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Effects of dexmedetomidine on cardiac electrical activity and ion currents: an experimental animal study

  • Funda Arun ORCID logo EMAIL logo , Nihal Ozturk ORCID logo , Orhan Erkan ORCID logo , Semir Ozdemir ORCID logo , Oguzhan Arun ORCID logo , Sirma Basak Yanardag and Murat Ayaz ORCID logo
Published/Copyright: May 8, 2025
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Turkish Journal of Biochemistry
From the journal Turkish Journal of Biochemistry Volume 50 Issue 4

Abstract

Objectives

Dexmedetomidine is a potent and highly selective alpha-2 adrenergic receptor agonist recognized for its sedative, hypnotic, analgesic, and sympatholytic properties. The diverse cardiac and hemodynamic effects of dexmedetomidine have been thoroughly documented. Consequently, we investigated its impact on electrophysiological parameters, including action potential and contraction in ventricular myocytes.

Methods

Freshly isolated ventricular myocytes from adult Wistar rats were used for experiments. The contraction and relaxation responses, action potentials, L-type calcium currents, and potassium channel currents of the myocytes were recorded using a video-based contractility system and the whole-cell patch clamp technique.

Results

While higher concentrations of dexmedetomidine progressively inhibit the contractile responses of cardiomyocytes, they did not significantly impact the action potential repolarization phase or potassium currents (including both transient outward and inward rectifiers). However, there was a decrease in L-type calcium currents, particularly at potential values ranging from 0 to 30 mV. Furthermore, although dexmedetomidine shifted the V50 value toward more positive values in the deactivation-reactivation curve of the L-type calcium channel, no statistically significant difference was observed.

Conclusions

Our study demonstrates that dexmedetomidine causes a dose-dependent reduction in contractility and decreases calcium currents. These findings indicate that dexmedetomidine may significantly influence the mechanical and electrical functions of cardiac cells. Additional research is needed to clarify the molecular mechanisms underlying these changes.

Keywords: action potential; calcium current; cardiac electrical activity; dexmedetomidine; ion currents; potassium current

Introduction

Dexmedetomidine is a selective and potent α2-adrenoceptor agonist clinically used for its anxiolytic, sedative, amnestic, and analgesic properties [1]. The drug was initially approved by the US Food and Drug Administration in late 1999 for intravenous (iv) administration only for up to 24 h for sedation of mechanically ventilated adult patients in the intensive care unit (ICU). Then, it was approved for the sedation of non-intubated patients before or during interventional operations in 2008 and for sedation of adult ICU patients requiring conscious sedation in 2011 [2], [3]. From a more global perspective, dexmedetomidine has been approved for registration in different countries for different indications. As seen from ‘off-label’ use reports, it is increasingly used for other indications in various patient groups, such as agitated delirium and familial dysautonomia in adults and premedication, procedural sedation, ICU sedation, and anesthesia in children [4], [5], [6].

Dexmedetomidine produces a typical biphasic hemodynamic response during clinical use as hypotension and hypertension at low and high plasma concentrations, respectively [7]. Administration of an intravenous bolus of dexmedetomidine resulting in a high (peak) plasma concentration causes an increase in blood pressure accompanied by marked bradycardia. During this phase, there is a marked increase in systemic vascular resistance, which is thought to result from α2-receptor activation in vascular smooth muscle, causing peripheral vasoconstriction and hypertension. These effects are accompanied by a rapid reduction in heart rate, possibly caused by the baroreceptor reflex [8]. In a clinical study, the incidence of bradycardia was 26.4 % and 30.4 % at a loading dose of 0.5 μg/kg and one µg/kg, respectively [9]. When plasma concentrations of dexmedetomidine decrease, vasoconstriction is reduced because dexmedetomidine also causes vasodilation by activating α2 receptors on vascular endothelial cells, resulting in a hypotensive phase with presynaptic α2-adrenoreceptors inhibiting the sympathetic release of catecholamines and increased vagal activity [10]. A long-term decrease in mean arterial blood pressure of 13–27 % after the first dose of dexmedetomidine has been reported, and this has been explained by a sustained 60–80 % dose-dependent decrease in circulating plasma catecholamines. As with initial high plasma concentrations after an intravenous bolus or rapid loading dose, higher maintenance doses are associated with progressive increases in mean arterial pressure. Hypertensive effects limit hypotensive effects at concentrations between 1.9 and 3.2 ng/mL [11].

