Effect of trimetazidine treatment on the transient outward potassium current of the left ventricular myocytes of rats with streptozotocin-induced type 1 diabetes mellitus

Cardiovascular complications are a leading cause of mortality in patients with diabetes mellitus (DM). The present study was designed to investigate the effects of trimetazidine (TMZ), an anti-angina drug, on transient outward potassium current (Ito) remodeling in ventricular myocytes and the plasma contents of free fatty acid (FFA) and glucose in DM. Sprague-Dawley rats, 8 weeks old and weighing 200-250 g, were randomly divided into three groups of 20 animals each. The control group was injected with vehicle (1 mM citrate buffer), the DM group was injected with 65 mg/kg streptozotocin (STZ) for induction of type 1 DM, and the DM + TMZ group was injected with the same dose of STZ followed by a 4-week treatment with TMZ (60 mg·kg-1·day-1). All animals were then euthanized and their hearts excised and subjected to electrophysiological measurements or gene expression analyses. TMZ exposure significantly reversed the increased plasma FFA level in diabetic rats, but failed to change the plasma glucose level. The amplitude of Ito was significantly decreased in left ventricular myocytes from diabetic rats relative to control animals (6.25 ± 1.45 vs 20.72 ± 2.93 pA/pF at +40 mV). The DM-associated Ito reduction was attenuated by TMZ. Moreover, TMZ treatment reversed the increased expression of the channel-forming alpha subunit Kv1.4 and the decreased expression of Kv4.2 and Kv4.3 in diabetic rat hearts. These data demonstrate that TMZ can normalize, or partially normalize, the increased plasma FFA content, the reduced Ito of ventricular myocytes, and the altered expression Kv1.4, Kv4.2, and Kv4.3 in type 1 DM.

Ionic Mechanisms of Desflurane on Prolongation of Action Potential Duration in Rat Ventricular Myocytes

PURPOSE: Despite the fact that desflurane prolongs the QTC interval in humans, little is known about the mechanisms that underlie these actions. We investigated the effects of desflurane on action potential (AP) duration and underlying electrophysiological mechanisms in rat ventricular myocytes. MATERIALS AND METHODS: Rat ventricular myocytes were enzymatically isolated and studied at room temperature. AP was measured using a current clamp technique. The effects of 6% (0.78 mM) and 12% (1.23 mM) desflurane on transient outward K+ current (I(to)), sustained outward current (I(sus)), inward rectifier K+ current (I(KI)), and L-type Ca2+ current were determined using a whole cell voltage clamp. RESULTS: Desflurane prolonged AP duration, while the amplitude and resting membrane potential remained unchanged. Desflurane at 0.78 mM and 1.23 mM significantly reduced the peak I(to) by 20+/-8% and 32+/-7%, respectively, at +60 mV. Desflurane (1.23 mM) shifted the steady-state inactivation curve in a hyperpolarizing direction and accelerated inactivation of the current. While desflurane (1.23 mM) had no effects on I(sus) and I(KI), it reduced the L-type Ca2+ current by 40+/-6% (p<0.05). CONCLUSION: Clinically relevant concentrations of desflurane appear to prolong AP duration by suppressing Ito in rat ventricular myocytes.

The underlying proantiarrhythmic mechanism of 5-HT_4 receptor agonist and 5-HT_3 receptor antagonist 2-[1-(4-piperonyl)piperazinyl]benzothiazole / 中国药理学通报

Aim To investigate the effects of 5-HT_4 receptor agonist and 5-HT_3 receptor antagonist 2-[1-(4-piperonyl)piperazinyl]benzothiazole on rat heart rhythm and the involved ionic mechanisms.Methods Langendorff-perfused rat hearts were subjected to 0.1～10 μmol·L~(-1) 2-[1-(4-piperonyl)-piperazinyl]benzothiazole for 15 minutes with simultaneous ECGs recording.The whole-cell patch-clamp electrophysiology was used to record effects of 2-[1-(4-piperonyl)piperazinyl]benzothiazole on inward rectifier K~+ current(I_(K1)),transient outward K~+ current(I_(to)),resting membrane potential(RMP)and action potential(AP)in enzymatic dissociated rat ventricular myocytes.Results In ex vivo Langendorff-perfused hearts,0.1～10 μmol·L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole elicited singnificant rhythm disturbances.In the presence of 10 μmol·L~(-1) agent,the total of PVB were 236±37,87.5%(7/8)hearts exhibited VT,and 62.5%(5/8)hearts exhibited VF(P<0.01).At the concentration of 0.1～10 μmol·L~(-1),2-[1-(4-piperonyl)piperazinyl]benzothiazole could inhibit I_(K1)(EC50=0.74 μmol·L~(-1))and I_(to)(EC50=2.16 μmol·L~(-1)),decrease RMP and prolong action potential duration(APD)in concentration-dependent manners(n=6,P<0.01).Conclusion Inhibition of IK1,Ito and resultant prolongation of APD,depolarization of RMP might be the critical causes for induction of arrhythmias by 2-[1-(4-piperonyl)piperazinyl]benzothiazole in rat.

