oxadiazoles and Heart-Arrest

Lipid emulsion has been shown to be effective in resuscitating bupivacaine-induced cardiac arrest but its mechanism of action is not clear. Here we investigated whether fatty-acid oxidation is required for rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats. We also compared the mitochondrial function and calcium threshold for triggering of mitochondrial permeability transition pore opening in bupivacaine-induced cardiac arrest before and after resuscitation with lipid emulsion.. Prospective, randomized animal study.. University research laboratory.. Adult male Sprague-Dawley rats.. Asystole was achieved with a single dose of bupivacaine (10 mg/kg over 20 secs, intravenously) and 20% lipid emulsion infusion (5 mL/kg bolus, and 0.5 mL/kg/min maintenance), and cardiac massage started immediately. The rats in CVT-4325 (CVT) group were pretreated with a single dose of fatty-acid oxidation inhibitor CVT (0.5, 0.25, 0.125, or 0.0625 mg/kg bolus intravenously) 5 mins prior to inducing asystole by bupivacaine overdose. Heart rate, ejection fraction, fractional shortening, the threshold for opening of mitochondrial permeability transition pore, oxygen consumption, and membrane potential were measured. The values are mean ± SEM.. Administration of bupivacaine resulted in asystole. Lipid Emulsion infusion improved the cardiac function gradually as the ejection fraction was fully recovered within 5 mins (ejection fraction=64±4% and fractional shortening=36±3%, n=6) and heart rate increased to 239±9 beats/min (71% recovery, n=6) within 10 mins. Lipid emulsion was only able to rescue rats pretreated with low dose of CVT (0.0625 mg/kg; heart rate~181±11 beats/min at 10 mins, recovery of 56%; ejection fraction=50±1%; fractional shortening=26±0.6% at 5 mins, n=3), but was unable to resuscitate rats pretreated with higher doses of CVT (0.5, 0.25, or 0.125 mg/kg). The calcium-retention capacity in response to Ca²⁺ overload was significantly higher in cardiac mitochondria isolated from rats resuscitated with 20% lipid emulsion compared to the group that did not receive Lipid Emulsion after bupivacaine overdose (330±42 nmol/mg vs. 180±8.2 nmol/mg of mitochondrial protein, p<.05, n=3 in each group). The mitochondrial oxidative rate and membrane potential were similar in the bupivacaine group before and after resuscitation with lipid emulsion infusion.. Fatty-acid oxidation is required for successful rescue of bupivacaine-induced cardiotoxicity by lipid emulsion. This rescue action is associated with inhibition of mitochondrial permeability transition pore opening.

Topics: Animals; Bupivacaine; Calcium; Fat Emulsions, Intravenous; Fatty Acids; Heart Arrest; Heart Massage; Hemodynamics; Homeostasis; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Oxadiazoles; Oxidation-Reduction; Rats; Rats, Sprague-Dawley

To study specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus.. Although serotonergic system dysfunction is implicated in posthypoxic myoclonus, anatomic specificity and linkage to receptor subtypes are not delineated.. The authors performed a pharmacologic study to identify specific serotonin receptor subtype antagonists effective in inhibiting myoclonus in posthypoxic rats. Sprague-Dawley rats underwent cardiac arrest for 8 minutes and were resuscitated. On the day of pharmacologic testing, animals were rated every 10 minutes at -30 minutes to time 0 (drug injection) and from +60 to +150 minutes. Using a blinded methodology, animals were injected with normal saline, vehicle, or one of seven serotonin antagonists given at a dose that maintains serotonin receptor subtype specificity: WAY100135 (5-HT1A), methiothepin mesylate (5-HT1B/1D/2), mesulergine hydrochloride (5-HT2A/2B), GR 127935 (5-HT1D), SR 46349 (5-HT2), ondansetron (5-HT3), or GR 125487 (5-HT4). Drugs that produced a significant decrease in myoclonus compared with the control were studied in a dose-response study with six doses across a range from the original dose studied to 10% of that dose.. Two drugs were significantly different from placebo: methiothepin mesylate and mesulergine hydrochloride. GR 127935 showed a trend toward reducing myoclonus. Dose-response studies showed that all doses of methiothepin mesylate and the three highest doses of mesulergine hydrochloride inhibited myoclonus effectively.. 5-HT1B, 5-HT2A/2B, and possibly 5-HT1D receptor subtypes likely play a role in posthypoxic myoclonus. More specific 5-HT antagonists that affect these receptor subtypes are candidates for future testing in this model and in Lance-Adams syndrome.

Topics: Acoustic Stimulation; Animals; Brain Chemistry; Disease Models, Animal; Dose-Response Relationship, Drug; Ergolines; Heart Arrest; Hypoxia; Hypoxia, Brain; Male; Methiothepin; Myoclonus; Oxadiazoles; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists