Positive inotropic effects of the calcium sensitizer CGP 48506 in failing human myocardium.
In trabeculae carneae from failing human myocardium, CGP 48506 increased the force of contraction, which reached 310 +/- 41% of predrug values at 100 mumol/l. Its stereoisomer CGP 48508 did not affect the force of contraction (100 mumol/l). The positive inotropic effect of CGP 48506 was not sensitive to 10 mumol/l carbachol. The positive inotropic effect of CGP 48506 was accompanied by increases in time to peak tension and time of relaxation amounting to 175 +/- 4% and 205 +/- 15% of control, respectively, at 100 mumol/l. CGP 48506 but not CGP 48508 sensitized skinned trabeculae from failing human myocardium to calcium with an EC50 value of 10 mumol/l. However, CGP 48506 and CGP 48508 (up to 300 mumol/l) did not affect the activity of PDE isoenzymes I to IV from failing human myocardium. CGP 48506 is the first inotropic agent with calcium-sensitizing properties in the human heart that has been found to be devoid of inhibitory activity on human cardiac PDE isoenzymes.
Neumann
J
J
Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität, Münster, Germany.
Eschenhagen
T
T
Grupp
I L
IL
Haverich
A
A
Herzig
J W
JW
Hirt
S
S
Kalmár
P
P
Schmitz
W
W
Scholz
H
H
Stein
B
B
Wenzlaff
H
H
Zimmermann
N
N
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D001392:Azocines / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects*
D001392:Azocines; D002316:Cardiotonic Agents; C095056:BA 41899; D002217:Carbachol; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine