Motor nerve blockade potency and toxicity of non-racemic bupivacaine in rats.

BACKGROUND: Racemic [RS(+/-)] bupivacaine can be associated with severe cardiotoxicity. The S(-) isomer is known to be less neuro- and cardiotoxic, but demonstrates a lower potency to block motor activity than RS(+/-) bupivacaine. Thus, the potency and toxicity of a non-racemic bupivacaine mixture were studied. METHODS: Gastrocnemic muscle twitches induced by electrical stimulation of sciatic nerves in rats were used to compare the impact by bupivacaine solutions on motor activity. Field stimulation at 1 Hz eliciting ventricular muscle twitches was used to investigate the effects on cardiac contractility. The lethal dose of each local anesthetic agent was determined following drug infusions during general anesthesia in mechanically ventilated rats. RESULTS: Non-racemic (75S:25R) bupivacaine was more potent (P<0.05) than S(-) or R(+) enantiomers to block motor nerve activity. The concentrations of RS(+/-), 75S:25R, R(+) and S(-) bupivacaine to inhibit nerve conduction by 50% were 0.84 (0.37- 2.20), 0.84 (0.47-2.48), 2.68 (0.98-3.42) and 2.11 mM (1.5-4.03), respectively. Pronounced reductions in ventricular muscle twitches were observed with RS(+/-) and R(+) bupivacaine at low concentrations (0.5-4 microM). Lethal doses for 75S:25R (39.9 mg kg(-1)), and S(-) (34.7 mg kg(-1)) were higher (P<0.05) than for R(+) (16.2 mg kg(-1)) and RS(+/-) bupivacaine (18.4 mg kg(-1)), respectively. DISCUSSION: The potency of S(-) bupivacaine to block the motor activity in the sciatic nerve was enhanced when 25% of the S(-) isomer was replaced by the antipode R(+) bupivacaine. This effect was not associated with increased toxicity.

Impaired beta-adrenergic response and decreased L-type calcium current of hypertrophied left ventricular myocytes in postinfarction heart failure

Infarct-induced heart failure is usually associated with cardiac hypertrophy and decreased beta-adrenergic responsiveness. However, conflicting results have been reported concerning the density of L-type calcium current (I Ca(L)), and the mechanisms underlying the decreased beta-adrenergic inotropic response. We determined I Ca(L) density, cytoplasmic calcium ([Ca2+]i) transients, and the effects of beta-adrenergic stimulation (isoproterenol) in a model of postinfarction heart failure in rats. Left ventricular myocytes were obtained by enzymatic digestion 8-10 weeks after infarction. Electrophysiological recordings were obtained using the patch-clamp technique. [Ca2+]i transients were investigated via fura-2 fluorescence. beta-Adrenergic receptor density was determined by [ H]-dihydroalprenolol binding to left ventricle homogenates. Postinfarction myocytes showed a significant 25 percent reduction in mean I Ca(L) density (5.7 + or - 0.28 vs 7.6 + or - 0.32 pA/pF) and a 19 percent reduction in mean peak [Ca2+]i transients (0.13 + or - 0.007 vs 0.16 + or - 0.009) compared to sham myocytes. The isoproterenol-stimulated increase in I Ca(L) was significantly smaller in postinfarction myocytes (Emax: 63.6 + or - 4.3 vs 123.3 + or - 0.9 percent in sham myocytes), but EC50 was not altered. The isoproterenol-stimulated peak amplitude of [Ca2+]i transients was also blunted in postinfarction myocytes. Adenylate cyclase activation through forskolin produced similar I Ca(L) increases in both groups. beta-Adrenergic receptor density was significantly reduced in homogenates from infarcted hearts (Bmax: 93.89 + or - 20.22 vs 271.5 + or - 31.43 fmol/mg protein in sham myocytes), while Kd values were similar. We conclude that postinfarction myocytes from large infarcts display reduced I Ca(L) density and peak [Ca2+]i transients. The response to Beta-adrenergic stimulation was also reduced and was probably related to Beta-adrenergic receptor down-regulation and not to changes in adenylate cyclase activity

Impaired beta-adrenergic response and decreased L-type calcium current of hypertrophied left ventricular myocytes in postinfarction heart failure.

Infarct-induced heart failure is usually associated with cardiac hypertrophy and decreased -adrenergic responsiveness. However, conflicting results have been reported concerning the density of L-type calcium current (I Ca(L)), and the mechanisms underlying the decreased -adrenergic inotropic response. We determined I Ca(L) density, cytoplasmic calcium ([Ca2+]i) transients, and the effects of -adrenergic stimulation (isoproterenol) in a model of postinfarction heart failure in rats. Left ventricular myocytes were obtained by enzymatic digestion 8-10 weeks after infarction. Electrophysiological recordings were obtained using the patch-clamp technique. [Ca2+]i transients were investigated via fura-2 fluorescence. -Adrenergic receptor density was determined by [ H]-dihydroalprenolol binding to left ventricle homogenates. Postinfarction myocytes showed a significant 25% reduction in mean I Ca(L) density (5.7 0.28 vs 7.6 0.32 pA/pF) and a 19% reduction in mean peak [Ca2+]i transients (0.13 0.007 vs 0.16 0.009) compared to sham myocytes. The isoproterenol-stimulated increase in I Ca(L) was significantly smaller in postinfarction myocytes (Emax: 63.6 4.3 vs 123.3 0.9% in sham myocytes), but EC50 was not altered. The isoproterenol-stimulated peak amplitude of [Ca2+]i transients was also blunted in postinfarction myocytes. Adenylate cyclase activation through forskolin produced similar I Ca(L) increases in both groups. -Adrenergic receptor density was significantly reduced in homogenates from infarcted hearts (Bmax: 93.89 20.22 vs 271.5 31.43 fmol/mg protein in sham myocytes), while Kd values were similar. We conclude that postinfarction myocytes from large infarcts display reduced I Ca(L) density and peak [Ca2+]i transients. The response to -adrenergic stimulation was also reduced and was probably related to -adrenergic receptor down-regulation and not to changes in adenylate cyclase activity.