Effects of caffeine, verapamil, lithium, and KB-R7943 on mechanics and energetics of rat myocardial bigeminies

Abstract

We examined the effects of pharmacological alteration of Ca2+sources on mechanical and energetic properties of paired-pulse (“bigeminic”) contractions. The fraction of heat release that is related to pressure development and pressure-independent heat release were measured during isovolumic contractions in arterially perfused rat ventricles. The heat released by regular and bigeminic contractions showed two brief pressure-independent components (H1 and H2) and a pressure-dependent component (H3). We used the ratio of active heat (H′a) to pressure-time integral (PtI) and the ratio of H3 to PtI to estimate the energetic cost of muscle contraction (overall economy) and pressure maintenance (contractile economy), respectively. Neither of these ratios was affected by stimulation pattern. Caffeine (an inhibitor of sarcoplasmic reticulum function) significantly decreased mechanical responses and increased the energetic cost of contraction (Δ = 101 ± 12.6%). Verapamil (an L-type Ca2+channel blocker) decreased pressure maintenance of extrasystolic (Δ = 43.4 ± 3.7%) and postextrasystolic (Δ = 37.5 ± 3.5%) contractions without affecting postextrasystolic potentiation, suggesting that a verapamil-insensitive fraction is responsible for potentiation. The verapamil-insensitive fraction was further studied in the presence of lithium (45 mM) and KB-R7943 (5 μM), inhibitors of the Na+/Ca2+exchanger. Both agents decreased all mechanical responses, including postextrasystolic potentiation (Δ = 67.3 ± 3.3%), without altering overall or contractile economies, suggesting an association of the verapamil-insensitive Ca2+fraction to the sarcolemmal Na+/Ca2+exchanger. The effect of the inhibitors of the Na+/Ca2+exchanger on potentiation suggests an increased participation of extracellular Ca2+(and, thus, a redistribution of the relative participation of the Ca2+pools) during bigeminic contractions in rat myocardium.