The influence of the bolus injection rate of propofol on its cardiovascular effects and peak blood concentrations in sheep

The influence of the bolus injection rate of propofol on its cardiovascular effects has not been extensively studied. We therefore examined the influence of the injection rate of i.v. bolus doses of propofol on its acute cardiovascular effects and peak blood concentrations in seven chronically instrumented sheep. Each received i.v. propofol (200 mg) over 2 min (slow injection) and 0.5 min (rapid injection) on separate occasions in random order. The rapid injection was associated with more profound decreases in mean arterial blood pressure than slow injection (35.7% vs 23.7% maximal reductions from baseline, respectively; P = 0.02). There were no significant differences between the injection rates for peak reductions in myocardial contractility, increases in heart rate, or degree of respiratory depression. Concurrently, the rapid injections were associated with significantly higher arterial (26.9 vs 11.9 mg/L) propofol concentrations in a manner consistent with indicator dilution principles. There were no differences in the peak coronary sinus concentrations between the injection rates. We conclude that the rapid injection of propofol in the context of the induction of anesthesia produced significantly higher peak arterial propofol concentrations and suggest that it is these higher concentrations that produced relatively greater reductions in arterial blood pressure from rapid injections. Implications: Propofol is injected into a vein to initiate anesthesia. It can cause a rapid decrease in blood pressure, which may be dangerous to the patient. We examined the effect of rapid and slow injection rates of propofol in sheep and found that rapid injection caused a greater decrease in blood pressure. This was because rapid injection caused higher concentrations of propofol in the blood immediately after the injection. We believe that if the same processes occur in humans, there may be little advantage in injecting propofol rapidly.     

The effect of prior dural puncture on cerebrospinal fluid sufentanil concentrations in sheep after the administration of epidural sufentanil

Sufentanil is a highly lipid soluble opioid that provides potent analgesia when administered in the subarachnoid space. Unfortunately, the penetration of sufentanil into the cerebrospinal fluid (CSF) after epidural administration is poor, and limits its effectiveness for epidural analgesia. Dural puncture may enhance the movement of epidural sufentanil into the subarachnoid space and increase its effectiveness. To determine whether the administration of epidural sufentanil adjacent to a dural puncture results in significantly greater CSF concentrations, 18 adult ewes were studied. Animals in the control group had an epidural catheter placed at the superior border of the pelvis without dural puncture. Animals in the study group had an epidural catheter placed, followed by a dural puncture performed using an 18-gauge Touhy needle. The dural puncture was performed one interspace cephalad to the epidural catheter. One hour after dural puncture, each animal received a loading dose of 0.35 microg/kg of sufentanil (5 microg/mL) through the epidural catheter, followed by an infusion of epidural sufentanil 0.15 microg x kg(-1) x h(-1) for a period of 4 h. After 4 h, CSF was sampled from a site one interspace caudad to the epidural catheter as well as at the cisterna magna. The mean CSF concentration of sufentanil at the level of the pelvis for animals with a dural puncture was 12.1 +/- 3.0 ng/mL compared with 1.8 ng/mL in controls with intact dura. Sufentanil concentrations at the cisterna magna were below the level of detection (0.08 ng/mL) for all animals in both groups. We conclude that an 18-gauge dural puncture significantly increases movement of sufentanil from the epidural to the intrathecal space. This increase in sufentanil concentration at the level of the pelvis was not associated with detectable levels of sufentanil at the brainstem. Implications: This study addresses the effect of dural puncture on spinal fluid concentrations of sufentanil after epidural administration. A sheep model was used to measure drug concentrations in the spinal fluid at the levels of the pelvis and brainstem after epidural administration. Dural puncture significantly enhanced movement of sufentanil into the spinal fluid at the level of the pelvis, but brainstem concentrations were below the level of detection. Analgesic concentrations of spinal sufentanil in the clinical setting, as well as brainstem concentrations associated with respiratory depression, have yet to be defined.     

Plasma follistatin concentrations increase following lipopolysaccharide administration in sheep

1. The effect of inflammation induced by lipopolysaccharide (LPS) injection on plasma follistatin (FS) concentrations was investigated. 2. Plasma FS and tumour necrosis factor-alpha concentrations increase following LPS administration in ewes. 3. The rise in FS is similar, but more sustained, to that previously observed after surgery. 4. These results indicate a possible functional link between FS, inflammation and the acute-phase response.     

The effect of steroid contraceptives on the concentrations of brain monoamines in rats and mice

The effect of three estrogen-progestin combinations on biogenic amines in discrete brain areas of rats and mice has been investigated. With the exception of a significant decrease of brain 5-hydroxyindolacetic acid in the rats treated for 30 days with the combination norethynodrel + mestranol, no significant changes in the levels of serotonin, noradrenaline or dopamine in the rat brain were found following the administration of the compounds under study. On the other hand, in mice moderate but significant changes in the levels of serotonin, dopamine, noradrenaline and 5-hydroxyindolacetic acid were found in various brain areas depending on the estrogen-progestin combination used. The potential importance of these effects for the contraceptive as well as for some central actions of these compounds is discussed.     

