(-7) M) on the intracrine action of Ang II was also found, in vitro, but required an incubation period of, at least, 24 h. The inhibitory action of eplerenone on the intracellular action of Ang II was partially reversed by exposing the eplerenone-treated cells to aldosterone (10 nM) for a period of 24 h what supports the view that: a) the mineralocorticoid receptor(MR) was involved in the modulation of the intracrine action of the peptide; b) the effect of eplerenone on the intracrine as well as on the extracellular action of Ang II was related ,in part, to a decreased expression of membrane-bound and intracellular AT1 receptors.
  
  
  CONCLUSIONS
  a) eplerenone inhibits the intracrine action of Ang II on inward calcium current and reduces drastically the effect of extracellular Ang II on I(Ca); b) aldosterone is able to revert the effect of eplerenone; c) the mineralocorticoid receptor is an essential component of the intracrine renin angiotensin aldosterone system.
authors.affiliation: Department of Pharmacology, School of Medicine, Medical Sciences Campus, UPR, San Juan, PR 00936-5067, USA. wmello@rcm.upr.edu
authors.forename: Walmor C
authors.initials: WC
authors.lastname: De Mello
authors.forename: Yamil
authors.initials: Y
authors.lastname: Gerena
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D009202:Cardiomyopathies / Q000188:drug therapy / Q000503:physiopathology; D006224:Cricetinae; D000077545:Eplerenone; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology*; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D008955:Models, Cardiovascular; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology*; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000451:Mineralocorticoid Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone