REVERSIBLE DESENSITIZATION OF THE MYOCARDIAL CONTRACTILE APPARATUS FOR CALCIUM - A NEW CONCEPT FOR IMPROVING TOLERANCE TO COLD ISCHEMIA IN HUMAN MYOCARDIUM

The influence of 2,3-Butanedione monoxime (BDM) on the human myocardiu m's tolerance to cold ischemia was analyzed in two experimental series . Methods: I) Left ventricular human muscle fibers (0.6 x 4.0 mm) were obtained from recipient hearts (n = 10) and loaded with the fluoresce nt dye Fura-2. Simultaneous measurements of intracellular calcium tran sients (''ratio-method''; excitation wave lengths: 340 nm and 380 nm) and isometric force development of electrically driven (1 Hz) muscle f ibers were carried out at BDM concentrations ranging from 0 to 30 mM a t a bath temperature of 37-degrees-C; II) Left ventricular human muscl e strips were obtained from beating recipient hearts (n = 10), and rig ht atrial fibers from patients operated upon for aortic valve stenosis or combined mitral valve disease (n = 14). Muscle strips of these hea rts were incubated for parallel measurements in the following solution s: a) a 37-degrees-C oxygenated Krebs-Henseleit solution (KHS), b) a 4 -degrees-C Bretschneider's cardioplegic solution (HTK) without oxygena tion and c) a 4-degrees-C KHS containing 30 mM BDM without oxygenation (BDM solution). After standardized time intervals the muscle fibers w ere removed from the storage solutions, reperfused in KHS solution at 37-degrees-C and stretched to optimal length (supramaximal electrical stimulation). After obtaining a steady state of force development, the contractile behavior under isometric and isotonic measurement conditi ons was measured. The influence of the incubation periods and the incu bation solution was analyzed. Results: I) BDM reduced the isometric fo rce development of the electrically driven isolated human myocardial m uscle strip in a dose-dependent way. At 30 mM BDM, no force developed although the amplitude of the intracellular calcium transient was stil l 60% of the control without BDM. The BDM effects were immediately and completely reversible. II) Cold storage in 30 mM BDM solution improve d tolerance to ischemia of isolated human myocardium. The storage peri ods allowing maintenance of contractile function could be enlarged by a factor of about 4 as compared with HTK or KHS (P< 0.0001). Conclusio n: BDM causes a dose-dependent, reversible desensitization of the cont ractile apparatus for calcium in human atrial and ventricular myocardi um. This prevents activation of cross-bridges in the presence of calci um thereby reducing oxygen demand during ischemic periods. For that re ason reversible desensitization of the contractile apparatus for calci um should be considered as a new concept for improving myocardial pres ervation.