BACKGROUND: The role of the L-type calcium channel in human heart failure is unclear, on the basis of previous whole-cell recordings. METHODS AND RESULTS: We investigated the properties of L-type calcium channels in left ventricular myocytes isolated from nonfailing donor hearts (n= 16 cells) or failing hearts of transplant recipients with dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel recording technique was used (70 mmol/L Ba2+). Peak average currents were significantly enhanced in heart failure (38.2+/-9.3 fA) versus nonfailing control hearts (13.2+/-4.5 fA, P=0.02) because of an elevation of channel availability (55.9+/-6.7% versus 26.4+/-5.3%, P=0.001) and open probability within active sweeps (7.36+/-1.51% versus 3.18+/-1.33%, P=0.04). These differences closely resembled the effects of a cAMP-dependent stimulation with 8-Br-cAMP (n= 11). Kinetic analysis of the slow gating shows that channels from failing hearts remain available for a longer time, suggesting a defect in the dephosphorylation. Indeed, the phosphatase inhibitor okadaic acid was unable to stimulate channel activity in myocytes from failing hearts (n=5). Expression of calcium channel subunits was measured by Northern blot analysis. Expression of alpha1c- and beta-subunits was unaltered. Whole-cell current measurements did not reveal an increase of current density in heart failure. CONCLUSIONS: Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.
BACKGROUND: The role of the L-type calcium channel in humanheart failure is unclear, on the basis of previous whole-cell recordings. METHODS AND RESULTS: We investigated the properties of L-type calcium channels in left ventricular myocytes isolated from nonfailing donor hearts (n= 16 cells) or failing hearts of transplant recipients with dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel recording technique was used (70 mmol/L Ba2+). Peak average currents were significantly enhanced in heart failure (38.2+/-9.3 fA) versus nonfailing control hearts (13.2+/-4.5 fA, P=0.02) because of an elevation of channel availability (55.9+/-6.7% versus 26.4+/-5.3%, P=0.001) and open probability within active sweeps (7.36+/-1.51% versus 3.18+/-1.33%, P=0.04). These differences closely resembled the effects of a cAMP-dependent stimulation with 8-Br-cAMP (n= 11). Kinetic analysis of the slow gating shows that channels from failing hearts remain available for a longer time, suggesting a defect in the dephosphorylation. Indeed, the phosphatase inhibitor okadaic acid was unable to stimulate channel activity in myocytes from failing hearts (n=5). Expression of calcium channel subunits was measured by Northern blot analysis. Expression of alpha1c- and beta-subunits was unaltered. Whole-cell current measurements did not reveal an increase of current density in heart failure. CONCLUSIONS: Individual L-type calcium channels are fundamentally affected in severe humanheart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.
Authors: Henry M Colecraft; Badr Alseikhan; Shoji X Takahashi; Dipayan Chaudhuri; Scott Mittman; Vasan Yegnasubramanian; Rebecca S Alvania; David C Johns; Eduardo Marbán; David T Yue Journal: J Physiol Date: 2002-06-01 Impact factor: 5.182
Authors: Ira R Josephson; Antonio Guia; Eric A Sobie; W Jonathan Lederer; Edward G Lakatta; Michael D Stern Journal: Biochem Biophys Res Commun Date: 2010-05-10 Impact factor: 3.575
Authors: Janet R Manning; Catherine N Withers; Bryana Levitan; Jeffrey D Smith; Douglas A Andres; Jonathan Satin Journal: Am J Physiol Heart Circ Physiol Date: 2015-09-14 Impact factor: 4.733
Authors: Katharina Foerster; Tomas Kaeferstein; Ferdi Groner; Stefan Engelhardt; Jan Matthes; Walter J Koch; Martin J Lohse; Stefan Herzig Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2004-04-09 Impact factor: 3.000