Dexmedetomidine elevates the lethal dose threshold of bupivacaine in rats: A dosing study

Abstract

Dexmedetomidine (DMED), an alpha-2 adrenoreceptor agonist, has been widely used in regional anesthesia procedures. However, the effect of DMED on local anesthetic cardiotoxicity has not been well delineated. This study consisted of two experiments. In experiment A, 42 Sprague–Dawley (SD) rats were randomly divided into 6 groups ( n = 7), each group was pretreated with DMED 0 μg kg−1 (D0 group), 1 μg kg−1 (D1 group), 3 μg kg−1 (D3 group), 6 μg kg−1 (D6 group), 12 μg kg−1 (D12 group), and 24 μg kg−1 (D24 group), administered through the right femoral vein. In experiment B, 20 SD rats were randomly divided into 4 groups ( n = 5), such as control group, DMED group, yohimbine (YOH) group, and DMED + YOH group. Each subgroup in experiment B was also pretreated similarly as in experiment A. After pretreatment of rats as described above (in experiments A and B), bupivacaine 2.5 mg kg−1 min−1 was infused to induce cardiac arrest. In experiment A, the lethal dose threshold of bupivacaine and plasma bupivacaine concentration in D3 and D6 group were higher than the other groups. In experiment B, there was no interaction between DMED and YOH in lethal dose threshold, arrhythmia time, plasma concentration of bupivacaine, and myocardial content of bupivacaine. DMED doses of 3–6 μg kg−1 elevated the lethal dose threshold of bupivacaine without involvement of the alpha-2 adrenoceptors.

Effects of delta-opioid receptor agonist pretreatment on the cardiotoxicity of bupivacaine in rats

“…Our study firstly investigated the effect of DOR agonist on the cardiotoxicity of bupivacaine in rats, however, we didn't observe any positive effect. DOR is widely expressed in human and rodent myocardium and has been proved to involve in the cardioprotective and neuroprotective procedures in myocardial ischemia/reperfusion [8,9,13,19,20]. The mechanisms of DOR protective effects on the myocardium include triggering PKC, ERK1/2, Akt/PIK3, and other pathways.…”

“…The following toxic endpoints were recorded by an observer unaware of the grouping, and the doses of bupivacaine at each endpoint were calculated: the first arrhythmia, defined as the appearance of cardiac rhythm disturbance on the ECG accompanied by an abnormal pulsation on the arterial pressure trace; 50% MAP-reduction, defined as the MAP of 50% baseline value; 50% HR-reduction, defined as the HR of 50% baseline value; and asystole, defined as the lack of recognizable beat on the ECG for 10 s after the appearance of the last systole. These observed indexes were decided following previous studies [4,9,17].…”

“…And the expression of DOR increases in response to heart failure, hypoxia, aging, and other physical or pathological stimuli [7]. Many studies have proved that agonists of DOR can protect the myocardium against ischemia/reperfusion and heart failure [8][9][10][11]. However, no evidence is available concerning the direct effect of DOR agonists on the cardiotoxicity of local anesthetics.…”

SK2 channel deletion reduces susceptibility to bupivacaine-induced cardiotoxicity in mouse

“…In this study, arrhythmia was defined as the occurrence of the first dropped beat. 17 It is generally accepted that bupivacaine cardiotoxicity results from a widespread block of cardiac ion channels. [6][7][8] SK2 channel, as a channel widely distributed in the heart, plays an important role in cardiac electrophysiology.…”