title: The primary benefits of angiotensin-converting enzyme inhibition on cardiac remodeling occur during sleep time in murine pressure overload hypertrophy.
abstract: OBJECTIVE
  Our objective was to test the hypothesis that there is a significant diurnal variation for the therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors on pressure-overload cardiovascular hypertrophy.
  
  
  BACKGROUND
  Physiological and molecular processes exhibit diurnal rhythms that may affect efficacy of disease treatment (chronotherapy). Evidence suggests that the heart primarily remodels during sleep. Although a growing body of clinical and epidemiological evidence suggests that the timing of therapy, such as ACE inhibition, alters diurnal blood pressure patterns in patients with hypertension, the benefits of chronotherapy on myocardial and vascular remodeling have not been studied.
  
  
  METHODS
  We examined the effects of the short-acting ACE inhibitor, captopril, on the structure and function of cardiovascular tissue subjected to pressure overload by transverse aortic constriction (TAC) in mice. Captopril (15 mg/kg intraperitoneally) or placebo was administered at either murine sleep time or wake time for 8 weeks starting 1 week after surgery.
  
  
  RESULTS
  TAC mice given captopril at sleep time had improved cardiac function and significantly decreased heart: body weight ratios, myocyte cross-sectional areas, intramyocardial vascular medial wall thickness, and perivascular collagen versus TAC mice given captopril or placebo during wake time. Captopril induced similar drops in blood pressure at sleep or wake time, suggesting that time-of-day differences were not attributable to blood pressure changes. These beneficial effects of captopril were correlated with diurnal changes in ACE mRNA expression in the heart.
  
  
  CONCLUSIONS
  The ACE inhibitor captopril benefited cardiovascular remodeling only when administered during sleep; wake-time captopril ACE inhibition was identical to that of placebo. These studies support the hypothesis that the heart (and vessels) remodel during sleep time and also illustrate the importance of diurnal timing for some cardiovascular therapies.
authors.affiliation: Department of Biomedical Science, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Tami A
authors.initials: TA
authors.lastname: Martino
authors.forename: Nazneen
authors.initials: N
authors.lastname: Tata
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Simpson
authors.forename: Rachel
authors.initials: R
authors.lastname: Vanderlaan
authors.forename: Fayez
authors.initials: F
authors.lastname: Dawood
authors.forename: M Golam
authors.initials: MG
authors.lastname: Kabir
authors.forename: Neelam
authors.initials: N
authors.lastname: Khaper
authors.forename: Carlo
authors.initials: C
authors.lastname: Cifelli
authors.forename: Peter
authors.initials: P
authors.lastname: Podobed
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.forename: Scott
authors.initials: S
authors.lastname: Heximer
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sole
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D055870:Drug Chronotherapy; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors