Inotropic effect of the cardioprotective agent 2,3-butanedione monoxime in failing and nonfailing human myocardium.
The drug 2,3-butanedione monoxime (BDM) was suggested to be a potent cardioprotective agent useful for cardiopreservation. The present study investigated the activity of BDM and its mechanism of action in human myocardium. In electrically driven left ventricular papillary muscle strips and right atrial trabeculae from failing (heart transplants) and nonfailing (donor hearts) human myocardium, isometric force development and the force-frequency relationship were examined. To study the sarcolemmal actions of BDM, competition experiments with 125I-iodocyanopindolol, 3H-ouabain and 3H(+)PN 200-110 were performed. The effect of BDM on the contractile apparatus was tested by investigating its effects on Ca++ sensitivity and on the relaxation parameters of skinned fiber preparations. In papillary muscle strips and in atrial trabeculae, BDM (0.001-30 mM) depressed the isometric force of contraction in a concentration-dependent manner. BDM was more potent in atrial than in ventricular tissue and it shifted the Ca++ concentration-response curve in atrial and ventricular tissue to the right. The potency of BDM to depress force development was significantly lower compared with the L type of Ca++ channel antagonist nifedipine in both atrial and ventricular myocardium. In the presence of 10 mM BDM, the force-frequency relationship becomes positive in failing myocardium but not in the presence of 1 mM BDM, which did not affect the specific binding of 125I-iodocyanopindolol, 3H-ouabain or 3H(+)PN 200-110. This indicated there was no action on beta adrenoceptors, cardiac glycoside receptors and dihydropyridine-type Ca++ channels.(ABSTRACT TRUNCATED AT 250 WORDS)
Schwinger
R H
RH
Medizinische Klinik III, Universität zu Köln, Germany.
Böhm
M
M
Koch
A
A
Morano
I
I
Rüegg
J C
JC
Erdmann
E
E
D000328:Adult; D015220:Calcium Channels / Q000187:drug effects; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D020120:Iodocyanopindolol; D017275:Isradipine / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000378:metabolism; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects
D015220:Calcium Channels; D011943:Receptors, Adrenergic, beta; C028996:cardiac glycoside receptors; C004717:diacetylmonoxime; D010042:Ouabain; D020120:Iodocyanopindolol; D010869:Pindolol; D000254:Sodium-Potassium-Exchanging ATPase; D003931:Diacetyl; D017275:Isradipine