Ca++ sensitizers impair cardiac relaxation in failing human myocardium.
The present study was aimed at investigating the effect of two Ca++ sensitizers, EMD 57033 (without significant phosphodiesterase inhibition) and ORG 30029 (with phosphodiesterase inhibition), in myocardium from nonfailing and failing human hearts. In nonfailing myocardium both EMD 57033 and ORG 30029 increased force of contraction by 280 +/- 27% and 94 +/- 13%, respectively (n = 6); the time to 80% relaxation (t80%) by 278 +/- 45% and 155 +/- 21%; and diastolic force by 28 +/- 8% and 12 +/- 3%, respectively. In trabeculae from failing myocardium, the increase in active force was similar to that in nonfailing trabeculae (EMD, 305 +/- 30%; ORG, 88 +/- 12% (n = 6)). However, the increase in t80% (EMD, 378 +/- 56%; ORG, 230 +/- 26%) and diastolic force (65 +/- 12%; 24 +/- 5%) was more pronounced in failing myocardium. EMD had no effect on the peak of the [Ca++]i transient; however, it prolonged the time course of the [Ca++]i transient in both nonfailing and failing myocardial fibers. ORG increased the peak of the Ca++ transient and prolonged the time course in preparations from both nonfailing and failing hearts. Both EMD and ORG shifted the [Ca++]-force relationship toward lower [Ca++] (EMD > ORG). The Ca++ sensitizers EMD 57033 and ORG 30029 increased active force development in nonfailing and failing human myocardium, but both impaired relaxation in failing myocardium to a greater extent than in nonfailing human myocardium in a concentration-dependent fashion.
Hajjar
R J
RJ
Boston University School of Medicine, Evans Department of Medicine, MA, USA.
Schmidt
U
U
Helm
P
P
Gwathmey
J K
JK
D000328:Adult; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009930:Organic Chemicals; D011804:Quinolines / Q000494:pharmacology*; D013829:Thiadiazines / Q000494:pharmacology*
D002316:Cardiotonic Agents; D009930:Organic Chemicals; D011804:Quinolines; D013829:Thiadiazines; C062763:ORG 30029; C070609:EMD 53998; D002118:Calcium