Takahiko Kamibayashi

Dexmedetomidine Prevents Epinephrine-induced Arrhythmias Through Stimulation of Central α2 Adrenoceptors in Halothane-anesthetized Dogs

Since alpha 2-adrenergic agonists have important effects on the adrenergic system that have recently been applied to the anesthetic setting, we investigated the effect of stimulation of alpha 2 adrenoceptors on epinephrine-induced arrhythmias in halothane-anesthetized dogs. The arrhythmogenic threshold for epinephrine was determined during halothane anesthesia in the presence of dexmedetomidine, a selective alpha 2 agonist, and L-medetomidine, a stereoisomer of medetomidine that lacks alpha 2-agonist activity. Dexmedetomidine increased the arrhythmogenic threshold for epinephrine in a dose-dependent manner during halothane anesthesia. At the highest dose of dexmedetomidine, 0.5 microgram.kg-1.min-1, there was a three-fold increase in both the arrhythmogenic dose of epinephrine and the plasma epinephrine concentration that was reached at this dose. On the other hand, L-medetomidine over the same dose range did not effect the arrhythmogenic dose of epinephrine. Atipamezole, a central alpha 2 antagonist that crossed the blood-brain barrier, blocked the antiarrhythmic action of dexmedetomidine. L-659,066 a peripheral alpha 2 antagonist that does not penetrate the blood-brain barrier, did not affect the antiarrhythmic action of dexmedetomidine. Thus, dexmedetomidines antiarrhythmic effect on epinephrine-induced arrhythmias during halothane anesthesia appears to be mediated at least in part by stimulation of central alpha 2 adrenoceptors.

Alpha-2 adrenergic agonists

ConclusionThe use of α2 agonists, either alone or in combination, is becoming widespread in anaesthesia. The original enthusiasm for this class of compound for its plethora of beneficial effects appears to have been justified based on the more recent clinical studies reported here. In the next decade, the field will continue to evolve with the clinical introduction of the second generation of α2 agonists, notably dexmedetomidine which is a more selective, specific and efficacious compound than the prototype, clonidine. Furthermore, formulations allowing several different routes of administration, ranging from transdermal to neuraxial, will further extend its clinical utility.ConclusionEn anesthésie, l’utilisation des agonistes α2 seuls ou en association se répand rapidement. En vertu des nombreux avantages que les agonistes α2 procurent, l’enthousiasme initial démontré envers cette classe de composés semble justifié sur la base des plus récentes études cliniques que nous avons rapportées. La prochaine décennie verra se continuer cette évolution avec l’introduction en clinique de la deuxième génération des agonistes α2, en particulier de la dexmédétomidine qui est plus sélective, plus spécifique et plus efficace que son prototype, la clonodine. En outre, les cliniciens trouveront d’autres indications pour ces produits grâce à des préparations adaptées aux différents modes d’administration, de la voie transdermique à celle du système nerveux central.

Enhancement by propofol of epinephrine-induced arrhythmias in dogs

Although propofol is a widely used intravenous anesthetic, its effect on epinephrine-induced arrhythmias remains unknown. This study examined the possible interaction between propofol and epinephrine that might affect the induction of ventricular arrhythmias in dogs. The arrhythmogenic threshold of epinephrine was determined during anesthesia with halothane alone, propofol alone, etomidate alone, or etomidate plus varying doses of propofol. The arrhythmogenic dose and the corresponding plasma concentration of epinephrine during propofol anesthesia (blood propofol concentration 18.0 +/- 0.98 micrograms/ml) were 2.52 +/- 0.43 micrograms.kg-1.min-1 and 23.6 +/- 8.5 ng/ml, respectively. During halothane anesthesia (end-tidal 1.3 MAC), they were 2.66 +/- 0.21 micrograms.kg-1.min-1 and 35.7 +/- 1.9 ng/ml, respectively. During etomidate anesthesia, they were 9.67 +/- 1.06 micrograms.kg-1.min-1 and 205 +/- 27.5 ng/ml, respectively. The dose-effect relationship for propofol was examined during etomidate plus propofol anesthesia. Propofol reduced the arrhythmogenic plasma concentration of epinephrine in a concentration-dependent manner: at blood propofol concentrations of 2.33 +/- 0.46, 5.46 +/- 0.71, and 11.2 +/- 0.81 micrograms/ml, the corresponding plasma epinephrine concentrations were 182.6 +/- 52.5, 89.0 +/- 28.8, and 26.6 +/- 6.9 ng/ml, respectively. These results suggest that propofol enhances epinephrine-induced arrhythmias in a dose-dependent manner in dogs.

Role of the Vagus Nerve in the Antidysrhythmic Effect of Dexmedetomidine on Halothane/Epinephrine Dysrhythmias in Dogs

Background Dexmedetomidine, an alpha2 ‐adrenergic agonist, can prevent the genesis of halothane/epinephrine dysrhythmias through the central nervous system. Because stimulation of alpha2 adrenoceptors in the central nervous system enhances vagal neural activity and vagal stimulation is known to inhibit digitalis‐induced dysrhythmias, dexmedetomidine may exert the antidysrhythmic property through vagal stimulation. To address this hypothesis, the effect of dexmedetomidine in vagotomized dogs was examined and compared with that in intact dogs. In addition, the effect of vagotomy on the antidysrhythmic action of doxazosin, an alpha1 antagonist, was studied.

Thoracic Epidural Anesthesia Attenuates Halothane-induced Myocardial Sensitization to Dysrhythmogenic Effect of Epinephrine in Dogs

Background The autonomic nervous system plays a critical role in the central modulation of cardiac dysrhythmias. Because sympathetic blockade by thoracic epidural anesthesia has been documented to protect patients from various stress responses, the authors speculate that epidural anesthesia can attenuate the dysrhythmogenic interaction between halothane and epinephrine. Methods In adult mongrel dogs anesthetized with halothane, the dysrhythmogenic dose (DD) of epinephrine, defined as the smallest dose producing four or more premature ventricular contractions within a 15-s period, was determined in the presence of thoracic epidural mepivacaine or saline. To address the effect of circulating mepivacaine after epidural administration, the authors examined the DD of epinephrine in the presence of intravenous mepivacaine. They also investigated the effect of thoracic epidural anesthesia in bilaterally vagotomized dogs. Results Epidural mepivacaine significantly increased the DD of epinephrine compared with epidural saline. However, intravenous mepivacaine did not affect the DD of epinephrine, even when the plasma concentration of mepivacaine during the dysrhythmias was twice that in the epidural mepivacaine group. The beneficial effect of epidural mepivacaine was not seen in bilaterally vagotomized dogs. Conclusions Thoracic epidural anesthesia attenuated the myocardial sensitization by halothane, and vagal activity had an essential role in this action.

Antiarrhythmic action of rilmenidine on adrenaline‐induced arrhythmia via central imidazoline receptors in halothane‐anaesthetized dogs

1 To elucidate the role of central imidazoline receptors in the genesis of adrenaline‐induced arrhythmias under halothane anaesthesia, we investigated the effects of rilmenidine, a selective agonist at imidazoline receptors, on this type of arrhythmia in dogs. Rilmenidine (1, 3, 10 μg kg−1, i.v.) did not affect basal haemodynamic parameters (heart rate and blood pressure), but dose‐dependently inhibited adrenaline‐induced arrhythmias under halothane anaesthesia. 2 Although, rilmenidine has a weak affinity for α2‐adrenoceptors, pretreatment with idazoxan (10 μg kg−1, intracistenally i.c.), an imidazoline receptor antagonist which has also α2‐adrenoceptor blocking potency, blocked the antiarrhythmic effect of rilmenidine (10 μg kg−1, i.v.). In contrast, pretreatment with rauwolscine (20 μg kg−1, i.c.), a classical α2‐adrenoceptor antagonist with little affinity for imidazoline receptors, did not affect the effect of rilmenidine (10 μg kg−1, i.v.). Furthermore, bilateral vagotomy completely blocked the antiarrhythmic action of rilmenidine (10 μg kg−1, i.v.). 3 It is suggested that the antiarrhythmic action of rilmenidine is due to the activation of central imidazoline receptors and that vagal tone is critical for this action of rilmenidine.

Further characterization of the receptor mechanism involved in the antidysrhythmic effect of dexmedetomidine on halothane/epinephrine dysrhythmias in dogs

Background alpha2 Adrenoceptors in the central nervous system mediate various physiologic processes, including cardiovascular control. Recently, some of these actions have been reported to be mediated by a nonadrenergic receptor, namely an imidazoline receptor. The authors previously reported that dexmedetomidine, a selective alpha2 agonist, prevents the genesis of halothane‐epinephrine dysrhythmias through a central mechanism. Because dexmedetomidine also binds to imidazoline receptors, we performed the current study to examine the precise receptor mechanism involved in the antidysrhythmic property of dexmedetomidine.

Myocardial epinephrine sensitization with subanesthetic concentrations of halothane in dogs.

The authors investigated myocardial epinephrine sensitization by subanesthetic concentrations of halothane. The dose-response relationship for the action of halothane was examined with etomidate plus varying subanesthetic concentrations of halothane in dogs. The arrhythmogenic threshold of epinephrine was decreased in a dose-dependent manner at end-tidal concentrations of halothane between 0.1 and 0.3%. At end-tidal halothane is greater than 0.3%, and no further reduction of arrhythmogenic threshold of epinephrine occurred. The plasma concentrations of epinephrine producing four or more premature ventricular contractions in 15 s were 201.3 +/- 34.3, 98.1 +/- 13.9, 60.3 +/- 8.63, 57.9 +/- 12.8, 54.5 +/- 8.61, and 53.9 +/- 4.86 ng/ml (mean +/- SEM), at 0, 0.1, 0.3, 0.5, 1.0, and 1.5% of halothane at end-tidal concentrations, respectively. The results suggest that in the presence of etomidate, halothane produces myocardial sensitization to epinephrine at subanesthetic concentrations as low as 0.1%. Increasing halothane to 0.3% produces a further reduction in the arrhythmogenic dose of epinephrine.

The involvement of pertussis toxin-sensitive G proteins in the post receptor mechanism of central I1-imidazoline receptors.

To elucidate the possible involvement of pertussis toxin (PTX)‐sensitive G proteins in the post receptor mechanism of α2‐adrenoceptors and imidazoline receptors, we examined the effect of pretreatment of the central nervous system with PTX on the antidysrhythmic effect of dexmedetomidine, a selective α2‐adrenoceptor agonist, and rilmenidine, a selective I1‐imidazoline receptor agonist on halothane‐adrenaline dysrhythmias in rats. Dexmedetomidine (0, 1.0, 2.0, 5.0 μg kg−1 min−1, i.v.) and rilmenidine (0, 1.0, 3.0, 10, 20 μg kg−1, i.v.) prevented the genesis of halothane‐adrenaline dysrhythmias in a dose‐dependent fashion. Both idazoxan (10, 20 μg kg−1, intracerebroventricularly (i.c.v.)), an α2‐adrenoceptor antagonist with high affinity for imidazoline receptors, and rauwolscine, (40 μg kg−1, i.c.v.), an α2‐adrenoceptor antagonist with low affinity for imidazoline receptors inhibited the action of dexmedetomidine (5.0 μg kg−1 min−1, i.v.), but the inhibitory potency of idazoxan was much greater than that of rauwolscine. While the pretreatment with PTX (0.1, 0.5, 1.0 μg kg−1, i.c.v.) did not change the dysrhythmogenecity of adrenaline, this treatment completely blocked the antidysrhythmic property of rilmenidine (20 μg kg−1, i.v.) as well as dexmedetomidine (5.0 μg kg−1 min−1, i.v.). It is suggested that central I1‐imidazoline receptors as well as α2‐adrenoceptors may be functionally coupled to PTX‐sensitive G proteins.

Role of Imidazoline-preferring Receptors in the Genesis of Epinephrine-induced Arrhythmias in Halothane-anesthetized Dogs

BackgroundDrugs with a central α2-adrenergic action can increase the threshold for halothane-eplnephrine-lnduced arrhythmias. Recently, imidazoline-preferrlng receptors were shown to play a significant role in the hypotensive effect of α2-adrenergic agonists containing an imidazole ring in their structure. To address the question of whether the antiar-rhythmic property of the α2-adrenergic agonists was caused by activation of α2-adrenoceptors or imldazoline-preferrlng receptors in the central nervous system, the effect of an 1ml-dazollne (atipamezole) and a nonimidazollne (L-659,066 and yohimbine) α2-adrenerglc antagonist were examined as etiologic factors in the genesis of halothane-eplnephrine-induced arrhythmias in dogs. MethodsAdult mongrel dogs were anesthetized with halo-thane (1.3%) and monitored continuously for systemic arterial pressure and for premature ventricular contractions. The ar-rhythmogenic dose (AD) of epinephrlne, defined as the smallest dose producing four or more premature ventricular contractions within a 15-s period, was determined in the presence of atipamezole (an imidazollne compound that crosses the blood-brain barrier), L-659,066 (a nonimidazoline compound that does not penetrate the blood-brain barrier), and yohimbine (a nonlmidazollne compound that passes the blood-brain barrier). These drugs were administered either intravenously or into the clsterna magna to assess the site of action for changes in responsiveness. ResultsIntravenous atipamezole decreased the AD of epinephrine in the dose-dependent fashion. However, neither L-659,066 nor yohimblne, administered peripherally, decreased the AD of epinephrine. Central administration of atipamezole also decreased the AD of epinephrine, while L-659,066, even if administered centrally, did not affect the AD of epinephrine in the presence of halothane. ConclusionsBecause the imidazollne ring-containing α2-adrenergic antagonist (atipamezole) potentiated the halothaneepinephrine-induced arrhythmias and the nonimidazole α2-adrenerglc antagonist (L-659,066 and yohimblne) did not, it is possible that the imidazoline-preferring, rather than the α2-adrenerglc, receptor is responsible for the antlarrhythmic property of α2-adrenerglc agonists.