Low-dose ramipril treatment improves relaxation and calcium cycling after established cardiac hypertrophy.
Rapid cooling contractures were used in this study to test whether low-dose ramipril improves sarcoplasmic reticulum (SR) Ca(2+) uptake and Na(+)/Ca(2+) exchanger function in isolated hypertrophied rat myocytes. Compensated cardiac hypertrophy was induced by abdominal aortic constriction for 5 wk followed by administration of ramipril (50 microg x kg(-1) x day(-1)) or vehicle for 4 wk. Myocyte cell length and cell width were significantly (P < 0.05) increased in both hypertrophied groups (+/-ramipril). Myocytes were loaded with indo 1, and relaxation was investigated after rapid cooling. Hypertrophied myocyte relaxation in Na(+)-free/Ca(2+)-free solution was 63% slower (P < 0.01) and the fall in intracellular Ca(2+) was 60% slower (P < 0.05) than the relaxation of control cells. After ramipril treatment both relaxation and the decline in intracellular Ca(2+) returned to control rates through improved SR Ca(2+)-ATPase function. Relaxation in caffeine showed no change after hypertrophy; however, after ramipril treatment the time to 50% relaxation in caffeine decreased by 30% (P < 0.05). The improvement in Ca(2+) extrusion across the sarcolemmal membrane occurred independently of changes in Na(+)/Ca(2+) exchanger mRNA and protein abundance. These data demonstrate that ramipril improves both SR-dependent and non-SR-dependent calcium cycling after established cardiac hypertrophy. However, the improvements in function are independent of transcriptional activation and likely to involve altered intracellular ion concentrations.
Boateng
S Y
SY
Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine, London SW3 6LY, United Kingdom.
Naqvi
R U
RU
Koban
M U
MU
Yacoub
M H
MH
MacLeod
K T
KT
Boheler
K R
KR
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000493:pharmacokinetics*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D009126:Muscle Relaxation / Q000187:drug effects*; D009200:Myocardial Contraction / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D012964:Sodium; D000252:Calcium-Transporting ATPases; D017257:Ramipril; D002118:Calcium