Differential effects of desflurane and halothane on peripheral airway smooth muscle

Volatile anaesthetics have been shown to have direct relaxant effects on airway smooth muscle. We have examined the effects of 0.9, 1.9, and 2.8 dog MAC of desflurane and halothane on isolated proximal and distal canine airways precontracted with acetylcholine. The proximal and distal airway smooth muscle relaxed with increasing concentration of each anaesthetic in a dose-related manner. Desflurane had a greater relaxant effect than halothane on the proximal airway only at 2.8 MAC. Desflurane relaxed the distal airway to a greater extent than halothane at 1.9 and 2.8 MAC. The distal airway smooth muscle was more sensitive to volatile anaesthetics than the proximal airway smooth muscle with either halothane or desflurane at all concentrations tested. This effect may be a result of differences in cartilage content, myosin content, epithelium-dependent effects, receptor density, myofilament sensitivity to Ca2+, sarcoplasmic reticulum Ca2+ control, or ionic fluxes in the proximal airway compared with the distal airway. The increased sensitivity of airway smooth muscle to desflurane compared with halothane is not known but may be related to possible differences in the effects of Ca2+ homeostasis.      

Region distribution of the gangliosides in rat brain after chronic ethanol treatment

In this study the effects of chronic ethanol administration on the regional distribution of brain gangliosides were investigated. A total of 36 60-d-old male Wistar rats weighing approximately 200 g was divided into two groups of 18 animals each. The ethanol-consuming group was offered drinking fluid (25% sucrose-32% ethyl alcohol, w/w) ad libitum, and the control group was given a sucrose solution isocaloric with the ethanol-sucrose solution. After 6 mo of chronic ethanol treatment, cerebral cortex, N. caudatus, hypothalamus, thalamus, and hippocampus were analyzed with respect to their ganglioside pattern (G_M2, G_M1, G_D1a, G_D1b, G_T1b, and G_Q). The results showed that there were highly significant effects of ethanol on hypothalamus G_D1b and G_T1b, thalamus G_M1 and G_D1a, and hippocampus G_M1, G_D1b, and G_T1b ganglioside distribution. It was found that ethanol differently affected the gangliosides in these brain regions.     

Volatile anesthetics attenuate sympathomimetic actions on the guinea pig SA node

The authors examined and compared the direct effects of three volatile anesthetic agents and three sympathomimetic agonists on transmembrane action potential (AP) characteristics and automaticity of sinoatrial (SA) nodal pacemaker cells. SA nodal tissue was isolated from guinea pig hearts and suffused in vitro with oxygenated Krebs-Ringer solution. Electrophysiologic variables measured were: amplitude of the AP, slopes of phase 4 and of phase 0 of the AP, AP duration, and spontaneous sinus rate. The authors found that 1 and 2 MAC equivalents of each anesthetic, 0.8 and 1.6 vol % halothane, 1.4 and 2.8 vol % isoflurane, and 1.7 and 3.4 vol % enflurane similarly depressed the slopes of phase 4 and 0 of the AP, prolonged AP duration, and slowed the sinus rate at 1 and 2 MAC equivalents. Isoproterenol, 0.25 microM, and epinephrine, 50 microM, maximally enhanced the slopes of phase 4 and 0 of the AP, shortened AP duration, and increased the sinus rate, but phenylephrine, 50 microM, only moderately increased the slope of phase 4 and the sinus rate. Each of the three anesthetics caused baseline depressions of phase 4 and phase 0 slopes and of automaticity of SA nodal cells; the fall in sinus rate was counteracted, but was not reversed maximally by increasing the concentrations of isoproterenol, epinephrine, or phenylephrine. Regression analyses of linearly transformed data showed that each of the anesthetics similarly depressed basal sinus rate, so that changes in rate produced with isoproterenol and epinephrine were not different from those observed with beta agonists in the absence of anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Halothane reduces dysrhythmias and improves contractile function after global hypoperfusion in isolated hearts.

We investigated the effects of halothane on changes in cardiac function during hypoperfusion and recovery of function after reperfusion in the isolated perfused guinea pig heart. Heart rate, atrioventricular (AV) conduction time, the incidence and severity of dysrhythmias, and isovolumetric left ventricular systolic pressure (LVSP) and its derivative were measured. Hearts (n = 85) were divided into three groups for 30 min of perfusion at 0% (no flow), 10%, and 25% of the control perfusion pressure (PP, 55 mm Hg). These groups were subdivided and exposed to 0%, 0.74% (0.23 +/- 0.01 mM), or 1.65% (0.51 +/- 0.01 mM) halothane 10 min before, during, and 10 min after hypoperfusion. Hypoperfusion was followed by 40 min of reperfusion at control PP. Exposure to 0.74% and 1.65% halothane before hypoperfusion produced a 9% and 13% decrease in heart rate, a 2% and 30% increase in AV conduction time, and a 25% and 51% decrease in LVSP and dLVP/dtmax, respectively. During the 30 min of hypoperfusion, heart rate decreased and AV conduction time increased; second- and third-degree AV block occurred in all hearts in the 0% and 10% PP groups, but only in some hearts in the 25% PP groups. Left ventricular systolic pressure rapidly decreased during hypoperfusion in all groups. During early reperfusion ventricular fibrillation and ventricular tachycardia occurred in the 0% and 10% PP groups but not in the 25% PP groups. During reperfusion 0.74% and 1.65% halothane greatly reduced the duration of ventricular fibrillation from 8.1 +/- 3.3 min to 1.5 +/- 0.8 and 1.9 +/- 1.2 min in the 0% and 10% PP groups, respectively. A concentration of 0.74% halothane increased the incidence of supraventricular tachycardia on reperfusion in the 10% group (from a control of 20% to 65%), and 1.65% halothane increased the duration (2.6 +/- 2.5 min) and incidence (38%) of supraventricular tachycardia on reperfusion in the 0% PP group. A concentration of 1.65% halothane facilitated recovery of LVSP after hypoperfusion in the 25% group but not in the 0% and 10% PP groups. These results indicate that halothane, in some instances, can have protective cardiac effects after graded hypoperfusion as assessed by improved contractility and by reduced severity of some dysrhythmias during reperfusion; however halothane may also increase the incidence of supraventricular tachycardia. The cardiac protection by halothane could be a result of reduced cardiac work before, during, and after hypoperfusion, or of some other direct protective cellular effects.     

Effects of haloperidol and clozapine on sensorimotor gating deficits induced by 5-hydroxytryptamine depletion in the brain

Evidence is increasing for a role of brain 5-hydroxytryptamine (5-HT) systems in schizophrenia. We previously showed that brain 5-HT depletion causes disruption of prepulse inhibition, a measure of sensorimotor gating that is deficient in schizophrenia. Antipsychotic treatment has been reported to reverse these deficits in patients with schizophrenia. The present study was designed to investigate the ability of antipsychotic drugs to reverse prepulse inhibition deficits caused by lesions of the brain 5-HT system in rats. In male Sprague-Dawley rats, selected parts of the brain 5-HT systems were lesioned by micro-injection of the 5-HT neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus (DRN) or median raphe nucleus (MRN). The effects of antipsychotic drugs on lesion-induced changes in prepulse inhibition were examined 2 weeks after the surgery. There was significant disruption of prepulse inhibition in the MRN-lesioned group compared to sham-operated controls. This deficiency in prepulse inhibition was restored by clozapine (1 and 5 mg kg(-1)) treatment, and by treatment with a relatively high dose of haloperidol (0.25 mg kg(-1)). There was no significant effect of the DRN lesions on prepulse inhibition compared with sham-operated controls. These results indicate that 5-HT depletion in MRN-innervated brain structures leads to disruption of prepulse inhibition. Treatment with both antipsychotic drugs, haloperidol and clozapine, significantly increased prepulse inhibition in these animals back to the level seen in sham-operated controls. The present findings highlight the importance of the 5-HT systems in cognitive models of schizophrenia.     