Electrophysiologic Mechanisms of Sevoflurane on Prolongation of the QT Interval: K+ Currents in Rat Ventricular Myocytes / 대한마취과학회지

BACKGROUND: Whereas sevoflurane (SEVO) has been reported to prolong the QT interval, little has been known on the electrophysiologic effects of SEVO which contributes to the prolongation of action potential (AP) duration. METHODS: The ventricular myocytes were obtained from enzymatically treated rat hearts. The standard whole cell voltage-clamp methods were used. The AP was measured using current clamp technique. As a repolarizing K+ current, the transient outward K+ current (I(to)), the sustained outward K+ current (I(sus)), and the inwardly rectifying K+ current (I(kI)) were measured. The L-type Ca2+ current (I(Ca), L) was also obtained. After the baseline measurements, the myocytes were exposed to 1.7 and 3.4% SEVO. SEVO concentrations in Tyrode superfusate at room temperature were 0.35 and 0.7 mM for 1.7 and 3.4% SEVO, respectively. Results are mean +/- SEM. RESULTS: SEVO prolonged the AP duration, while the amplitude and the resting membrane potential remained unchanged. At membrane potential of +60 mV, peak I(to) was significantly reduced by 18 +/- 2 and 24 +/- 2% by 0.35 and 0.7 mM SEVO, respectively. 0.7 mM SEVO did not shift the steady-state inactivation curve. Isus was unaffected by 0.7 mM SEVO. The I(kI) at -130 mV was little altered by 0.7 mM SEVO. I(Ca), L was significantly reduced by 28 +/- 3 and 33 +/- 1% by 0.35 and 0.7 mM SEVO, respectively. CONCLUSIONS: Prolongation of AP duration by SEVO in rat ventricular myocytes is likely to be caused by a reduction of I(to). Resting membrane potential was unaffected by SEVO, which seems to be related to no alteration of I(kI).

Electrophysiologic Effect of Desflurane on the Prolongation of Action Potential Duration in Ventricular Myocytes / 대한마취과학회지

BACKGROUND: Desflurane has been reported to prolong the QTc. Several ionic currents that contribute to the prolongation of the action potential (AP) duration were investigated using guinea pig (GP) and rat ventricular myocytes. METHODS: The normal APs were measured in isolated GP papillary muscles at 37 degrees C. Ventricular myocytes were obtained from GP and rat hearts. Both the delayed outward K+ current (I(K)) and the inward rectifier K+ current (I(KI)) were assessed using a voltage ramp protocol. A more detailed study on the I(K) was performed. The ICa, L was measured. In the rat ventricular myocytes, the transient outward K+ current (I(to)) was obtained. All the patch clamp experiments were carried out at room temperature. The values are presented as mean +/- SD. RESULTS: 0.91 mM desflurane significantly prolonged the APD in the GP ventricular myocytes. Using a linear voltage ramp protocol, the I(KI) at -130 mV and the peak outward I(KI) at -60 to -50 mV were not found to be significantly reduced by 0.78 and 1.23 mM desflurane, respectively. However, the peak outward I(K) at +60 mV was significantly reduced to 63 +/- 19% and 58 +/- 12% of the baseline by 0.78 and 1.23 mM desflurane, respectively. At a membrane potential of +60 mV, 0.78 and 1.23 mM desflurane reduced the Ito to 80 +/- 8% and 68 +/- 7%, respectively. A concentration-dependent reduction in the ICa, L was observed. CONCLUSIONS: The prolongation of the APD induced by clinically relevant concentrations of desflurane in GP and rat ventricular myocytes is most likely the result of I(K) and I(to) suppression.

Two types of voltage-dependent outward potassium currents in smooth muscle cells of rabbit basilar artery

We have investigated the two types of voltage-dependent outward potassium (K) currents, i.e. delayed rectifier K current (I-K(V)) and 'A-like' transient outward K current (I-to) with patch-clamp technique in single smooth muscle cells (SMCs) isolated from rabbit basilar artery, and investigated the characteristics of them. The time-courses of activation were well fitted by exponential function raised to second power (n-2) in I-K(v) and fourth power (n-4) in I-to. The activation, inactivation and recovery time courses of I-to were much faster than that of I-K(V). The steady-state activation and inactivation of I-K(V) was at the more hyperpolarized range than that of I-to contrary to the reports in other vascular SMCs. Tetraethylammonium chloride (TEA; 10 mM) markedly inhibited I-K(V) but little affected 1-to. 4-Aminopyridine (4-AP) had similar inhibitory potency on both currents. While a low concentration of Cd-2+ (0.5 mM) shifted the current-voltage relationship of I-to to the positive direction without change of maximum conductance, Cd-2+ did not cause any appreciable change for I-K(V).