The role of the cytosolic Ca (Cai) transient in determining the configuration of the cardiac action potential was further investigated. For this purpose, rat ventricular myocytes loaded with the Ca(2+) sensitive fluorescent dye indo-1 were used. Myocytes were loaded with either 1) the acetoxy-methyl ester of indo-1 (indo-1 AM), which provides qualitative information about changes in the Cai transient or 2) the Ca(2+) sensitive, free acid form of indo-1, which allows intracellular Cai to be quantified. The magnitude of the Cai transient was graded by various physiological and pharmacological interventions and membrane voltage or current was recorded using patch-type microelectrodes. Earlier work in indo-1 AM loaded cells had shown that phase-plane loops of membrane potential (Vm) vs indo-1 ratio from a stimulus train conformed to a common trajectory during the slow tail of repolarization, despite a beat-dependent decrease in the magnitude of the Cai transient. It was found that phase plane loops of the Vm vs. indo-1 ratio from spontaneous diastolic Cai oscillations also conformed to this trajectory. Experiments with indo-1 free acid, which was incorporated into the cell by inclusion in the microelectrode filling solution, showed that in rested beats peak Cai can exceed 2 microM and then decrease to 0.4 - 0.6 microM in the steady state. Evidence was found that both electrogenic Na/Ca exchange and a Ca(2+)-dependent ion channel current may participate in the modulation of the cardiac action potential by the Cai transient.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Aging
United States
Zip Code
Li, Xianwu; Cudaback, Eiron; Breyer, Richard M et al. (2012) Eicosanoid receptor subtype-mediated opposing regulation of TLR-stimulated expression of astrocyte glial-derived neurotrophic factor. FASEB J 26:3075-83
Marchani, Elizabeth E; Wijsman, Ellen M (2011) Estimation and visualization of identity-by-descent within pedigrees simplifies interpretation of complex trait analysis. Hum Hered 72:289-97
Keene, C Dirk; Cudaback, Eiron; Li, Xianwu et al. (2011) Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease. Curr Opin Neurobiol 21:920-8
Tsuang, Debby; Larson, Eric B; Li, Ge et al. (2010) Association between lifetime cigarette smoking and lewy body accumulation. Brain Pathol 20:412-8
Marchani, Elizabeth E; Bird, Thomas D; Steinbart, Ellen J et al. (2010) Evidence for three loci modifying age-at-onset of Alzheimer's disease in early-onset PSEN2 families. Am J Med Genet B Neuropsychiatr Genet 153B:1031-41
Woltjer, Randall L; Sonnen, Joshua A; Sokal, Izabela et al. (2009) Quantitation and mapping of cerebral detergent-insoluble proteins in the elderly. Brain Pathol 19:365-74
Longstreth Jr, W T; Sonnen, Joshua A; Koepsell, Thomas D et al. (2009) Associations between microinfarcts and other macroscopic vascular findings on neuropathologic examination in 2 databases. Alzheimer Dis Assoc Disord 23:291-4
Sonnen, Joshua A; Larson, Eric B; Gray, Shelly L et al. (2009) Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking. Ann Neurol 65:226-9
Marchani, Elizabeth E; Callegaro, Andrea; Daw, E Warwick et al. (2009) Combining information from linkage and association methods. Genet Epidemiol 33 Suppl 1:S81-7
Maltsev, Victor A; Lakatta, Edward G (2007) Normal heart rhythm is initiated and regulated by an intracellular calcium clock within pacemaker cells. Heart Lung Circ 16:335-48