25 research outputs found
From Action Potential-Clamp to "Onion-Peeling" Technique – Recording of Ionic Currents Under Physiological Conditions
Can the Electrophysiological Action of Rosiglitazone Explain its Cardiac Side Effects?
Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 mu M) shortened AP duration at 90% level of repolarization (APD(90)) and increased the AP amplitude (APA) in a concentration-dependent manner. In rat ventricular papillary muscle cells R (1-30 mu M) caused a significant reduction of APA and maximum velocity of depolarization (V(max)) which was accompanied by lengthening of APD(90). In single canine ventricular myocytes at concentrations >= 10 mu M R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced V(max). R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC(50) value for this inhibition was 25.2 +/- 2.7 mu M for the transient outward K(+) current (I(to)), 72.3 +/- 9.3 mu M for the rapid delayed rectifier K(+) current (I(Kr)), and 82.5 +/- 9.4 mu M for the L-type Ca(2+) current (I(Ca)) with Hill coefficients close to unity. The inward rectifier K(+) current (I(K1)) was not affected by R up to concentrations of 100 mu M. Suppression of I(to), I(Kr), and I(Ca) has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patient
15+ MILLION TOP 1% MOST CITED SCIENTIST 12.2% AUTHORS AND EDITORS FROM TOP 500 UNIVERSITIES 7 From Action Potential-Clamp to "Onion-Peeling" Technique -Recording of Ionic Currents Under Physiological Conditions
Role of gap junction channel in the development of beat-to-beat action potential repolarization variability and arrhythmias
Endocardial versus epicardial differences in L-type calcium current in canine ventricular myocytes studied by action potential voltage clamp
Changes in intracellular calcium concentration influence beat-to-beat variability of action potential duration in canine ventricular myocytes
Dynamics of the late Na(+) current during cardiac action potential and its contribution to afterdepolarizations
The objective of this work is to examine the contribution of late Na(+) current (I(Na,L)) to the cardiac action potential (AP) and arrhythmogenic activities. In spite of the rapidly growing interest toward this current, there is no publication available on experimental recording of the dynamic I(Na,L) current as it flows during AP with Ca(2+) cycling. Also unknown is how the current profile changes when the Ca(2+)-calmodulin dependent protein kinase II (CaMKII) signaling is altered, and how the current contributes to the development of arrhythmias. In this study we use an innovative AP-clamp Sequential Dissection technique to directly record the I(Na,L) current during the AP with Ca(2+) cycling in the guinea pig ventricular myocytes. First, we found that the magnitude of I(Na,L) measured under AP-clamp is substantially larger than earlier studies indicated. CaMKII inhibition using KN-93 significantly reduced the current. Second, we recorded I(Na,L) together with I(Ks), I(Kr), and I(K1) in the same cell to understand how these currents counterbalance to shape the AP morphology. We found that the amplitude and the total charge carried by I(Na,L) exceed that of I(Ks). Third, facilitation of I(Na,L) by Anemone toxin II prolonged APD and induced Ca(2+) oscillations that led to early and delayed afterdepolarizations and triggered APs; these arrhythmogenic activities were eliminated by buffering Ca(2+) with BAPTA. In conclusion, I(Na,L) contributes a significantly large inward current that prolongs APD and unbalances the Ca(2+) homeostasis to cause arrhythmogenic APs