Mg-ATPase and Ca+ activated myosin AtPase activity in ventricular myofibrils from non-failing and diseased human hearts--effects of calcium sensitizing agents MCI-154, DPI 201-106, and caffeine.
We investigated the effects of two purported calcium sensitizing agents, MCI-154 and DPI 201-106, and a known calcium sensitizer caffeine on Mg-ATPase (myofibrillar ATPase) and myosin ATPase activity of left ventricular myofibrils isolated from non-failing, idiopathic (IDCM) and ischemic cardiomyopathic (ISCM) human hearts (i.e. failing hearts). The myofibrillar ATPase activity of non-failing myofibrils was higher than that of diseased myofibrils. MCI-154 increased myofibrillar ATPase Ca2+ sensitivity in myofibrils from non-failing and failing human hearts. Effects of caffeine similarly increased Ca2+ sensitivity. Effects of DPI 201-106 were, however, different. Only at the 10(-6) M concentration was a significant increase in myofibrillar ATPase calcium sensitivity seen in myofibrils from non-failing human hearts. In contrast, in myofibrils from failing hearts, DPI 201-106 caused a concentration-dependent increase in myofibrillar ATPase Ca2+ sensitivity. Myosin ATPase activity in failing myocardium was also decreased. In the presence of MCI-154, myosin ATPase activity increased by 11, 19, and 24% for non-failing, IDCM, and ISCM hearts, respectively. DPI 201-106 caused an increase in the enzymatic activity of less than 5% for all preparations, and caffeine induced an increase of 4, 11, and 10% in non-failing, IDCM and ISCM hearts, respectively. The mechanism of restoring the myofibrillar Ca2+ sensitivity and myosin enzymatic activity in diseased human hearts is most likely due to enhancement of the Ca2+ activation of the contractile apparatus induced by these agents. We propose that myosin light chain-related regulation may play a complementary role to the troponin-related regulation of myocardial contractility.
Okafor
Chukwuka
C
Boston University School of Medicine, Cambridge, MA 02138, USA.
Liao
Ronglih
R
Perreault-Micale
Cynthia
C
Li
Xiaoping
X
Ito
Toshiro
T
Stepanek
Anna
A
Doye
Angelia
A
de Tombe
Pieter
P
Gwathmey
Judith K
JK
D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D009202:Cardiomyopathies / Q000201:enzymology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009210:Myofibrils / Q000187:drug effects* / Q000201:enzymology; D009218:Myosins / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology
D002316:Cardiotonic Agents; D010879:Piperazines; D011724:Pyridazines; D002110:Caffeine; C046261:DPI 201-106; C052228:MCI 154; D017301:Ca(2+) Mg(2+)-ATPase; D009218:Myosins; D002118:Calcium