Effect of thymol on kinetic properties of Ca and K currents in rat skeletal muscle

BACKGROUND: Thymol is widely used as a general antiseptic and antioxidant compound in the medical practice and industry, and also as a stabilizer to several therapeutic agents, including halothane. Thus intoxication with thymol may occur in case of ingestion or improper anesthesia. In the present study, therefore, concentration-dependent effects of thymol (30–600 micro-grams) were studied on calcium and potassium currents in enzymatically isolated rat skeletal muscle fibers using the double vaseline gap voltage clamp technique. RESULTS: Thymol suppressed both Ca and K currents in a concentration-dependent manner, the EC(50 )values were 193 ± 26 and 93 ± 11 μM, with Hill coefficients of 2.52 ± 0.29 and 1.51 ± 0.18, respectively. Thymol had a biphasic effect on Ca current kinetics: time to peak current and the time constant for inactivation increased at lower (100–200 μM) but decreased below their control values at higher (600 μM) concentrations. Inactivation of K current was also significantly accelerated by thymol (200–300 μM). These effects of thymol developed rapidly and were partially reversible. In spite of the marked effects on the time-dependent properties, thymol caused no change in the current-voltage relationship of Ca and K peak currents. CONCLUSIONS: Present results revealed marked suppression of Ca and K currents in skeletal muscle, similar to results obtained previously in cardiac cells. Furthermore, it is possible that part of the suppressive effects of halothane on Ca and K currents, observed experimentally, may be attributed to the concomitant presence of thymol in the superfusate

Can the electrophysiological action of rosiglitazone explain its cardiac side effects?

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Antiarrhythmic and Inotropic Effects of Selective Na+/Ca2+ Exchanger Inhibition: What Can We Learn from the Pharmacological Studies?

Life-long stable heart function requires a critical balance of intracellular Ca2+. Several ion channels and pumps cooperate in a complex machinery that controls the influx, release, and efflux of Ca2+. Probably one of the most interesting and most complex players of this crosstalk is the Na+/Ca2+ exchanger, which represents the main Ca2+ efflux mechanism; however, under some circumstances, it can also bring Ca2+ into the cell. Therefore, the inhibition of the Na+/Ca2+ exchanger has emerged as one of the most promising possible pharmacological targets to increase Ca2+ levels, to decrease arrhythmogenic depolarizations, and to reduce excessive Ca2+ influx. In line with this, as a response to increasing demand, several more or less selective Na+/Ca2+ exchanger inhibitor compounds have been developed. In the past 20 years, several results have been published regarding the effect of Na+/Ca2+ exchanger inhibition under various circumstances, e.g., species, inhibitor compounds, and experimental conditions; however, the results are often controversial. Does selective Na+/Ca2+ exchanger inhibition have any future in clinical pharmacological practice? In this review, the experimental results of Na+/Ca2+ exchanger inhibition are summarized focusing on the data obtained by novel highly selective inhibitors

Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents

Based on recent findings, an increased late sodium current (INa,late) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is INa,late and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased INa,late in heart diseases, and also discusses how the upregulated INa,late can play a role in the generation of cardiac arrhythmias. The last part of the article is about INa,late inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials

Reverse rate dependency is an intrinsic property of canine cardiac preparations

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Selective Inhibition of Cardiac Late Na+ Current Is Based on Fast Offset Kinetics of the Inhibitor

The present study was designed to test the hypothesis that the selectivity of blocking the late Na+ current (INaL) over the peak Na+ current (INaP) is related to the fast offset kinetics of the Na+ channel inhibitor. Therefore, the effects of 1 µM GS967 (INaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on INaL and INaP were compared in canine ventricular myocardium. INaP was estimated as the maximum velocity of action potential upstroke (V+max). Equal amounts of INaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of INaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V+max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of INaL over INaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of INaL over INaP is related to the fast offset kinetics of the Na+ channel inhibitor

Intercalation of small molecules into DNA in chromatin is primarily controlled by superhelical constraint

The restricted access of regulatory factors to their binding sites on DNA wrapped around the nucleosomes is generally interpreted in terms of molecular shielding exerted by nucleosomal structure and internucleosomal interactions. Binding of proteins to DNA often includes intercalation of hydrophobic amino acids into the DNA. To assess the role of constrained superhelicity in limiting these interactions, we studied the binding of small molecule intercalators to chromatin in close to native conditions by laser scanning cytometry. We demonstrate that the nucleosome-constrained superhelical configuration of DNA is the main barrier to intercalation. As a result, intercalating compounds are virtually excluded from the nucleosome-occupied regions of the chromatin. Binding of intercalators to extranucleosomal regions is limited to a smaller degree, in line with the existence of net supercoiling in the regions comprising linker and nucleosome free DNA. Its relaxation by inducing as few as a single nick per ~50 kb increases intercalation in the entire chromatin loop, demonstrating the possibility for long-distance effects of regulatory potential