CK inhibition accelerates transcytosolic energy signaling during rapid workload steps in isolated rabbit hearts

The effect of graded creatine kinase (CK) inhibition on the response time of mitochondrial O-2 consumption to dynamic workload jumps (t(mito)) was studied in isolated rabbit hearts. Tyrode-perfused hearts (n = 7/group) were exposed to 15 min of 0, 0.1, 0.2, or 0.4 mM iodoacetamide (IA) (CK activity = 100, 14, 6, and 3%, respectively). Pretreatment tmito was similar across groups at 6.5 +/- 0.5 s (mean +/- SE). The increase observed over time in control hearts (33 +/- 8%) was progressively reversed to 16 +/- 6, -20 +/- 6 (P < 0.01 vs. control), and -46 +/- 6 (P < 0.01 vs, control) % in the 0.1, 0.2 and 0.4 mM IA groups, respectively. The faster response times occurred without reductions in mitochondrial oxidative capacity (assessed in vitro) or myocardial O-2 consumption of the whole heart during workload steps. Isovolumic contractile function assessed as rate-pressure product (RPP) and contractile reserve (increase in RPP during heart rate steps) were significantly reduced by IA. We conclude that CK in the myofibrils and/or cytosol does not speed up transfer of the energy-related signal to the mitochondria but rather acts as an energetic buffer, effectively slowing the stimulus between myofibrils/ion pumps and oxidative phosphorylation. This argues against the existence of an obligatory creatine phosphate energy shuttle, because CK is effectively bypassed.