In the presence of mild hypocapnic alkalosis, the values of HR were significantly lower only in rats given bupivacaine (Table 3), but there was no significant difference in BRS among rats given saline, 3 mg/kg of bupivacaine, and 6 mg/kg of ropivacaine (Table 4 and Figure 2).
The responses of MAP to phenylephrine did not differ significantly between rats given bupivacaine and those given ropivacaine under the conditions of either acidosis or alkalosis. However, the reflex bradycardia induced by phenylephrine was significantly greater in the saline group with hypercapnic acidosis (Table 4).
In our pilot study, we investigated the effects of bupivacaine and ropivacaine on BRS under the condition of combined hypoxia and hypercapnic acidosis. Five rats could not endure the administration of small amounts of bupivacaine and ropivacaine and suffered cardiac arrest; when phenylephrine was given to increase arterial blood pressure, four rats survived. Dysrhythmia and sudden onset of ventricular fibrillation followed, and we were unable to assess BRS in the presence of combined respiratory acidosis and hypoxemia.
The results of the present study demonstrated that intravenous administration of both bupivacaine and ropivacaine suppressed BRS when a subconvulsive or convulsive dose [previously reported to be 4.31 +/- 0.36 mg/kg and 4.88 +/- 0.47 mg/kg, respectively ] was given in rats anesthetized with pentobarbital. The suppression was not augmented with acute mild hypercapnic acidosis, which per se appeared to enhance BRS. Mild hypocapnic alkalosis, on the other hand, reversed the suppression of BRS induced by bupivacaine and ropivacaine. These results suggest that bupivacaine and ropivacaine may produce baroreflex resetting that could affect the mechanisms for maintaining cardiovascular stability . However, mild alkalosis is likely to offset the potential detrimental effects due to systemic toxicity of potent local anesthetics.
BRS would be suppressed by anesthetic state. A recent rat study using pentobarbital  indicates that baroreflex gain differs between graded infusion and bolus administration of phenylephrine, as well as in its dosage. BRS after phenylephrine injection appeared to be independent of the dose used . In the present study, since we used the same dose of pentobarbital, 50 mg/kg intraperitoneally, a fixed dose of phenylephrine, and a fixed timing of administration, if an interaction between pentobarbital and local anesthetics occurred, it could be represented equally for all animals. In addition to basic anesthesia, there are many factors that might contribute to the present results, such as hypoxemia, metabolic changes, changes in plasma concentration of electrolytes, airway pressure, and the muscle relaxant used. For example, hyperkalemia has been shown, experimentally, to enhance bupivacaine cardiotoxicity  and could affect the pressure threshold at which the baroreceptor discharges are initiated . Although small changes in plasma K+ concentration were noted, the other factors were either absent or similarly present in all rats of the same set of experiments.
The blunting of BRS could occur due to the depressant effect of bupivacaine (2-3 mg/kg) and ropivacaine (6 mg/kg) on all the components of the reflex arc, including either the arterial baroreceptors, afferent nerve pathways, vasomotor neurons of the central nervous system (CNS), sympathetic ganglionic transmission, efferent pathways, and effector organs such as cardiac chronotropic function and vasculatures. When an abrupt change in AP occurs, arterial baroreceptors located at the bifurcation of the common carotid artery and arch of the aorta function primarily as sensors for autonomic nervous system regulation for restoring AP to a normal level . Since local anesthetics given intravenously appear to more readily depress neuronal activity  and sympathetic transmission  than nerve conduction, subconvulsive and convulsive doses of systemic bupivacaine and ropivacaine are unlikely to block nerve conduction of the efferent and afferent pathways of the reflex arc. The action of a local anesthetic on the arterial baroreceptors was very recently investigated by Chang et al.  who demonstrated in an in vitro study that bupivacaine, in a clinically relevant concentration of 5-10 micro M (3.2-16 micro g/mL), depressed aortic baroreceptor discharge frequencies in rats. Although the mechanism(s) by which bupivacaine and ropivacaine suppress BRS seems to be multifunctional, it is suggested that systemic bupivacaine and ropivacaine could act principally on the baroreceptor membrane.
Although manifestations of CNS toxicity, such as convulsion, are not directly related to the influence of local anesthetics on the CNS components of the baroreflex arc, it is feasible that CNS neurons are more readily affected by bupivacaine and ropivacaine than cardiac cells. The ratios of myocardial and cerebral concentrations of bupivacaine and ropivacaine were reported to be 3.3:0.71 and 2.2:0.89 in sheep, respectively . In another study using sheep, Rutten et al.  compared the action of bupivacaine and ropivacaine on the CNS and cardiovascular responses with lidocaine, and found that ropivacaine is less toxic to the CNS and cardiovascular function than bupivacaine. The anesthetic potency ratio between bupivacaine and ropivacaine is approximately 1.3:1 . Although BRS suppression observed in the present study is likely to agree with that, the CNS toxicity of local anesthetics is proportional to their anesthetic potency . The suppression on BRS seems to differ from anesthetic potency (approximately 2 for bupivacaine vs 1 for ropivacaine).
There have been no reports to date as to a potential influence of acidosis and alkalosis on BRS. Acute hypercapnia increases plasma catecholamines , systolic AP, and sympathetic nerve discharges ; systemic acidosis activates catecholamine activity in the vasomotor center . Carbon dioxide has a direct stimulating effect on CNS function and evokes sympathoadrenal responses through the activation of chemoreceptors . In the presence of hypercapnia, vascular responses due to vagotomy are likely to be enhanced . As observed in the present results, hypercapnic state could modulate peripheral vascular response to alpha1-adrenergic receptor stimulation due to phenylephrine . Those mentioned above may explain why acute moderate hypercapnia per se enhanced (or reset) BRS in the present results.
Respiratory alkalosis has long been suggested as one therapeutic tool for local anesthetic-induced convulsions  because it increases intracellular pH, resulting in decreased intracellular concentration of the active form of local anesthetics . The reasons that mild hypocapnic alkalosis offsets BRS suppression induced by bupivacaine and ropivacaine are speculative. With the tertiary form of local anesthetics, the binding interactions have been reported to be drastically altered by pH . For bupivacaine, changing pH from 7.0 to 7.4 increases its protein binding by approximately 2% at 1 micro g/mL and 10% at 100 micro g/mL . This alkalosis-induced change in pharmacodynamics of bupivacaine could be responsible, although only in part, for offsetting the suppression. Thus, we speculate that the reversing effects of hypocapnic alkalosis on local anesthetic-induced suppression of BRS could be multifunctional and occur due to some combination of pH-induced increase of the baroreceptors' activity, the effector organs, and pH-induced alteration of local anesthetic pharmacodynamics.
Since we could assess only the baroreceptor response to a vasopressor and not to a vasodepressor, the results of the present animal experiments could not provide definite information about unexplained cardiac arrest after bradycardia and hypotension during regional anesthesia using bupivacaine . We can only speculate that acute mild hypercapnia may not be the sole contributor, but that combined with hypoxia would be an important contributing factor in cardiac arrest. Bupivacaine decreases cardiac electrophysiologic activities and enhances such action in the presence of hypercapnia, acidosis, and hypoxia . Neither hypoxia, metabolic acidosis, nor respiratory acidosis alone enhanced atrial depression and contractile force caused by bupivacaine, whereas combined hypoxia/acidosis seemed to greatly enhance bupivacaine-induced cardiac depression in vitro  and in vivo . In a clinical situation, patients could quickly become severely hypoxic and acidotic after seizure . Although only mild hypercapnic acidosis was investigated in the present study, during our pilot study using the condition of combined hypoxia and hypercapnic acidosis, rats could not endure even a smaller dose of bupivacaine and ropivacaine or had cardiac arrest when phenylephrine was given to increase arterial pressure in the survivors. Dysrhythmia and sudden onset of ventricular fibrillation followed. Further studies are needed to clarify potential combined effects of hypercapnia and hypoxia.
Bupivacaine and ropivacaine, in a convulsive dose, suppressed BRS, and respiratory alkalosis seemed to reverse the local anesthetic-induced suppression of BRS. Although the suppression of the baroreflex was not aggravated in the presence of moderate hypercapnic acidosis, the mechanisms of potent local anesthetic-induced cardiac collapse could be due not only to anesthetic action on the heart but also to local anesthetic effects on BRS for maintaining cardiovascular stability.
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