Propranolol increases the threshold for lidocaine-induced convulsions in awake rats: a direct effect on the brain.
BACKGROUND
Propranolol is a beta-adrenoceptor antagonist used clinically. Local anesthetics are used for controlling pain, whereas propranolol is concomitantly given to treat hypertension and tachycardia. However, there are few studies examining the effects of propranolol on the toxicity of local anesthetics. We investigated the effect of propranolol on lidocaine-induced convulsions in awake, spontaneously breathing rats.


METHODS
Male Sprague-Dawley rats were randomly divided into six groups (n = 8, each group). Rats were pretreated with intracerebroventricular saline (cerebroventricle-control: CV-C group), 10 or 30 microg/kg of (S)-(-)-propranolol (propranolol) (cerebroventricle-small dose: CV-S and cerebroventricle-large dose: CV-L groups, respectively) or i.v. saline (IV-control: IV-C group), 1 or 3 mg/kg of propranolol (IV-small dose: IV-S and IV-large dose: IV-L groups, respectively). Three minutes later, lidocaine was administered i.v. at 4 mg x kg(-1) x min(-1) until tonic-clonic convulsions occurred.


RESULTS
The convulsive dose of lidocaine in the CV-L group was significantly larger than that in the CV-C group (30.6 +/- 5.1 vs 23.5 +/- 2.2 mg/kg, respectively, P = 0.008). Plasma concentrations of total and protein-unbound lidocaine, concentrations of lidocaine in the brain at the onset of convulsions were also significantly higher in the CV-L group than those in the CV-C group (36.1 +/- 4.8 vs 26.0 +/- 3.8 microg/mL, 22.5 +/- 3.5 vs 13.7 +/- 2.6 microg/mL, 82.7 +/- 7.1 vs 57.3 +/- 5.7 microg/g, P < 0.001 for all). The convulsive dose, plasma concentrations of total and protein-unbound lidocaine, and brain lidocaine in the IV-L group were also significantly larger than those in IV-C group and comparable with those in the CV-L group. The plasma concentration of propranolol before starting an infusion of lidocaine in the IV-L group was approximately 60-fold higher than that in the CV-L group (554.7 +/- 104.6 and 9.3 +/- 6.7 ng/mL, respectively).


CONCLUSIONS
Propranolol increased the threshold for lidocaine-induced convulsions by directly acting on the brain.
Nakamura
Taketo
T
Department of Anesthesiology, Osaka City University Graduate School of Medicine, 1-5-7 Asahimachi, Abeno-ku, Osaka 545-8586, Japan.
Oda
Yutaka
Y
Takahashi
Ryota
R
Tanaka
Katsuaki
K
Hase
Ichiro
I
Asada
Akira
A
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D007276:Injections, Intraventricular; D008012:Lidocaine / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D008297:Male; D011433:Propranolol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D014851:Wakefulness
D000319:Adrenergic beta-Antagonists; D000779:Anesthetics, Local; D000927:Anticonvulsants; D008012:Lidocaine; D011433:Propranolol