Rebound hypertension after sodium nitroprusside-induced hypotension.

Patients undergoing surgical procedures using sodium nitroprusside-induced hypotension were studied to determine the role of the renin-angiotensin system in the pathogenesis of rebound hypertension (RH) after discontinuing sodium nitroprusside (SNP) infusion. Retrospective observations documented RH in 9 of 12 patients (group I) with a systolic blood pressure (SBP) increase from 112 +/- 3.92 before SNP to 144 +/- 5.60 torr 10 min after SNP (p less than 0.001). In 12 patients (group II), plasma renin activity (PRA) rose from 950 +/- 432 to 3,611 +/- 1.874 pg/ml/hr (p less than 0.0005) during SNP and remained elevated (2,504 +/- 792 pg/ml/hr) 30 min after cessation of SNP. SBP rose from a control (pre-SNP) value of 112 +/- 5.24 to 129 +/- 8.52 torr after discontinuation of SNP (p less than 0.05). Significant PRA and SBP changes did not occur in a matched group of patients (group III) who did not receive SNP. That RH after cessation of SNP infusion was associated with persistent elevation of PRA leads us to suggest that RH may be attributable to the unopposed effects of the renin-angiotensin system after the rapid plasma disappearance of SNP.

The pattern of memory loss resulting from intravenously administered diazepam.

A word recognition task was designed to determine the stage in memory affected by a single 10-mg intravenous injection of diazepam and the duration of the effect. Injection in three experimental subjects produced an anterograde amnesia for the 14 to 24-minute period immediately after injection. Memory loss resulted from impaired storage, the stage during which information is entered into memory. Retention and retrieval stages of memory were unaffected. This temporary amnesia may result from increased inhibition in the hippocampal system produced by diazepam, which shares many properties with the inhibitory neurotransmitter gamma-aminobutyric acid.

Antinociceptive effects of azepexole (BHT 933) in mice.

Subcutaneous (s.c.) administration of azepexole (BHT 933) at doses between 4 and 40 mg/kg produced dose-dependent antinociceptive effects in mice as assessed by tail-immersion, tail-pinch and acetic acid writhing tests. The ED16s were 5.6 +/- 0.4, 6.7 +/- 1.2 and 2.96 +/- 0.2 mg/kg respectively. Similarly, morphine produced analgesia in the same tests with ED16s of 0.87 +/- 0.03, 0.47 +/- 0.1 and 0.45 +/- 0.01 mg/kg respectively. In all instances naloxone (0.1 mg/kg s.c.) shifted the dose-response curves to morphine to the right in a parallel manner. Naloxone (0.1 and 1 mg/kg s.c.) partially antagonized the effect of azepexole in the tail-immersion and tail-pinch tests but significantly decreased the slope of the dose-response curve suggesting that a competitive interaction at the level of the opioid receptors did not occur. Naloxone had no effect on the antinociceptive action of azepexole in the acetic acid writhing test.

Surface alterations due to endotracheal intubation.

The varied complication of prolonged endotracheal intubation, including tracheal stenosis, stricture and tracheomalacia, are thought to be directly related to lateral tracheal wall pressure. To investigate the initiation, relevance and duration of these changes, studies were undertaken to assess the effects of intubation on the surface anatomy of the trachea by scanning electron microscopy. Tracheal mucosal morphology was studies in (1) anesthetized "normal" dogs; (2) d-ogs sacrificed 2 hours after intubation with cuff deflated or inflated to the "just seal" point using a cuff system producing the lowest tracheal wall pressure; and (3) dogs intubated for 2 hours and then examined at 2 and 7 days after extubation. Intubation without cuff inflation resulted in distinct linear areas of nearly complete ciliary denudation along the tract of tubal insertion within 2 hours. Inflated cuffs produced similar but more widespread changes especially over tracheal rings, indicating that pressure in areas of least resiliency significantly contributes to these alterations. Regeneration of cilia could be seen 2 days after extubation, but many anatomic features remained distorted; at 7 days, regeneration was nearly complete, but isolated areas of denudation could still be identified. Scanning electron micrographs of human tracheas taken at autopsy from patients who had had prolonged intubation with the same cuff system correlated well with those obtained from dogs.

Naloxone elicits an excitatory response in the morphine-tolerant mouse vas deferens.

