The agent 2,3-butanedione monoxime (BDM) has been reported to reduce the sensitivity of myofilament force development to calcium ions, without affecting the calcium transient in myocardium. One would predict, therefore, that BDM should reduce the contractile state of the heart without reducing the amount of oxygen that is consumed to fuel the process of excitation-contraction coupling. The purpose of the present experiment was to test this hypothesis using isovolumically contracting, isolated, blood perfused canine hearts during β-blockade induced by continuous intra-coronary infusion of propranolol (1 mg/h). Contractile state was increased in seven hearts by CaCl2 infusion. Subsequently, while the CaCl2 infusion was continued at the highest rate, contractile state was reduced by BDM infusion. At each contractile state, we measured the left-ventricular end-systolic pressure-volume relation (ESPVR), the relation between myocardial oxygen consumption and its mechanical correlate, pressure-volume area (MVO2 vs PVA), and the duration of the LV pressure waveform. Contractile state was quantified by interpolated developed pressure at a reference ventricular volume of 25 ml (P25). BDM infusion (0.5-7 mm) caused a dose-dependent reduction in contractile state (50% reduction in P25 at 2.4 ± 0.3 mm), and a dose-independent increase in coronary blood flow. Furthermore, BDM significantly reduced the duration of the pressure waveform up to 40% at the highest rate of BDM infusion compared to the pressure waveform duration measured at maximum CaCl2 infusion. We observed a direct relationship between MVO2 of the mechanically unloaded heart and contractility; this relation was unaffected by BDM infusion (P>0.3). The slope of the MVO2-PVA relation decreased with increases in contractile state, but this decrease was unaffected by BDM (P≥0.4). We conclude that in the isolated canine heart, BDM does not act energetically as expected for a myofibrillar calcium desensitizing agent.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cardiology and Cardiovascular Medicine
- Myocardial oxygen consumption
- Pressure-volume area
- Pressure-volume relationship