Effect of Vasoconstrictive Agents Added to Lidocaine on Intravenous Lidocaine-induced Convulsions in Rats

Abstract

Epinephrine is reported to decrease the threshold of intravenous lidocaine-induced convulsions. However, the mechanism underlying this effect is not clear. Therefore, we carried out a study to examine the role of vasopressor-induced hypertension. Fifty-six awake Wistar rats were assigned to seven groups of eight. All groups received a continuous intravenous infusion of lidocaine at a rate of 4 mg.kg-1.min-1 until generalized convulsions occurred. The control group (group C) received plain lidocaine. The acute hypertensive groups received lidocaine with epinephrine (group E), norepinephrine (group N), or phenylephrine (group P) to increase mean arterial blood pressure (MAP) to 150 +/- 5 mmHg. Sodium nitroprusside (SNP) was added to prevent an increase in mean arterial pressure in the remaining three groups (vasopressor-SNP groups). The acute hypertensive groups required significantly smaller cumulative doses of lidocaine to produce convulsions compared with control (C = 41.5 +/- 2.9 > E = 24.1 +/- 2.7, N = 27.1 +/- 2.8, P = 26.7 +/- 2.5 mg.kg-1; values are mean +/- SD, P < 0.01). In addition, plasma lidocaine concentrations (C = 11.0 +/- 0.7 > E = 7.4 +/- 0.5, N = 7.9 +/- 0.6, P = 8.1 +/- 0.8 micrograms.ml-1, P < 0.01) and brain lidocaine concentrations (C = 50.9 +/- 4.5 > E = 32.6 +/- 4.2, N = 34.5 +/- 4.8, P = 37.1 +/- 4.5 micrograms.g-1, P < 0.01) were less in the acute hypertensive groups at the onset of convulsions. In the vasopressor-SNP groups, the plasma and brain lidocaine concentrations at the onset of convulsions returned to the control values, although epinephrine and norepinephrine, but not phenylephrine, still decreased cumulative convulsant doses of lidocaine significantly (P < 0.01) compared with control (E + SNP = 30.8 +/- 2.9 < N + SNP = 34.8 +/- 2.8, P < 0.01) < P + SNP = 40.2 +/- 3.0 mg.kg-1, P < 0.01). The brain/plasma concentration ratios were similar for the seven groups. An equal degree of acute hypertension induced by these three different vasopressors may play a role in reducing the threshold (plasma and brain lidocaine concentrations) as well as the cumulative convulsant doses associated with lidocaine-induced convulsions.