The effect of varying stimulus rate and duration on brain activity during reading

The effect of the presentation rate and exposure duration of visually presented words on brain activity was investigated using positron emission tomography. Subjects either read aloud or silently mouthed the names of words. In regions associated with early visual analysis, activity increased with both rate and duration; in regions associated with response generation, activity increased with increasing rate but was unaffected by duration; and in regions associated with word recognition, activity decreased with increasing duration. The variable responses of different brain regions illustrate the functional segregation of these regions. Of particular interest was the dissociation between activity in the posterior fusiform gyri and that in the medial lingual gyrus--in the former, activity increased with rate and duration but the latter was unaffected by either variable. This finding suggests that word processing in the lingual gyrus during reading is distinct from that in the posterior fusiform gyri. A further observation was that during reading aloud, when subjects can hear the sound of their own voice, the response in the primary auditory cortices increased with stimulus rate, demonstrating that subjects process the sound of their own voice in a qualitatively similar way to words spoken by another.     

The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy

OBJECTIVE: To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA. DESIGN: Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine]. METHODS: The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k. RESULTS: A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k. CONCLUSIONS: The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.     

The effect of chronic L-dopa administration on supersensitive pre- and postsynaptic dopaminergic receptors in rat brain

Chronic administration of haloperidol induced supersensitivity of the pre- and postsynaptic dopaminergic receptors in rat brain. The response of the presynaptic receptors was determined by an enhanced inhibitory effect of apomorphine on dopamine synthesis after gamma-butyrolactone injection. This change in the receptor function was detected both in the nigrostriatal and mesolimbic pathways. Haloperidol also increased the 3H-spiperone binding sites in striatal membranes, indicating supersensitivity of the postsynaptic receptors. Subsequent prolonged treatment with high doses of L-DOPA/carbidopa resulted in a decrease in 3H-spiperone binding sites, but had no effect on the supersensitive presynaptic receptors. It is suggested that tardive dyskinesia may be a state of both pre- and postsynaptic dopamine receptor supersensitivity and that chronic L-DOPA treatment may have a differential effect on these sites.     

The effect of carotid sinus denervation on fetal heart rate variation in normoxia, hypoxia and post-hypoxia in fetal sheep

BACKGROUND: Previous reports documented high rates of tobacco use among Alaska Natives (Eskimos, Indians, and Aleuts). In this population, tobacco use is the leading preventable cause of death. Lung cancer is the leading cause of cancer death among Alaska Natives and tobacco is responsible for over one-third of all cancer deaths in this population. Until recently there has been no systematic surveillance of the prevalence of tobacco use in this high-risk population. Data that did exist were not readily available to those primarily responsible for the health care of this population. This is the first time since 1990 that data on Alaska Natives have been collected in one analysis; this permits a more representative evaluation of tobacco use. METHODS: Data on tobacco use were obtained and analyzed from national and state surveys and selected research projects from 1988 to 1993. RESULTS: Alaska Natives have high prevalence of tobacco use, including both cigarettes and smokeless tobacco. Tobacco use prevalence among Alaska Natives exceeds that of Alaska non-Natives, U.S. whites, and American Indians/Alaska Natives in the United States outside of Alaska. Smoking prevalence among Alaska Native women is twice that of non-Native women in Alaska and nearly twice as high among pregnant Alaska Natives than pregnant non-Natives. Overall, prevalence of smokeless tobacco use was four times higher among Alaska Natives than comparative state and national populations. CONCLUSION: Because this population has such high rates of tobacco use, it is important to public health that monitoring and educational programs be in place and that data specific to Alaska Natives be made available.     

The effect of propofol on midazolam metabolism in human liver microsome suspension

We have studied the inhibitory effects of propofol on the metabolism of midazolam using human liver microsomes. In addition, we also investigated whether the lipid in which propofol is solubilised inhibits the metabolism of midazolam. Only high concentrations of propofol (> 100 mmol), greater than those found in clinical practice, inhibited the metabolism of midazolam. The lipid had no effect on the metabolism of midazolam. This study differs from other laboratory studies looking at the inhibitory effects of propofol. These showed inhibition at concentrations similar to those seen in patients. The reasons for the differences may be explained by the use of different substrates or methodology. Propofol may be an enzyme inhibitor, but this remains to be shown to be important in patients.     

The effect of propofol on the electroencephalogram of patients with epilepsy

The effect of propofol on the electroencephalogram (EEG) in patients with epilepsy is still unclear. Case reports with electroencephalographic documentation highlight pro- and anticonvulsant effects and beta activation of the EEG. This prospective study sought to determine the effect of propofol in 17 patients undergoing cortical resection for intractable epilepsy. Each patient received 2 mg/kg of propofol intravenously and the EEG was recorded from chronically implanted subdural electrodes placed during a previous craniotomy. Frequency of interictal spikes, time to burst suppression, and appearance of beta activation were recorded. The median frequency of interictal spikes decreased significantly from 2 spikes/min before to 0 spikes/min after propofol (P = 0.001). Seizure activity did not increase after propofol. Profound burst suppression and an increase in beta activity were noted consistently. The use of propofol in patients with epilepsy seems to be safe but may interfere with the recording of EEG spikes.     

Antiemetic effect of propofol

Propofol is known to possess direct antiemetic effects. Its use for induction and maintenance of anaesthesia has been shown to be associated with a lower incidence of postoperative nausea and vomiting (PONV) when compared to any other anaesthetic drug or technique. However, its mechanism of action in this context is still not well understood. In this article, the best ways to take advantage of propofol's antiemetic properties are emphasized. The possible effects of propofol on the cerebral cortex, its interactions with the dopaminergic and the serotoninergic systems are evaluated by the known clinical and basic science results. Finally, the advantages and disadvantages of using propofol to decrease the incidence of PONV in clinical practice are discussed.     

The effect of angiotensin AT1 receptor blockade in the brain on the maintenance of blood pressure during haemorrhage in sheep

The effect of systemic or intracerebroventricular (ICV) infusion of the angiotensin AT1 receptor antagonist losartan on blood pressure during hypotensive haemorrhage was investigated in five conscious sheep. Mean arterial pressure (MAP) was measured during haemorrhage (15 mL kg-1 body wt). Losartan (1 or 0.33 mg h-1) was given to sheep by ICV, intravenous or intracarotid administration, beginning 60 min before and continuing during the haemorrhage. During control infusion of ICV artificial cerebrospinal fluid, MAP was maintained until 13.16 +/- 0.84 mL kg-1 blood loss, when a rapid reduction of at least 15 mmHg in arterial pressure occurred (the decompensation phase). ICV infusion of losartan at 1 mg h-1 caused an early onset of the decompensation phase after only 9.8 +/- 0.8 mL kg-1 of blood loss compared with control. Intravenous infusion of losartan (1 mg h-1) also caused an early onset (P < 0.05) of the decompensation phase at 10.2 +/- 1.0 mL kg-1 blood loss. This dose of losartan inhibited the pressor response to ICV angiotensin II, but not to intravenously administered angiotensin II, indicating that only central AT1 receptors were blocked. Bilateral carotid arterial administration of losartan at 0.33 mg h-1 caused an early onset of the decompensation phase during haemorrhage at 11.06 +/- 0.91 mL kg-1 blood loss (P < 0.05), which did not occur when infused by intravenous or ICV routes. The results indicate that an angiotensin AT1-receptor-mediated mechanism is involved in the maintenance of MAP during haemorrhage in sheep. The locus of this mechanism appears to be the brain.     

The effect of bilateral thoracoplasty on lung development in fetal sheep

The relationship of breathing movements to lung development in the ovine fetus was investigated by partially removing ribs on each side of the chest and closing the deficiencies with silicone membranes at 114 days of gestation; the increase in compliance of the chest wall that resulted caused blunting of the amplitude of phasic negative pressures recorded in the trachea to less than 10 torr. Compared to sham operated controls (n = 5), the lungs of the thoracoplasty group (n = 5) at term weighed significantly (P less than 0.05) less, both wet (1.5 +/- 0.2 v. 2.3 +/- 0.1% of body weight) and dry (0.14 +/- 0.01 v. 0.18 +/- 0.01% of body weight. In addition, DNA content of the thoracoplasty group was less than that of the control group (0.47 +/- 0.05 mg v. 0.72 +/- 0.20 mg). Distensibility of the left lung with air at 40 cmH20 was less than in the thoracoplasty group than in controls (10.0 +/- 2.0 v. 18.9 +/- 3.0 ml.kg-1 body weight) but no differences were found in the concentrations of saturated phosphatidylcholine in lung tissue and lavage fluid, in DNA concentrations or in the amount of lung water (as % of wet weight of lung). It is concluded that phasic negative pressures of normal intensity are necessary for normal development of the fetal lungs.     

The effect of diazoxide on uterine blood flow in pregnant sheep

Diazoxide, a labor inhibiting agent, was administered intravenously at various rates to seven pregnant, near-term sheep to evaluate its effect on cardiovascular and uterine hemodynamics. Uterine blood flow was measured with electromagnetic flow transducers. Rapid administration of diazoxide resulted in a profound maternal tachycardia with hypotension, an increase in uterine vascular resistance, and a significant decrease in uterine blood flow. With slow infusion of the drug, the changes in heart rate and blood pressure were minimized, uterine vascular resistance was decreased, and uterine blood flow was maintained. Therefore, slow infusion appears to be the preferred method for inhibiting labor with diazoxide.     

