Myofibrillar responsiveness to cAMP, PKA, and caffeine in an animal model of heart failure.
We investigated whether an alteration of myofilament calcium responsiveness and contractile activation may in part contribute to heart failure. A control group of Broad Breasted White turkey poults was given regular feed without additive, whereas the experimental group was given the control ration with 700 ppm of furazolidone at 1 week of age for 3 weeks (DCM). At 4 weeks of age, left ventricular trabeculae carneae were isolated from hearts and calcium-force relationships studied. No differences in calcium-activation between fibers from control or failing hearts were noted under standard experimental conditions. Also failing hearts demonstrated no significant shift in the population of troponin T isoforms but we did observe a significant 4-fold decrease in TnT content in failing hearts compared to non-failing hearts. Addition of caffeine, however, resulted in a greater leftward shift on the calcium axis in fibers from failing hearts. At pCa 6, caffeine increased force by 26+/-2.1% in control fibers and 44.5+/-8.7% in myopathic fibers. Cyclic AMP resulted in a greater rightward shift on the calcium axis in failing myocardium. In control muscles, the frequency of minimum stiffness (f(min)) was higher than in muscles from failing hearts. cAMP and caffeine both shifted f(min) to higher frequencies in control fibers whereas in fibers from failing hearts both caused a greater shift. These results lead us to conclude that heart failure exerts differential effects on cAMP and caffeine responsiveness. Our data suggest that changes at the level of the thin myofilaments may alter myofilament calcium responsiveness and contribute to the contractile dysfunction seen in heart failure.
Okafor
Chukwuka C
CC
Boston University Medical Center, 715 Albany Street, Boston, MA 02118-22526, USA.
Saunders
Lori
L
Li
Xiaoping
X
Ito
Toshiro
T
Dixon
Meredith
M
Stepenek
Anna
A
Hajjar
Roger J
RJ
Wood
June R
JR
Doye
Angelia A
AA
Gwathmey
Judith K
JK
D008841:Actin Cytoskeleton / Q000737:chemistry; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000032:analysis; D046508:Culture Techniques; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004285:Dogs; D004548:Elasticity; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D020107:Troponin T / Q000378:metabolism; D014422:Turkeys
D020107:Troponin T; D002110:Caffeine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium