title: Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats.
abstract: Aldosterone breakthrough during ACE inhibitor therapy has been reported. This study investigates changes in plasma aldosterone concentration (PAC) and its mechanism and effects on target organ damage during long-term angiotensin II type 1 (AT1) receptor antagonist (AT1A) therapy in hypertensive rats. An AT1A (candesartan, 1 mg/kg per day PO) was administered in stroke-prone spontaneously hypertensive rats from 4 weeks of age for 34 weeks. PAC was significantly decreased during the first 4 weeks but showed aldosterone breakthrough after 8 weeks of AT1A administration. Plasma angiotensin II concentration was significantly elevated, whereas no change was seen in plasma ACTH or serum potassium. The mechanism(s) of aldosterone breakthrough were investigated by giving high doses of candesartan (3 mg/kg per day PO), dexamethasone (200 microg/kg per day IP), or the AT2 antagonist (PD123319, 10 mg/kg per day SC) during the last week of the 24-week AT1A treatment period. Dexamethasone and AT2 antagonist but not high-dose AT1A produced a significant decrease in PAC, with a larger decrease produced by the AT2 antagonist. To clarify the effects of the residual aldosterone, effects of coadministration of low-dose spironolactone (10 mg/kg per day SC), an aldosterone antagonist, on left ventricular hypertrophy and expression of brain natriuretic peptide mRNA were determined. Low-dose spironolactone further improved left ventricular hypertrophy and brain natriuretic peptide mRNA expression despite no additional depressor effect. These results suggest that aldosterone breakthrough occurs during long-term AT1A therapy, mainly by an AT2-dependent mechanism. Residual aldosterone may attenuate the cardioprotective effects of AT1A.
authors.affiliation: Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Tokyo, Japan. mtsnaruse@endm.twmu.ac.jp
authors.forename: Mitsuhide
authors.initials: M
authors.lastname: Naruse
authors.forename: Akiyo
authors.initials: A
authors.lastname: Tanabe
authors.forename: Atsuhisa
authors.initials: A
authors.lastname: Sato
authors.forename: Sachiko
authors.initials: S
authors.lastname: Takagi
authors.forename: Ken
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Imaki
authors.forename: Kazue
authors.initials: K
authors.lastname: Takano
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000450:Aldosterone / Q000097:blood*; D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D011355:Prodrugs; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013148:Spironolactone / Q000494:pharmacology; D020521:Stroke / Q000209:etiology; D013777:Tetrazoles; D013997:Time Factors
chemical_list: D057911:Angiotensin Receptor Antagonists; D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D011355:Prodrugs; D011725:Pyridines; D012333:RNA, Messenger; D013777:Tetrazoles; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; C073402:PD 123319; D013148:Spironolactone; D000450:Aldosterone; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; C077793:candesartan cilexetil; D003345:Corticosterone