| dc.description | Cardiac excitation-contraction (E-C) coupling includes two mechanisms: (1) calcium-induced calcium release (CICR); (2) the voltage-sensitive release mechanism (VSRM). Cell shortening and currents were measured in voltage clamped guinea pig or hamster ventricular myocytes at 37°C. Na + current was inhibited. Transient outward current also was inhibited in hamster cells. In cardiomyopathic (CM) hamster myocytes, VSRM but not CICR contractions were significantly reduced in magnitude. Sarcoplasmic reticulum (SR) Ca2+, content, assessed with 10 mM caffeine, was unaltered in CM cells. Fractional SR Ca2+ release was estimated by normalizing VSRM and CICR contractions to caffeine-induced contractures. Fractional SR Ca2+ release by the VSRM, but not CICR was significantly reduced in CM cells. In guinea pig myocytes, the nonspecific phosphodiesterase (PDE) inhibitor IBMX increased both VSRM and CICR contractions and also stimulated L-type Ca2+ current (ICa-L). In contrast, the specific PDE III inhibitor amrinone enhanced VSRM contractions without stimulation of ICa-L or CICR. Both IBMX and amrinone increased SR Ca 2+ content. However, both drugs increased fractional SR Ca 2+ release by the VSRM, but not CICR. In normal hamster myocytes, amrinone selectively enhanced the VSRM without an effect on CICR. In contrast, amrinone had no effect on contractions in CM cells. In addition, amrinone decreased ICa-L in normal and CM cells. Amrinone also caused a small increase in SR Ca2+ content and selectively increased VSRM fractional release in normal cells, but this action was absent in CM cells. Together, these results suggest that impaired contractility in CM cells is attributable to depression of the VSRM, which is related to defective fractional release of SR Ca2+ by the VSRM. Amrinone selectively potentiates the VSRM in normal cells, but cannot restore depressed VSRM contractions in CM cells. This may be related to an inability of amrinone to increase fractional release by the VSRM in CM myocytes. | en_US |
