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Item ANALYSIS OF MULTICHANNEL SIGNALS USING A CHANNEL SIMULATOR(Office of the Vice Chancellor for Research, 2012-04-13) Palacio, Luis A.; Petrache, Horia I.In biological systems ion channels can be thought of as opening and clos-ing pores that allow the flow of ion through a membrane. Ion channels are responsible for intracellular communication and keeping an osmotic equilib-rium across cell membranes. Measurements of ion channel activities that generate multichannel events (the opening of more than one channel at a time) are important to understand, but difficult to analyze. In many cases the multichannel events are discarded instead of used in the analysis. The availability of a channel signal simulator offers an excellent opportunity to develop and test statistical models for analysis of multichannel signals. We have generated single channel traces for various open probabilities and then digitally superimposed these signals to obtain multichannel events. We then applied our simplified analysis to these multichannel traces to calculate sin-gle channel parameters such as the average ON and OFF times and their statistical distribution of the ON times. The average ON time as well as the ON time distribution matched the single channel input mean open time. The importance of our findings is that our proposed analysis will be able to use the statistical distribution of ON times, in addition to the traditional “dwell time” (or average ON time) parameter, to characterize ion channels.Item Apamin-Sensitive Calcium-Activated Potassium Currents in Rabbit Ventricles with Chronic Myocardial Infarction(Wiley Online Library, 2013-10-24) Lee, Young Soo; Chang, Po-Cheng; Hsueh, Chia-Hsiang; Maruyama, Mitsunori; Park, Hyung Wook; Rhee, Kyoung-Suk; Hsieh, Yu-Cheng; Shen, Changyu; Weiss, James N.; Chen, Zhenhui; Lin, Shien-Fong; Chen, Peng-Sheng; Department of Medicine, IU School of MedicineIntroduction Apamin-sensitive small-conductance calcium-activated potassium current (IKAS) is increased in heart failure. It is unknown if myocardial infarction (MI) is also associated with an increase of IKAS. Methods and Results We performed Langendorff perfusion and optical mapping in 6 normal hearts and 10 hearts with chronic (5 weeks) MI. An additional 6 normal and 10 MI hearts were used for patch clamp studies. The infarct size was 25% [95% confidence interval, 20 to 31] and the left ventricular ejection fraction was 0.5 [0.46 to 0.54]. The rabbits did not have symptoms of heart failure. The action potential duration measured to 80% repolarization (APD80) in the peri-infarct zone (PZ) was150 [142 to 159] ms, significantly (p=0.01) shorter than in the normal ventricles (158 to 177] ms). The intracellular Ca transient duration was also shorter in the PZ (148 [139 to 157] ms) than in normal ventricles (168 [157 to 180] ms; P=0.017). Apamin prolonged the APD80 in PZ by 9.8 [5.5 to 14.1] %, which is greater than in normal ventricles (2.8 [1.3 to 4.3] %, p=0.006). Significant shortening of APD80 was observed at the cessation of rapid pacing in MI but not in normal ventricles. Apamin prevented postpacing APD80 shortening. Patch clamp studies showed that IKAS was significantly higher in the PZ cells (2.51 [1.55 to 3.47] pA/pF, N=17) than in the normal cells (1.08 [0.36 to 1.80] pA/pF, N=15, p=0.019). Conclusion We conclude that IKAS is increased in MI ventricles and contributes significantly to ventricular repolarization especially during tachycardia.Item Contribution of K+ Channels to Coronary Dysfunction in Metabolic Syndrome(2009-06-24T12:58:39Z) Watanabe, Reina; Tune, Johnathan D.Coronary microvascular function is markedly impaired by the onset of the metabolic syndrome and may be an important contributor to the increased cardiovascular events associated with this mutlifactorial disorder. Despite increasing appreciation for the role of coronary K+ channels in regulation of coronary microvascular function, the contribution of K+ channels to the deleterious influence of metabolic syndrome has not been determined. Accordingly, the overall goal of this investigation was to delineate the mechanistic contribution of K+ channels to coronary microvascular dysfunction in metabolic syndrome. Experiments were performed on Ossabaw miniature swine fed a normal maintenance diet or an excess calorie atherogenic diet that induces the classical clinical features of metabolic syndrome including obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, hyperleptinemia, and atherosclerosis. Experiments involved in vivo studies of coronary blood flow in open-chest anesthetized swine as well as conscious, chronically instrumented swine and in vitro studies in isolated coronary arteries, arterioles, and vascular smooth muscle cells. We found that coronary microvascular dysfunction in the metabolic syndrome significantly impairs coronary vasodilation in response to metabolic as well as ischemic stimuli. This impairment was directly related to decreased membrane trafficking and functional expression of BKCa channels in vascular smooth muscle cells that was accompanied by augmented L-type Ca2+ channel activity and increased intracellular Ca2+ concentration. In addition, we discovered that impairment of coronary vasodilation in the metabolic syndrome is mediated by reductions in the functional contribution of voltage-dependent K+ channels to the dilator response. Taken together, findings from this investigation demonstrate that the metabolic syndrome markedly attenuates coronary microvascular function via the diminished contribution of K+ channels to the overall control of coronary blood flow. Our data implicate impaired functional expression of coronary K+ channels as a critical mechanism underlying the increased incidence of cardiac arrhythmias, infarction and sudden cardiac death in obese patients with the metabolic syndrome.Item Correlations of Specific Ionic Effects using Ion Channels and Surface Charge Measurements(Office of the Vice Chancellor for Research, 2014-04-11) Roark, Torri C.; Hermida, Oscar Teijido; Rostovtseva, Tatiana K.; Gurnev, Philip A.; Petrache, Horia I.; Bezrukov, Sergey M.Specific ionic effects, as captured in the Hofmeister series, have been observed in many biological phenomena including protein folding and aggregation and lipid bilayer interactions. Previously we have shown that the Hofmeister effect is present in the activity of gramicidin A channels. In particular, measurements of channel open lifetime and conductance in potassium salts clearly show the existence of two distinct ionic classes that could be identified as kosmotropic and chaotropic. To further investigate this behavior, we have measured the zeta potential of diphytanoyl phosphatidylcholine (DPhPC) liposomes in salt solutions. We observe that anions alter the surface charge of the liposomes depending on the classification of the anion as kosmotropic or chaotropic. Chaotropic anions (SCN-, ClO4-) decrease the surface charge of the liposomes while kosmotropic anions (Cl-, H2PO4-, SO42-) have the opposite effect. These results correlate with our previous studies of cation conductance through gramicidin A channels adding new insight into ionic interactions at the lipid-water interface.Item HODGKIN-HUXLEY MODEL FOR ACTION POTENTIAL: MEMRISTIVE CHARACTERISTICS(Office of the Vice Chancellor for Research, 2012-04-13) Mirza, Qurat-ul-Ann; Joglekar, YogeshMemristor, a short for memory resistor, is the fourth ideal circuit element whose value varies as a function of charge that has passed through the de-vice. Voltage-gated ion channels in biological membranes share this charac-teristic of a memristor. In 1952, Hodgkin and Huxley (H-H) developed an electrical circuit model (HH model) to describe the time-dependent action potentials mediated by voltage-gated ion channels. We investigate the de-pendence of the action potential, including the onset of repeated spiking, on the applied current I, sodium and potassium channel conductance, and the membrane capacitance. We use a MATLAB code with the fourth-order Runge-Kutta method to solve the HH equations. Our results suggest that the memristive characteristics of the ion channels can be tuned over a wide range of parameters.