Physical and thermal characterisation of chiral omeprazole sodium salts

The physical properties of drug substances may affect stability, manufacturing, dissolution and bioavailability. Variations in the degree of crystallinity in a pharmaceutical substance may exhibit physicochemical differences that impact at therapeutic, manufacturing, commercial and legal levels, yet no reference has been found on the physical properties of micronised omeprazole. This study reports on the physical and thermal characterisation of the sodium salts of S- and R-omeprazole, using diffuse reflectance infrared Fourier transform spectroscopy (DRIFT), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), microthermal analysis (microTA) and powder X-ray diffraction (XRPD). DSC experiments were performed in order to determine not only their thermal stability, but also the thermal history of both forms. SEM results indicate similar morphology, particle size and shape of powdered drug, while, microTA of processed discs shows different topographical images for S- and R-omeprazole, exhibiting a smoother surface for the S-form, indicative of the smoother particle size not evident in the SEM results. The low level of crystallinity of both enantiomers was confirmed by DRIFT spectroscopy and XRPD. Thermal stability by DSC of S- and R-omeprazole sodium salts was superior to that of the neutral omeprazole. This study has examined the physical and thermal properties of both forms and in highlighting their differences provides an explanation for the potential differences in bioavailability and therapeutic efficacy.     

Mechanism of cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel activation by isoflurane in a heterologous expression system

BACKGROUND: Activation of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channel during metabolic stress initiates cellular events that preserve cardiac performance. Previous studies showed that halogenated anesthetics prime KATP channels under whole cell voltage clamp and act in intracellular pH (pHi)-dependent manner on KATP channels in excised membrane patches. However, it is not known how halogenated anesthetics interact with these channels. METHODS: The authors evaluated the effect of pHi and isoflurane on the KATP channel subunits, the pore-forming inward rectifier Kir6.2, and the regulatory sulfonylurea receptor SUR2A, using HEK293 cells as a heterologous expression system. Single channel activity was recorded in the inside-out patch configuration. RESULTS: At pHi 7.4, isoflurane had negligible effect on activity of wild-type Kir6.2/SUR2A, but at pHi 6.8, the channel open probability was increased by isoflurane (0.177 +/- 0.077 to 0.364 +/- 0.164). By contrast, the open probability of truncated Kir6.2DeltaC26, which forms a functional channel without SUR2A, was attenuated by isoflurane at both pHi 7.4 and pHi 6.8. Coexpression of Kir6.2DeltaC26 with SUR2A restored pHi sensitivity of channel activation by isoflurane. Site-directed mutagenesis within the Walker motifs of SUR2A abolished isoflurane activation of KATP channel at pHi 6.8. In addition, the pancreatic-type channels expressing sulfonylurea receptor SUR1 could not be activated by isoflurane. CONCLUSIONS: The nucleotide binding domains of SUR2A play a crucial role in isoflurane facilitation of the KATP channel activity at moderately acidic pHi as would occur during early ischemia. These findings support direct and differential interaction of isoflurane with the subunits of the cardiac sarcolemmal KATP channel.     

Chromosomal substitution-dependent differences in cardiovascular responses to sodium pentobarbital

In this study we addressed initial laboratory observations of enhanced cardiovascular sensitivity to sodium pentobarbital (PTB) in normotensive Dahl Salt Sensitive rats (SS) compared to Brown Norway (BN) rats. We also used unique consomic (chromosomal substitution) strains to confirm preliminary observations that such differences were related to chromosome 13. Increasing concentrations of PTB were administered sequentially to SS, BN, and SS strains with BN chromosomal substitutions until the point of cardiovascular collapse. Both spontaneous and controlled ventilation were studied. The effect of large (450 microg/mL) and small (35 microg/mL) concentrations of PTB on in situ transmembrane potential of mesenteric arterial vascular smooth muscle (VSM) cells was also measured in these animals with local sympathetic innervation both intact and eliminated. An analysis of variance was used to identify significant differences among groups. Despite virtually identical plasma clearance of PTB, cardiovascular collapse occurred at approximately 35%-45% smaller cumulative doses of administered PTB in SS and other strains compared with BN and SS.13BN (introgression of BN chromosome 13 into an SS) in both spontaneous and controlled ventilation. In neurally intact preparations, large dose PTB-induced VSM hyperpolarization was 4-5 times greater than the small dose in SS and SS.16BN but not in BN and SS.13BN strains. Denervation eliminated this strain difference. These results suggest that enhanced cardiovascular sensitivity to PTB in SS rats is related to greater hyperpolarization of VSM transmembrane potential in resistance vessels and this effect is associated with chromosome 13.