The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Sep 1999
Influence of hypovolemia on the pharmacokinetics and the electroencephalographic effect of etomidate in the rat.
The influence of hypovolemia (removal of 30% of the blood volume) on the pharmacokinetics and pharmacodynamics of etomidate was investigated in the rat. Chronically instrumented animals were randomly allocated to either a control (n = 9) or a hypovolemia (n = 9) group, and etomidate was infused (50 mg/kg/h) until isoelectric periods of 5 s or longer were observed in the electroencephalogram. The changes observed in the electroencephalogram were quantified using aperiodic analysis in the 2.5- to 7.5-Hz frequency band and used as a surrogate measure of hypnosis. ⋯ The concentration at the return of righting reflex was 16% (p <.05) lower in the hypovolemic animals. In conclusion, an increased hypnotic effect of etomidate was observed during hypovolemia that is mainly attributed to pharmacokinetic changes. Our data also suggest a small increase in central nervous system sensitivity for etomidate in hypovolemic animals.
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J. Pharmacol. Exp. Ther. · Sep 1999
Cocaine-reinforced responding in rhesus monkeys: pharmacological attenuation of the hypothalamic-pituitary-adrenal axis response.
Intravenously self-administered cocaine produces a dose-dependent release of adrenocorticotropic hormone (ACTH) and cortisol in male rhesus monkeys. This study investigated whether the acute disruption of cortisol and/or ACTH release had any effect on ongoing cocaine-maintained responding. Four hypothalamic-pituitary-adrenal (HPA) axis inhibitors were examined: etomidate and ketoconazole, both of which are cortisol synthesis inhibitors; astressin, a peptidic corticotropin-releasing factor (CRF) antagonist that binds CRF(1) receptors predominantly in the pituitary gland; and dexamethasone, a highly selective glucocorticoid receptor agonist whose long-lasting effects reduce or abolish the endogenous release of ACTH and cortisol. ⋯ Pretreatment with etomidate and ketoconazole dose-dependently inhibited the cocaine-induced rise in cortisol and, at the highest doses, produced a compensatory increase in ACTH release. Astressin and dexamethasone attenuated or abolished cocaine-induced cortisol and ACTH release. Despite the efficacy exhibited by these pretreatments and the variety of mechanisms by which they inhibited the HPA axis, there was no evidence for any change in cocaine-reinforced behavior (response rate or infusion number), an indication that acute changes in the ACTH or cortisol response to cocaine do not play a direct role in modulating cocaine-seeking behavior under these behavioral circumstances.
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J. Pharmacol. Exp. Ther. · Aug 1999
Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused guinea pig heart.
The majority of clinically used inotropes act by increasing cytosolic calcium levels, which may hypothetically worsen reperfusion stunning and provoke arrhythmias. We tested the hypothesis that the calcium sensitizer levosimendan (levo) given during ischemia alone or ischemia and reperfusion would improve reperfusion function without promoting arrhythmias. The Langendorff-perfused guinea pig heart, subjected to 40-min low-flow ischemia (0.4 ml/min) with or without levo (10-300 nM) given during ischemia or ischemia/reperfusion was used. ⋯ Levo-treated hearts had no ischemia/reperfusion arrhythmias whereas 83% (p <.05 versus control) of dobutamine-treated hearts developed ventricular tachycardia and 33% (p <.05 versus levo) developed reperfusion ventricular fibrillation. Levo improved reperfusion function without promoting arrhythmias in this model. This was possibly achieved by opening the K(ATP) channels during ischemia and sensitizing myocardial contractile apparatus instead of elevating cytosolic calcium levels in reperfused hearts.
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J. Pharmacol. Exp. Ther. · Jul 1999
Biphasic modulation of visceral nociception by neurotensin in rat rostral ventromedial medulla.
A potential role for neurotensin in the rostral ventromedial medulla (RVM) in modulation of visceral nociceptive transmission was examined in this study. Microinjection of neurotensin (3-3000 pmol) into the RVM of awake rats produced a dose-dependent inhibition of the visceromotor response (VMR) to noxious colorectal distension (CRD) that lasted 30 to 120 min. Additionally, intra-RVM injection of neurotensin (300 pmol) significantly reduced the slope of the stimulus-response function to graded CRD (20-80 mm Hg), whereas the greatest dose of neurotensin (3000 pmol) completely inhibited the VMR at all intensities of CRD. ⋯ Additionally, intra-RVM injection of the neurotensin-receptor antagonist SR48692 (0.3-300 fmol) in naive animals produced dose-dependent inhibition of VMR to noxious CRD, whereas a lesser dose (0.03 fmol) enhanced the VMR. These data support a role for neurotensin in the RVM in biphasic modulation of visceral nociception. The results obtained with SR48692 suggest that endogenous neurotensin in the RVM modulates VMR to noxious CRD via a prominent interaction with neurotensin receptors that mediate facilitatory influences and a lesser interaction with neurotensin receptors that mediate masked inhibitory influences.
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J. Pharmacol. Exp. Ther. · Jul 1999
Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats.
In this study, we investigated the effectiveness of gabapentin (Neurontin), administered spinally with a microdialysis fiber, in reducing nociceptive behavioral responses induced by a knee joint inflammation model. This model is produced by injection of the knee joint with kaolin and carrageenan in rats. The resultant knee joint inflammation produces a secondary hyperalgesia to radiant heat applied to the hindpaw. ⋯ In animals with fully developed knee joint inflammation, gabapentin produced a reversal of heat hyperalgesia. The paw withdrawal latency responses and subjective pain scores were no longer significantly different from baseline, but joint circumference increases remained. These data suggest that gabapentin is an effective antinociceptive agent when administered either before or after induction of knee joint inflammation acting through a central neurogenic mechanism.