Effects Of Dexmedetomidine On Sarcolemmal ATP-sensitive Potassium Current In Rat Ventricular Myocytes

Dexmedetomidine(DEX)is an imidazoline derivatives and a new type of ?2 adrenergic receptor agonists.As an anesthesia adjuvant drug,DEX is wildly used in recent years.Clinical study found that DEX has a wide range of myocardial protection,can fight against myocardial ischemia and reperfusion injury,and inhibit the occurrence of arrhythmia,but the mechanism is not yet clear.A large number of studies have shown that ATP-sensitive potassium channels(sarc KATP)play an important role in the conduction disorder and arrhythmia during myocardial ischemia and hypoxia.However,whether the mechanism is associated with the sarc KATP is unknow.Objective: In this study,whole-cell patch-clamp technique was used to observe the effect of dexmedetomidine on sarcolemmal ATP-sensitive potassium current(sarc KATP)in rat ventricular myocytes and investigate the electrophysiological mechanism of its effect on cardiomyocytes.Methods: Adult male rats were used in this study.The single ventricular myocytes were isolated by Langendorff technique with the enzymatic dissociation method.The changes of ATP-sensitive potassium current in ventricular myocytes were recorded by patch clamp technique.The cells were placed in recording chamber mounted on the microscope,perfused with normal extemal solution in constant temperature and constant velocity extracellular fluid perfusion.Under controlling of micromanipulator,the glass microelectrode and the cell membrane in close cantact with the formation of the giga sea,then give a certain negative pressure to obtain the whole cell patch clamp mode.The current was induced and recording by running pclamp program in voltage clamp mode.The KATP channels were opened by adding KATP channel-specific opener pinacidil(PIN)to 100?M in normal potassium ion perfusate.Then the cells were randomly divided into four groups according to the different administration of perfusate,four cells per groups:1 Glib group,glibenclamide(50?M)were added into normal potassium perfusion,then observed the current changes.2 DEX group,dexmedetomidine(0.01?M,1?M,100?M)were added into normal potassium perfusion in turn,then observed the current changes.3 DEX+YOH group,1?M of dexmedetomidine were added into normal potassium perfusion,and then added the yohimbine(1?M).Recorded the changes in current.4 DEX+IDA group,1?M of dexmedetomidine were added into normal potassium perfusion,and then added the idazoxan(1?M).Recorded the changes in current.Results:1 In the Glib group,the current(at 60 m V)of the background were 10.7±1.1p A/p F,20.6±1.3p A/p F after the addition of pinacidil 100?M,11.5±1.3p A/p F after the addition of glibenclamide 50?M.Compared with the background potassium current,the current after the addition of pinacidil was significantly increased(P<0.05),and reinstated after glibenclamide.This experiment proved that the increase showed IKATP after the pinacidil.This current could be completely blocked by 50 ?M glibenclamide.2 In the DEX group,pinacidil(100?M),dexmedetomidine(0.01?M,1?M,100?M)were added into normal potassium perfusion in turn.At 60 m V of test potential,IKATP were 10.1±0.4,9.0±0.7,6.6±0.6,1.7±0.5p A/p F,respectively.Compared with pinacidil,IKATP was inhibited 11.2±3.8%,34.2±4.5%,82.7±5.1% by 0.01?M,1?M and 100?M DEX,respectively.There was a decreasing trend in the current after low concentration of DEX(0.01?M),no significant difference yet(P > 0.05).Medium and high concentration of DEX(1?M,100?M)could significantly inhibited the IKATP in a concentration-dependent manner(P <0.05,P<0.01).The results showed that DEX had an inhibitory effect on KATP channels.3 In the DEX+YOH group,IKATP were 10.3±0.7p A/p F after the pinacidil,6.6±1.2p A/p F after DEX,and 6.2±1.5p A/p F after yohimbine in combination with DEX at 60 m V of test potential.There was no significant change in the current value before and after yohimbine(P>0.05).4 In the DEX+IDA group,IKATP were 10.3±0.7p A/p F after the pinacidil,6.6±1.2p A/p F after DEX,and 6.2±1.5p A/p F after idazoxan in combination with DEX at 60 m V of test potential.There was a significant change in the current value before and after idazoxan(P<0.05).Inhibition of IKATP by DEX was partially reversed by idazoxan.Conclusions: DEX could inhibit the KATP channels of rat ventricular myocytes in a concentration-dependent manner.Imidazoline receptors mediated this process.This effect may be one of the electrophysiological mechanisms of DEX antiarrhythmic effect.