The effect of solidification rate on microsegregation

An X-ray diffraction technique has been utilized to determine the second phase content and average composition of the primary phase in aluminum-copper and aluminum-silicon alloys solidified at a cooling rate in the range of 0.06 to l0⁵ K/s. For the Al-Cu samples, the normalized Θ phase content (ratio of the 6 content to the value predicted by the Scheil model) was found to be 0.71 at 0.1 K/s (solidification rate = 0.001 cm/s) and to increase with increasing cooling rate to 0.96 at about 180 K/s (1 cm/s). Beyond this cooling rate, it decreased with increasing the cooling rate to 0.44 at about 3.7 x lO4 K/s. The same trend was observed in the Al-Si samples, except that the normalized silicon content was much lower. Also, for both systems the normalized average composition of the primary phase was found to decrease progressively with increasing the solidification rate until it reached a minimum at 1 cm/s, beyond which it increased with higher solidification rates. The results are discussed with respect to the prevailing segregation models that include back-diffusion in the solid, dendrite tip undercooling, and the eutectic temperature depression. An equation which combines these effects at all cooling rates is given.     

The effect of modelling on drinking rate

Interaction between cholesterine and phosphatidilcholines (PC) of three types: 1,2-disaturated (SS), 1,2-diunsaturated (UU) and 1-saturated-2-unsaturated (SU) was studied in bilayer vesicular membranes (BVM) by means of NMR-1H spectroscopy. BVM were obtained by sonification of aqueous (D2O) dispersions of individual (PC) and their mixtures. It is found that molecular special specificity of the interaction between PC AND cholesterine is preserved not only during phase division but also in the case when all the phospholipid components of the bilayer are in a liquid crystal state. At low content of cholesterine it favourably interacts with UU-PC, further on with the increase of concentration cholesterine starts to interact with SU- and SS-types of PC. It has been shown that such behaviour of cholesterine can not be explained by means of static models, i.e. by the differences in stability of its stechiometric complexes with CP molecules of different types. An attempt has been undertaken to interpret the selective character of PS-cholesterine interaction proceeding from the suggestion about the anisotropic character of lateral diffusion in the membranes, consisting of various structural types of PC.     

The effect of dexamethasone administration at different stages of gestation on maternal plasma steroid concentrations in the baboon (Papio cynocephalus)

Dexamethasone administration at different stages of gestation in the baboon was studied for its effect on maternal steroid hormone concentrations. Dexamethasone (2 mg i.m. at 12 h intervals for three doses) was administered at early (days 37-39), mid (days 76-85) or late (days 112-123) gestation and morning blood samples were collected before, during and after dexamethasone suppression for 6 consecutive days. Dexamethasone treatment, at all stages of pregnancy, resulted in a significant decline in maternal serum cortisol concentrations, which rapidly return to normal concentrations after treatment. Progesterone concentrations were not affected by dexamethasone at any stage of gestation. Serum concentrations of oestradiol, testosterone and androstenedione were unchanged following dexamethasone administration in early pregnancy. A trend toward lower serum oestradiol was observed following dexamethasone administration in both mid and late gestation, but this was not significant. Both testosterone and androstenedione were significantly decreased following dexamethasone in both mid and late pregnancy and recovered to pretreatment concentrations within a few days after cessation of treatment. These results confirm other studies which demonstrate that adrenal precursors (maternal or fetal) are a major contributor to maternal serum concentrations of oestradiol. They also demonstrate that these adrenal precursors increase serum concentrations of testosterone and androstenedione in the pregnant baboon. Since these changes are only evident after that time (>40 days) when the fetal adrenal is steroidogenically competent, a role for fetal adrenal involvement in maternal serum androgen concentrations is suggested.     

Effect of stress-like concentrations of cortisol on gonadotroph function in orchidectomized sheep

The effects of the small noncatalytic subunit of myosin light chain phosphatase (MLCPsr) on the Ca2+-induced contraction of smooth muscle were investigated in the Triton X-100-permeabilized porcine renal artery. The full-length recombinant chicken MLCPsr obtained by the bacterial expression system induced an additional contraction at a constant [Ca2+]i and shifted the [Ca2+]i-force relation curve to the left. A deletion mutant containing the N-terminal 78 amino acids of MLCPsr retained the full action, compared with the full-length MLCPsr, while the deletion of this region completely abolished its effect. The process of relaxation was also delayed by the fragment containing the N-terminal 78 amino acids. These results indicated that MLCPsr increases the Ca2+ sensitivity of the contractile apparatus while the N-terminal 78 amino acids are responsible for this effect in vascular smooth muscle.