Evaluation of mean arterial blood pressure, heart rate, and sympathetic nerve activity in rabbits after administration of two formulations of etomidate.

OBJECTIVE: To evaluate and compare the effects of the aqueous sulfobutyl ether beta-cyclodextrin (SBE-CD) etomidate formulation and the commercial etomidate formulation on mean arterial pressure (MAP), heart rate, and sympathetic outflow using neuraxis-intact and baro-denervated rabbits. STUDY DESIGN: Prospective experimental study. ANIMALS: Twenty-seven male New Zealand white rabbits. METHODS: Under basal anesthesia (urethane) and ventilation with intermittent positive pressure (IPPV), the New Zealand white rabbits underwent surgical preparation including isolation of the left renal sympathetic nerve and, in the baro-denervated models, additional combined denervation of bilateral carotid sinus, aortic, and vagal nerves. After hemodynamic stabilization, both neuraxis-intact and baro-denervated animals received bolus intravenous (IV) injection (0.6 mg kg(-1)) of either the SBE-CD or commercial etomidate formulation over 5 seconds (n = 6 animals per group). RESULTS: Mean arterial pressure decreased significantly in all four groups to the same extent. However, the rate of MAP decrease was lower in the SBE-CD-treated groups relative to the commercial formulation. Renal sympathetic nerve activity was decreased significantly less in the SBE-CD group in the baro-denervated studies. Independent pharmacokinetic evaluation demonstrated that the two formulations had comparable plasma concentration-time profiles. CONCLUSIONS AND CLINICAL RELEVANCE: Etomidate in the commercial drug product is solubilized with propylene glycol, a cosolvent associated with adverse side effects on injection. An aqueous formulation of etomidate has been developed, which utilizes SBE-CD as a solubilizing agent. The data suggest that the SBE-CD etomidate formulation may be a safer IV induction formulation than the commercial etomidate drug product.

Protamine after heparin produces hypotension resulting from decreased sympathetic outflow secondary to increased nitric oxide in the central nervous system.

To elucidate whether there are linkages among protamine-induced hypotension, nitric oxide (NO), and sympathetic nerve activity, we administered 3 mg/kg protamine sulfate after 300 U/kg heparin after 20 mg/kg of N(G)-nitro-D-arginine methyl ester (D-NAME) or N(G)-nitro-L-arginine methyl ester (L-NAME) as a pretreatment to baroreceptor-denervated rabbits and compared changes in hemodynamic variables and renal sympathetic nerve activity (RSNA). In the D-NAME group, heart rate (HR), mean arterial blood pressure (MAP), and RSNA significantly decreased to 93.7% +/- 0.7%, 75.0% +/- 5.1% and 65.2% +/- 4.6% (mean +/- SE), respectively. In the L-NAME group, the pretreatment of L-NAME significantly inhibited the depressant effects of protamine on these variables. Because the animals were totally baroreceptor-denervated, decreased RSNA was attributable to the central depressant effect of protamine, and decreased sympathetic outflow could have contributed to the reduction of HR and MAP. The depressant effect of protamine on sympathetic outflow was inhibited by the pretreatment with L-NAME, a NO synthase inhibitor, suggesting that decreased sympathetic outflow secondary to a protamine-induced increase in NO concentration in the central nervous system may contribute to protamine-induced cardiovascular depression.

Inhibitory effects of extracellular matrix modulator(s) on lipopolysaccharide (LPS)- and acidosis-damaged glia containing cerebellar granule cell cultures.

The inhibitory effects of a novel chondroitin sulfate compound on lipopolysaccharide (LPS)- and acidosis-induced neuronal dysfunctions were examined. Cell viabilities in cultured neurons and/or astrocyte-rich cerebellar granule cells were measured by the calcein-AM method. Ten and 20 microg, as a final dosage, of LPS damaged less than 20% cells during a-2 h incubation. More than 5000 ng/ml of chondroitin sulphate-dipalmitoylphosphatidylethanolamine (CS-PE), but not chondroitin sulfate (CS) treatment, significantly inhibited such damage. Twenty microg of LPS damaged more than 40% cells during 24 h incubation, and these cell damages were significantly inhibited by less than 1000 ng/ml of CS-PE. Moreover, treatments with between 5 and 500 ng/ml CS-PE, but not CS, significantly reduced the number of acidosis-damaged cells in a dose-dependent manner. The current results indicate that modulator(s) of ECM and its derivative containing covalently linked dipalmitoylphosphatidylethanolamine show neuroprotective effects under conditions of brain inflammation.