Dexmedetomidine may increase systemic and pulmonary vascular resistance, which can lead to pulmonary and systemic hypertension both in adults and children [11], [12]. It may be a limiting factor for the clinical use of dexmedetomidine, particularly in patients with known cardiac problems where heart rate is known to be essential to ensure adequate cardiac output. However, when loading and maintenance doses of dexmedetomidine are administered in a controlled manner, this side effect may not be seen, and dexmedetomidine can be used safely even in pulmonary hypertensive patients at low doses [13], [14]. Nevertheless, there are reports of off-label uses at doses well above the recommended dose range of 0.2–0.7 μg/kg/h, such as 1.0–2.5 μg/kg/h, putting patients at risk for cardiac side effects, particularly in the ICU [15], [16].

The clinical safety of dexmedetomidine has been evaluated in various surgical patient groups with conflicting results. Some clinical studies have reported that the perioperative use of dexmedetomidine, especially in cardiac surgery, is associated with a decrease in the rate of abnormal hemodynamic response, including atrial fibrillation, cardiac arrest, and postoperative delirium and 30-day mortality, durations of mechanical ventilation, ICU stay, and hospital stay [17], [18], [19]. In contrast to this view, some studies have emphasized that the use of dexmedetomidine is associated with adverse cardiac and hemodynamic side effects such as hypotension, bradycardia, increased vasopressor requirement, and asystole in the perioperative period, and increased postoperative mortality [20], [21], [22].

Dexmedetomidine is a drug that suppresses sympathetic activity and may increase parasympathetic tone, leading to a decrease in blood pressure and heart rate. However, it should be used with caution in cardiac patients due to its cardiovascular side effects, especially hypotension and bradycardia. A detailed study of cardiac electrophysiologic effects may help to determine the optimal dose and its safe use. In addition, whether it causes blockade of the cardiac conduction system in the intraoperative or postoperative period is a critical research topic, especially for patients at risk of atrioventricular block. Some studies suggest that dexmedetomidine may prevent ventricular arrhythmias, while others suggest that it may increase the risk of arrhythmias such as QT prolongation or torsades de pointes. Investigation of the cardiac electrophysiologic effects of dexmedetomidine is of great importance to ensure safe and effective use of the drug, to determine the risks of arrhythmias and to identify appropriate patient groups. Electrophysiologic investigations contribute to determining the most appropriate use of the drug, especially for patients with heart disease, the elderly, intensive care patients or patients requiring sedation after surgery.

Although there are studies on the arrhythmia risks and electrophysiological effects of dexmedetomidine in the current literature, there is a lack of studies that clarify clinical outcomes in particular. There is no clear consensus on whether it increases the risk of arrhythmias or in which patients it is safe, and the mechanisms of electrophysiologic effects at the cellular and ion channel level are still poorly understood.

Therefore, in this study, we aimed to investigate whether dexmedetomidine significantly affects electrophysiologic parameters, including action potential (AP), contraction, and ionic currents in ventricular myocytes, regarding its cardiac and hemodynamic effects observed in the clinic. With the new information to be obtained from this study, we think that the potential mechanisms of cardiac side effects that may occur due to the clinical use of dexmedetomidine will be better understood, and this will be advantageous for ensuring safe and effective use of the drug, determining arrhythmia risks and identifying appropriate patient groups.

Materials and methods

Study groups

After approval of the Local Ethical Committee of Akdeniz University for Animal Experiments (Protocol number: 1187/2020.10.017), the study was carried out using 3-month-old (200–250 g) male Wistar rats, with a total of six rats included in the experiments. Rats were obtained from Akdeniz University Experimental Animal Research Center, and the experimental procedures were performed in the Akdeniz University Faculty of Medicine, Department of Biophysics laboratories. The rats were kept in the controlled environment of the experimental animal unit under appropriate temperature in a 12-h light and 12-h dark cycle with free access to food and water until the experiments. Drug applications on myocytes isolated from experimental animals were performed in vitro with a cumulative dose schedule.

Isolation of cardiomyocytes

While the animals were under anesthesia (intraperitoneal pentobarbital sodium, 40 mg/kg), the hearts were rapidly removed and separated from excess tissue in a cold and low Ca+2 solution. To perform cell isolation by enzymatic method, the hearts were reverse perfused from the aorta with a Langendorff perfusion system and washed with Ca+2-free perfusion solution containing 137 NaCl; 5.4 KCl; 1.2 MgSO4; 1.2 KH2PO4; 5.8 HEPES; 20 glucose (all in mM) for 7 min. The solution was continuously bubbled with O2 to achieve pH 7.2 equilibrium. Then the enzyme mixture (Worthington, Collagenase, Type 2) (0.7 mg/mL) and protease (0.06 mg/mL) prepared with the same dilution were passed through the heart for 20–25 min and the heart was allowed to reach the appropriate consistency. Then, the left ventricle was separated and sliced into small pieces with scissors. The chopped heart tissue was passed through a fine filter, and several washes were used to remove dead cells. Finally, Ca2+ was gradually added to the cells to adapt them to physiological Ca2+ levels. Left ventricular myocytes were used in all experiments, and the recordings were made in a cell bath at 36 ± 1 °C.

Electrophysiological recordings

Measurement of contraction parameters

A platin electrode was placed in the cell chamber and continuously perfused with Tyrode’s solution for electrical field stimulation to obtain contraction responses of ventricular myocytes. Then, those cells placed in the bath were stimulated with 5–8 V amplitudes at a frequency of 1 Hz, and changes in sarcomere length were recorded for at least 200 s until a stable response occurred (IonOptix LLC, Milton USA). The contraction parameters were then analyzed using the IonWizard software (IonOptix, USA). At the end of the analysis, the percentage of fractional shortening (%L/L0) along with contraction and relaxation velocities (µm/s) were determined and compared between groups.

Measurement of action potential

AP recordings were also measured from the isolated myocytes. Pipette resistances were set to 2–2.5 MΩ for all recordings. The content of the pipette solution consisted of 125 K-aspartate, 20 KCl, 5 MgATP, 10 NaCl, 10 EGTA, and 10 HEPES (all in mM) and was adjusted with KOH to pH=7.2. To obtain AP recordings, depolarizing pulses were applied with the current-clamp mode of the patch amplifier to stimulate the cell, and the time-dependent change of the potential was recorded. The duration of repolarization phases of 25 %, 50 %, 90 % (APD25, 50, 90 %), resting membrane potential, and peak value of AP were measured.

Measurement of L-type Ca2+ currents

L-type Ca2+ current was recorded by whole-cell mode of voltage clamping technique with 2–2.5 MΩ electrodes. The pipette solution for the measurements was prepared with 120 L-aspartate, 20 CsCl, 10 NaCl, 5 MgATP, 10 HEPES, and 10 EGTA (all in mM), and pH was adjusted to 7.2 with CsOH. The standard external solution was prepared with 137 NaCl, 5.4 KCl, 1.5 CaCl2, 0.5 MgCl2, 10 Glucose, 11.8 HEPES, and pH=7.35 (all in mM), and KCl was replaced with CsCl to block K+ currents. After applying a pre-pulse of −45 mV to cells held at −70 mV for inactivation of Na+ currents, 300 ms depolarizing pulses were applied in 10 mV steps from −50 mV to +60 mV to recruit L-type Ca2+ currents. The currents passed through a 3 kHz filter of patch-clamp amplifier (Axon 200B, Molecular Devices, USA) were recorded with pClamp 10 software (Axon Instrument, Foster City CA, USA) at the 5 kHz sampling rate of a Digidata 1200 and analyzed with Clampfit 11.0.3 software. The current amplitude was calculated by subtracting the last parts of the 300 ms pulse from the peak value. Finally, to eliminate the effect of cell size on the currents, each current value was divided by the cell capacitance and presented as current density (pA/pF).

The steady-state inactivation was measured by applying a 300 ms conditioning step pulse from −60 to 10 mV and a 300 ms test pulse to 0 mV, where the maximum current was evoked during the current-voltage protocol. Inactivation curves were constructed by plotting the current amplitude obtained with the test pulse as a function of the voltage command of the conditioning pulses and fitted to the following equation,

I / Imax = 1 + exp V 1 / 2 − V m / k − 1

where V1/2 is half-inactivation potential, Vm is membrane potential, and k is the slope value. Following a prepulse to −45 mV for 500 ms (for inactivation of the Na+ currents), two consecutive depolarizing pulses to 0 mV were applied with varying interpulse time intervals to determine reactivation kinetics. The amplitude of the current measured by the test pulse was divided by the current obtained by the conditioning pulse and plotted as a function of the interpulse interval. Reactivation curves were analyzed by the peak current of the test pulse concerning conditional peak current and fitted to the following equation,

I / Imax = 1 − exp − t / τ

where t is time andτ is the time constant.

Measurement of potassium currents

Current recordings were taken in the whole-cell configuration of the voltage clamping method, and borosilicate glass pipettes with a resistance of 1.5–2.5 MΩ were used as electrodes for recording. A pre-pulse of −45 mV was applied to block Na+ currents, and then 3 s pulses were given at 4 s intervals. Thirteen episodes were applied in 10 mV steps from −50 mV to +70 mV to obtain Ito and Iss. Currents passed through a 3 kHz filter in voltage-clamp mode of a patch-clamp amplifier (Axon 200B, Molecular Devices, USA) were recorded with pClamp 10 software (Axon Instrument, Foster City, CA, USA) at the 5 kHz sampling rate of a Digidata 1200. The extracellular solution contained 137 NaCl, 5.4 KCl, 1.5 CaCl2, 0.5 MgCl2, 10 Glucose, 11.8 HEPES (pH=7.35) (all in mM), while the pipette was prepared with 125 K-aspartate, 20 KCl, 5 MgATP, 10 NaCl, 10 HEPES and 10 EGTA (pH=7.2) (all in mM). 250 μM CdCl2 was added to the external solution to block L-type Ca+2 currents. Ito was calculated by subtracting the steady-state current values (Iss) at the end of the 3-s pulse from the peak value. For IK1 measurements, after the electrode was clamped to the cell as in Ito recordings, pulses were applied from −120 mV to +10 mV in steps of 10 mV for 14 episodes. IK1 was calculated by taking the current values at the end of the 3-s pulse. To eliminate the effect of cell size on currents, they were divided by the cell’s capacitance and presented in terms of current density (pA/pF).

Statistical analysis

The SPSS Statistics 23.0 program was used for the study’s statistical analysis. Data were given as mean±standard error of the mean (SEM). Statistical analyses and data comparisons were performed with a Paired t-test where appropriate. However, repeated measures ANOVA with Tukey multiple comparison tests were conducted for more than two data groups. The statistical significance level was accepted as 95 %, where p<0.05.

Results

Our study evaluated the effects of dexmedetomidine at 0.1, 1, 10, and 100 µM doses. There are often many difficulties in determining the microscopic impact dose from a macroscopic point of view. The trial-and-error method is frequently used to determine the effect dose for a microscopic system. The determination of the functional effective dose for dexmedetomidine on cardiomyocytes is shown in Figure 1A, one of the continuous recordings for a wide dose range obtained during 1 Hz stimulation. The first functional effect of dexmedetomidine on cardiomyocytes was observed after 0.1 µM administration. This observation implies that the trials were also below the lower limit estimated by calculation at the design stage. Therefore, all the data obtained within the framework of the study have emerged with applications starting from this lower dose limit. At the upper limit point, experiments were carried out by applying the maximum non-toxic value of 100 µM. Thus, not only were the doses available within the study plan guaranteed, but results were also obtained for all values of the functional response.

Figure 1: Effect of dexmedetomidine on the contractile activity of ventricular myocytes. (A) Representative traces of sarcomere shortening measured at 1 Hz frequency stimulation in response to different concentrations of dexmedetomidine (0.1 μM, 1 μM, 10 μM and 100 μM), (B) concentration-dependent decrease in contractile function is measured as a fractional change in sarcomere length (%L/L0), (C) contraction velocity of myocytes, (D) relaxation velocity of myocytes, (E) mean values of the repolarization phase of single cell action potential for different doses of dexmedetomidine in vitro, (F) APDs which were used to describe the time taken for the repolarization to decrease to 25 % (APD25), 50 % (APD50), 75 % (APD75) and 90 % (APD90). Values are given as mean ± SEM (standard error of the mean). Con represents the contraction recordings without dexmedetomidine. WO, Washout; Con, control; Dex, dexmedetomidine; APD, action potential duration; ms, millisecond; mV, millivolt; s, seconds; µM, micromolar. (*) Represents the statistically significant difference compared to the control value.
Figure 1:

Effect of dexmedetomidine on the contractile activity of ventricular myocytes. (A) Representative traces of sarcomere shortening measured at 1 Hz frequency stimulation in response to different concentrations of dexmedetomidine (0.1 μM, 1 μM, 10 μM and 100 μM), (B) concentration-dependent decrease in contractile function is measured as a fractional change in sarcomere length (%L/L0), (C) contraction velocity of myocytes, (D) relaxation velocity of myocytes, (E) mean values of the repolarization phase of single cell action potential for different doses of dexmedetomidine in vitro, (F) APDs which were used to describe the time taken for the repolarization to decrease to 25 % (APD25), 50 % (APD50), 75 % (APD75) and 90 % (APD90). Values are given as mean ± SEM (standard error of the mean). Con represents the contraction recordings without dexmedetomidine. WO, Washout; Con, control; Dex, dexmedetomidine; APD, action potential duration; ms, millisecond; mV, millivolt; s, seconds; µM, micromolar. (*) Represents the statistically significant difference compared to the control value.

Figure 1A shows contraction recordings obtained by washing after 0.1, 1, 10, and 100 µM application of dexmedetomidine. Increasing the administered dose affected the observed contraction peak value reduction in a dose-dependent manner. On the other hand, the washing treatment (Washout, WO) showed that the decrease in the peak contraction value observed with dexmedetomidine returned to the values recorded for the control.

The mean values of the percentage changes of the fractional contraction recordings of the different doses of dexmedetomidine compared to the initial value are summarized in Figure 1B. Within the 0.1, 1, 10, and 100 µM application of dexmedetomidine, it was observed that the effect started with 0.1 µM and caused a dose-dependent and statistically significant decrease (p<0.05).

The mean values of the measured contraction and relaxation rates compared to the initial values are summarized in Figure 1C and D. When the values were analyzed, it was seen that the contraction rate started to decrease at 10 µM and after. In other words, the contraction rate began to slow down with the 10 µM dose of dexmedetomidine. In contrast to contraction kinetics, a 100 µM dose of dexmedetomidine was the starting point of the effect in relaxation (p<0.05). As a result of the detailed analysis of the contraction records obtained, it has been observed that increasing doses of dexmedetomidine progressively inhibit cardiomyocyte contractile responses (p=0.022). The percentages of decrease in peak tension compared to the initial values are summarized in Table 1.

Table 1:

Percentage inhibition values of dexmedetomidine on the peak value of cardiomyocyte contraction.

Dexmedetomidin dosage, µM Mean, % SEM
0.1 4.25 1.06
1 6.51 1.51
10 9.44 2.52
100 19.75 2.41

  1. SEM, standard error of the mean.

The mean values of the repolarization phase of single-cell APs of different doses obtained by in vitro administration of dexmedetomidine are summarized in Figure 1E and F. It was measured that the application of dexmedetomidine did not affect the single-cell AP repolarization (p=0.341).

Figure 2 shows the current-voltage (I-V) curves for potassium currents (Ito, Iss and IK1), which are prominent for early and late repolarization (phase 1) of the AP and maintaining the resting potential of myocytes. Dexmedetomidine administration did not affect these measured currents (p>0.05).

Figure 2: The original recording of potassium currents recorded in the absence and presence of sugammadex used in the experiment and the effects of dexmedetomidine (10 µM) on the I–V characteristics of (A) transient outward potassium currents (Ito); and steady-state K+ currents (Iss). (B) Inward rectifier K+ current (IK1). Con, control; Dex, dexmedetomidine; ms, millisecond; pA/pF, picoampere/picofarad; mV, millivolt; nA, nanoamper.
Figure 2:

The original recording of potassium currents recorded in the absence and presence of sugammadex used in the experiment and the effects of dexmedetomidine (10 µM) on the I–V characteristics of (A) transient outward potassium currents (Ito); and steady-state K+ currents (Iss). (B) Inward rectifier K+ current (IK1). Con, control; Dex, dexmedetomidine; ms, millisecond; pA/pF, picoampere/picofarad; mV, millivolt; nA, nanoamper.

The effects of dexmedetomidine administration on the measured ICaL currents are summarized in Figure 3. Although in vitro administration of dexmedetomidine did not cause any effect on the measured APD50 value, it was observed to have a depressing effect on the measured ICaL currents (p<0.001) (Figure 3A). Although there was a remarkable decrease in the overall I-V curve of ICaL compared to baseline measurements, the statistical significance of the effect was observed only at potential values ​​between 0 and 30 mV (Figure 3B). The results of the inactivation and reactivation curves of ICaL currents with dexmedetomidine application are summarized in Figure 3C, respectively. As a result of the analysis, it was observed that the application of dexmedetomidine shifted the V50 value of the inactivation curve towards a more negative potential (V50: Control, −19.81; Dex, −22.42 mV), but the difference was not statistically significant.

Figure 3: The effects of dexmedetomidine on calcium currents. (A) Peak values of calcium currents of sugammadex recorded at 0 mV, the current density obtained after dividing this current by the capacitance of the cell in which it was recorded, and average % change concerning the initial value (control); (B) I–V characteristics of L-type calcium currents; (C) mean values of inactivation and reactivation kinetics of L-type calcium currents for 10 µM of dexmedetomidine application. Con, control; Dex, dexmedetomidine; ICaL, L-type calcium channel current; nA, nanoampere; ms, millisecond; mV, millivolt; s, seconds; pA/pF, picoampere/picofarad. *Represents the difference (p<0.05) from baseline.
Figure 3:

The effects of dexmedetomidine on calcium currents. (A) Peak values of calcium currents of sugammadex recorded at 0 mV, the current density obtained after dividing this current by the capacitance of the cell in which it was recorded, and average % change concerning the initial value (control); (B) I–V characteristics of L-type calcium currents; (C) mean values of inactivation and reactivation kinetics of L-type calcium currents for 10 µM of dexmedetomidine application. Con, control; Dex, dexmedetomidine; ICaL, L-type calcium channel current; nA, nanoampere; ms, millisecond; mV, millivolt; s, seconds; pA/pF, picoampere/picofarad. *Represents the difference (p<0.05) from baseline.

Discussion

Our study revealed that dexmedetomidine had an increasingly inhibitory effect on the peak level of cardiomyocyte contraction in parallel with increasing doses from the first administration dose. There was no effect of dexmedetomidine on the generation of phase 1 of the AP and the formation of resting membrane potential. It was observed that dexmedetomidine application had a depressing effect on ICaL currents, especially for values between 0 and 30 mV. When the activation and reactivation curves of ICaL currents were examined, the dexmedetomidine application shifted the measured activation value V50 towards more negative values.

Several clinical studies have investigated dexmedetomidine’s electrophysiological effects on the cardiac conduction system and contraction. A clinical trial using dexmedetomidine in children found that sinus and atrioventricular node function was severely depressed, sinus node reversal time, a measure of sinus automaticity, and basal sinus cycle length, an indicator of sinus node function, were increased. Still, His-Purkinje conduction and atrioventricular muscle properties were unaffected. It was reported that no atrioventricular block was observed in any child during the administration. Still, the mean arterial blood pressure value decreased in all children in the first 10 min of the loading dose compared to the baseline value, and the heart rate decreased significantly compared to the baseline value [23]. A clinical trial investigating the effects of dexmedetomidine on ECG in pediatric patients showed an increase in corrected sinus node return time and basal sinus cycle length, prolongation in atrioventricular node function, ventriculoatrial block cycle length, and atrioventricular adequate refractor time, and a decrease in atrial excitability. The researchers emphasized that dexmedetomidine increased the efferent effect of the Vagus nerve, increased the duration of the effective refractor period in myocardial cells, decreased myocardial autonomy, and shortened the prolonged QTc period [24].

Several experimental studies investigating the possible arrhythmogenic effects of dexmedetomidine have also been conducted. In an in vitro study on the sinoatrial node in rabbit heart, the effects of dexmedetomidine on AP phase 4 diastolic depolarization rate, maximal depolarization rate, AP amplitude, APD 50 and 90 times, and pacemaker firing rate were investigated. It was found that AP amplitude, diastolic depolarization rate, and pacemaker firing rate decreased in a dose-dependent manner with increasing concentrations of dexmedetomidine. There was no significant change in the maximal depolarization rate and APD50 and 90 values. The investigators stated that dexmedetomidine had concentration-dependent inhibitory effects on rabbit sinoatrial node cells and these effects occurred independently of the α2-adrenoreceptor effect, unlike previous clinical studies [25]. In another study examining the effect of dexmedetomidine in different proarrhythmic models, dexmedetomidine at increasing concentrations (3, 5, and 10 mM) was first evaluated in 12 rabbit hearts, and it was found that it did not affect AP duration, had no proarrhythmic effect but decreased the spatial distribution of repolarization. The effects of dexmedetomidine were then examined in 12 rabbit hearts treated with erythromycin to induce long QT syndrome. It was found that the spatial distribution of repolarization was reduced and, therefore, had a suppressive effect on torsades de pointes. Next, the effects of dexmedetomidine were examined in 14 rabbit hearts in which the repolarization reserve was reduced by adding 0.5 mM veratridine, and no change in effect was found. Finally, 12 rabbit hearts in which a combination of acetylcholine (1 mM) and isoproterenol (1 mM) was used to induce atrial fibrillation were studied, and it was found that dexmedetomidine prolonged atrial AP duration but did not reduce atrial fibrillation episodes. In conclusion, the investigators emphasized that dexmedetomidine has a safe electrophysiological profile in different arrhythmic models [26].

Various studies have demonstrated the direct effects of dexmedetomidine on different ion channels. In a cell culture study, the effects of propofol and dexmedetomidine on Nav1.5, the predominant cardiac Na+ channel, were examined, and it was reported that dexmedetomidine produced concentration-dependent inhibition on Nav1.5 and inhibited the transient sodium current induced by veratridine. It was also noted that the blocking effect on Nav1.5 was comparable to cardiotoxic local anesthetics such as bupivacaine [27]. In a study on human pluripotent stem cell-derived cardiomyocytes using the conventional patch-clamp recording method, the effects of dexmedetomidine on spontaneous AP, pacemaker current If, potassium channel currents IK1and IKr, Na+ channel current INa and calcium channel current ICa were examined, and it was observed that dexmedetomidine inhibited the frequency of ventricle-like spontaneous AP and dose-dependently prolonged APD90. While the effects of dexmedetomidine on If, IK1, and IKr were found to be insignificant, it was reported to inhibit the amplitude of L-type calcium channel current and sodium current independent of α1 and α2-adrenoreceptors and imidazoline receptors. It was also reported that dexmedetomidine did not affect the shape of the calcium channel IV coupling curves. However, the investigators noted that the human stem cell-derived cardiomyocytes used in this study were structurally similar to human fetal ventricular cardiomyocytes, were smaller and mononucleated compared to human adult ventricular cardiomyocytes, lacked a t-tubule network, and were characterized by decreased electrical excitability, impaired ICP, and incomplete adrenergic sensitivity [28].

In a study examining the effect of dexmedetomidine on vascular and recombinant K+ channel currents, it was reported that dexmedetomidine did not affect potassium currents of IK1 and IKr, and If, which is a pacemaker current. At the same time, it had a dose-dependent direct effect on IKATP, an ATP-sensitive potassium current. It was emphasized that dexmedetomidine exerted this effect without affecting intracellular ATP concentration and ADP/ATP ratio, thus independent of intracellular metabolic events. It was also reported that the administration of yohimbine, an α2-adrenoreceptor antagonist, did not alter this effect. Therefore, it was possible that dexmedetomidine directly binds to the KATP channel. In light of the data obtained, it was also reported that the inhibitory effect of dexmedetomidine on the KATP channel was not tissue-specific [29].

