Antiarrhythmic drugs act on ion channels. Different potassium channel subtypes are involved in the repolarization process of action potential, maintenance of the resting potential and determine to a great extent the action potential duration in cardiac cells. A dysfunction of this channel may be the underlying cause in many types of cardiac arrhythmias during the ischemic and post-ischemic periods in patients. Ventricular fibrillation occur more frequently on reperfusion than during the preceding periods of ischemia. Specific K+ channels and/or non-specific K+ and Na+ channels may also be responsible for the oscillatory potentials mediated by increased intracellular calcium, (Ca)i. An important mediator of these oscillations is the sarcoplasmic reticulum (SR). In this proposal simulated hypoxia and ryoxygenation induced arrhythmias in canine ventricular and Purkinje tissue will be compared with arrhythmogenesis in general (drug induced or otherwise). Since many of the biophysical questions cannot be fully answered on tissue level experiments, a parallel study of whole cell voltage clamp will be carried out on canine ventricular myocyte and channels cloned from mammalian heart. It is realized however, that many experiments at tissue level cannot be exactly mimicked at the cellular level, and hence will be interpreted separately. The long term aims of this proposal are to determine the role played by the K channels, Ca++ channel, and the SR in the genesis of membrane potential perturbations (due to hypoxia, reperfusion and/or increased (Ca)i ). To achieve this goal the strategy will be to compare and contrast experiments involving whole tissue electrophysiology and single cell voltage clamp. Agents that modulate K+ channels (K+ channel openers, class III antiarrhythmic agents, e.g., sotalol, pinacidil) are of considerable therapeutic potential. These drugs may have direct or indirect effects on (Ca)i as well.
The specific aims will be, 1) to compare hypoxia/reoxygenation at the tissue level with that in whole cell subjected to metabolic blockade, 2) to test the effects of these modulators of K+ channels and those that regulate the SR (e.g., ryanodine) at the whole cell level ( in control and during metabolic blockade in native myocyte and cloned cells) as well as at the tissue level. There is a fundamental need to understand the behavior (similar or contrasting?) of antiarrhythmic agents both at the tissue and cellular level. The results will improve our understanding of antiarrhythmic drug action and thereby help in the development of newer and safer drugs.

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Pulliam, Stephanie R; Pellom Jr, Samuel T; Shanker, Anil et al. (2016) Butyrate regulates the expression of inflammatory and chemotactic cytokines in human acute leukemic cells during apoptosis. Cytokine 84:74-87
Chen, Chau-Kuang; Bruce, Michelle; Tyler, Lauren et al. (2013) Analysis of an environmental exposure health questionnaire in a metropolitan minority population utilizing logistic regression and Support Vector Machines. J Health Care Poor Underserved 24:153-71
Boadi, William Y; Harris, Shalandus; Anderson, Justin B et al. (2013) Lipid peroxides and glutathione status in human progenitor mononuclear (U937) cells following exposure to low doses of nickel and copper. Drug Chem Toxicol 36:155-62
Choudhury, Shahana A; Ladson, Gwinnett; Kabir, Madina S (2012) Evaluation of serotype-specific immunity to Streptococcus pneumoniae in pregnant women and cord blood of infants: impact of race and ethnicity. J Natl Med Assoc 104:251-7
Hall 3rd, Mack; Misra, Smita; Chaudhuri, Minu et al. (2011) Peptide aptamer mimicking RAD51-binding domain of BRCA2 inhibits DNA damage repair and survival in Trypanosoma brucei. Microb Pathog 50:252-62
Kawai, Yumiko; Garduño, Lakisha; Theodore, Melanie et al. (2011) Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem 286:7629-40
Rana, Tanu; Misra, Smita; Mittal, Mukul K et al. (2011) Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania. J Biol Chem 286:6614-26
Farrow, Anitra L; Rana, Tanu; Mittal, Mukul K et al. (2011) Leishmania-induced repression of selected non-coding RNA genes containing B-box element at their promoters in alternatively polarized M2 macrophages. Mol Cell Biochem 350:47-57
Sharma, Shvetank; Singha, Ujjal K; Chaudhuri, Minu (2010) Role of Tob55 on mitochondrial protein biogenesis in Trypanosoma brucei. Mol Biochem Parasitol 174:89-100
Sheng, Liu; Ding, Xinxin; Ferguson, Marcus et al. (2010) Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicol Sci 118:625-34

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