title: Long-term angiotensin-converting enzyme inhibition with fosinopril improves depressed responsiveness to Ca2+ in myocytes from aortic-banded rats.
abstract: BACKGROUND
  We have previously shown that long-term ACE inhibition with fosinopril prolongs survival and improves ventricular function despite persistent severe left ventricular pressure overload in ascending aortic-banded rats with left ventricular hypertrophy during the transition from compensation to failure.
  
  
  RESULTS
  To study the cellular mechanism of the effects of long-term ACE inhibition on the modification of the transition to failure in pressure-overload hypertrophy, we measured simultaneous intracellular Ca2+ transients and myocyte shortening in isolated left ventricular myocytes from fosinopril-treated aortic-banded rats (n = 9), untreated aortic-banded rats (n = 9), and normal age-matched control rats (n = 10). Fosinopril therapy was begun 6 weeks after banding and was continued until week 21 after banding, when the animals were killed. Collagenase-dissociated myocytes loaded with indo 1-AM were paced at 3 Hz at 36 degrees C and superfused at [Ca2+]o of 0.6, 1.2, and 3.0 mmol/L. In myocytes from untreated aortic-banded rats, peak systolic [Ca2+]i was higher than in control myocytes, and the relationship between myocyte shortening and [Ca2+]i was depressed relative to control myocytes, implicating impaired responsiveness to Ca2+. Long-term fosinopril treatment improved both myocyte shortening and the relationship of shortening to [Ca2+]i (P < .05 versus myocytes from untreated aortic-banded rats). Maximal Ca(2+)-activated force was depressed in chemically skinned left ventricular fibers from untreated aortic-banded hypertrophied rats relative to age-matched controls but not in the fosinopril-treated aortic-banded rats.
  
  
  CONCLUSIONS
  Long-term ACE inhibition improves responsiveness to Ca2+ in the presence of normalization of maximal Ca(2+)-activated force in aortic-banded rats subjected to persistent pressure overload. This may contribute to the favorable effects whereby ACE inhibition modifies the transition from compensated hypertrophy to failure.
authors.affiliation: Charles A. Dana Research Institute, Boston, Mass, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kagaya
authors.forename: R J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: J K
authors.initials: JK
authors.lastname: Gwathmey
authors.forename: W H
authors.initials: WH
authors.lastname: Barry
authors.forename: B H
authors.initials: BH
authors.lastname: Lorell
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D002118:Calcium / Q000494:pharmacology*; D002303:Cardiac Output, Low / Q000517:prevention & control; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology; D003250:Constriction; D017328:Fosinopril / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006973:Hypertension / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017328:Fosinopril; D002118:Calcium