To our knowledge, our study is one of only two studies to evaluate the effects of dexmedetomidine directly on ventricular cardiomyocytes. In the study by Zhao et al. in rat ventricular myocytes, dexmedetomidine decreased calcium entry by inhibiting L-type calcium channels and thus affected the contractility of cardiac cells [30]. These findings are consistent with the results obtained in our study. However, some differences stand out when our study is compared with this study. We first analyzed the effects of different ion channels and contraction dynamics with a more comprehensive methodological approach by evaluating different parameters such as action potential (AP), contraction kinetics, potassium currents (Ito, Iss, IK1) as well as L-type calcium currents. Also, in their study, dexmedetomidine did not affect the IV relationship of inactivation and shifted the reactivation curve downwards, whereas we did not reveal a significant effect on both the inactivation and reactivation portions. This difference could be possible because the experiments were performed at room temperature, species differences (they used Sprague Dawley), and the experimental environment or solutions were different. The authors also showed that Yohimbine can attenuate the inhibition of ICaL and thus noted that the inhibition of dexmedetomidine on ICaL may be mediated by the alpha 2-adrenergic receptor. We have not studied the possible mechanisms of this inhibition.

Certain limitations of our study should be taken into account. A single isolated myocyte may not fully represent the function of the entire heart, as the ventricular myocardium consists of millions of interconnected myocytes that operate as a synchronized unit. Therefore, assessments based on a single cell may not completely capture the complex interactions that occur within the myocardial tissue.

Additionally, fluctuations in action potential duration (APD) could be significantly reduced simply by connecting two myocytes or by selecting preparations consisting of two or three well-coupled cells. This suggests that experimental choices may influence the results and that data obtained from isolated myocytes may not fully reflect the physiological properties of the whole heart tissue.

Furthermore, the in vitro experimental environment cannot fully mimic the environment in actual clinical practice, particularly in terms of pharmacokinetic properties. Factors such as drug distribution, metabolism, and clearance in a living organism differ significantly from those observed in a controlled laboratory setting, which may limit the direct applicability of the findings to clinical scenarios.

Conclusions

Our analysis indicates that the L-type calcium channel inhibition caused a significant decrease in the measured ICaL of ventricular myocytes after dexmedetomidine administration. Although it is known that the decrease in current amplitude has a shortening effect on the AP duration, we did not observe it because the effect of these currents in rat AP is relatively weak, and there is no plateau as in the ventricular myocytes of higher mammals. Otherwise, the shortening of the AP duration due to the decrease in these currents will likely increase myocyte contraction rhythm and cardiac risks over time. Although our findings may explain clinical side effects such as hypotension and bradycardia that may occur due to dexmedetomidine use, we believe that further clinical and in vivo studies are needed to reach clear clinical conclusions.

Corresponding author: Funda Arun, Department of Pedodontics, Division of Anesthesiology, Faculty of Dentistry, Selcuk University, Alaaddin Keykubat Campus, Yeni Istanbul Cad. No 313 Selcuklu, Konya, Türkiye, E-mail:

Funding source: Selcuk University Research Foundation

Award Identifier / Grant number: 20112001

  1. Research ethics: Local Ethical Committee of Akdeniz University for Animal Experiments (Protocol number: 1187/2020.10.017).

  2. Informed consent: Not applicable.

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Use of Large Language Models, AI and Machine Learning Tools: None declared.

  5. Conflict of interest: The authors state no conflict of interest.

  6. Research funding: This work was supported by the Selcuk University Scientific Research Unit with Project Number 20112001.

  7. Data availability: Not applicable.

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Received: 2025-01-20
Accepted: 2025-03-28
Published Online: 2025-05-08

© 2025 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/tjb-2025-0025
Keywords for this article
action potential; calcium current; cardiac electrical activity; dexmedetomidine; ion currents; potassium current
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Review Article
  3. Systematic review and meta-analysis of dysregulated miRNAs in patients with severe pneumonia
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