The effects of naloxone on the electrically stimulated vas deferens from mice implanted with morphine (tolerant) or placebo (naive) pellets were studied. In tolerant vas deferens, naloxone produced an 86.6% increase of the twitch contractions when the preparations were stimulated with 15 V, while only a 12% increase was observed with supramaximal voltage (40 V). Naloxone had no effect at either voltage in preparations from naive animals. The effect of morphine in naive vas deferens stimulated with 15 V, was reversed by naloxone without further increase over baseline contractions. The results suggest that opioid receptors other than those located in the neuronal soma and/or coupled to adenylate cyclase may be involved in the development of dependence.

Effect of cocaine on macromolecular syntheses and cell proliferation in cultured glial cells.

In the present study the effect of cocaine on thymidine, uridine and leucine incorporation was assessed in primary cortical glial and C6 glioma cells. Cocaine exposure for 24 h inhibited thymidine and uridine incorporation in cortical glial and C6 glioma cells. However, the effect of cocaine on uridine incorporation was less prominent compared to thymidine incorporation. High concentrations of cocaine inhibited leucine incorporation in C6 glioma cells but not in cortical glia. Cocaine exposure for four days decreased cell proliferation of cortical glial and C6 glioma cells. Cocaine-induced attenuation of macromolecular syntheses was not due to cell death since cocaine-treated cells were not stained with Trypan Blue and did not release lactate dehydrogenase into culture supernatants. Furthermore, cocaine had no effect on glutamate uptake either in cortical glia or in C6 glioma cells. These results indicate that cocaine inhibits macromolecular syntheses in glial cells. The inhibition of macromolecular syntheses in glial cells may be the mechanism involved in cocaine-induced fetal brain growth retardation.

Guidelines for the treatment of acidaemia with THAM.

THAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37 degrees C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia. THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function. Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein: THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration. The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows: THAM (ml of 0.3 mol/L solution) = lean body-weight (kg) x base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient). When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH < or = 7.20), the use of THAM within a 'therapeutic window' is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi. THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose.

Effect of intrathecally administered local anesthetics on protein phosphorylation in the spinal cord.

To elucidate the biochemical mechanisms of spinal anesthesia, we studied the effects of procaine and tetracaine on protein phosphorylation in the mouse spinal cord. Mice were injected intrathecally with either procaine, tetracaine (67 mM/approximately 2%, 10 microL, N = 5/drug), or saline (N = 4/group). Five minutes after injection, animals were killed with a guillotine, and the spinal cord was removed. The caudal 3-cm cord segment was homogenized and centrifuged, and an aliquot of the supernatant was used for phosphorylation assays. Calcium-dependent phosphorylation was initiated by incubating the samples in buffer containing [gamma-32P]ATP at 37 degrees for 30 min. The proteins were electrophoresed using slab gel and two-dimensional electrophoresis, and phosphorylated proteins were visualized by autoradiography. The data demonstrated that spinal anesthesia changes the phosphorylation state of five endogenous substrate proteins with apparent molecular masses of 130 (protein-a), 105 (protein-b), 55 (protein-c), 47 (protein-d), and 33 (protein-e) kDa. In two-dimensional electrophoresis, protein-a resolved into two proteins (a1 and a2). Analysis of variance of the densitometric data suggested a significant effect for the treatment (F(2,16) 735, P < 0.00005). Post hoc comparisons with the saline-treated controls, using the Newman-Keuls test, indicated that local anesthetics significantly affected phosphoproteins (P < 0.05) except for protein-al in the tetracaine-treated group. Further characterization of these phosphoproteins should aid in determining their role in the signal transduction cascade affected by spinal anesthesia.

Urine and serum potassium levels after potassium cardioplegia.

Potassium cardioplegia for myocardial preservation is being used extensively in heart operations. This study was designed to determine the effect of potassium cardioplegia on serum and urine potassium levels. A control group of 11 patients was compared to a study group of 24 patients. Myocardial preservation in the control group was achieved by whole body cooling to 20 degrees to 30 degrees C and in the study group, by repeated injections every 30 minutes of 500 to 700 ml of cold pump blood, containing potassium chloride 30 mEq/L, into the aortic root after aortic clamping. Total potassium dose in the study group was 46 +/- 21 mEq (mean +/- SD). Mean serum potassium level was significantly higher during and after bypass in the study group (after bypass: control 3.65 +/- 0.11 mEq/L, study 4.24 +/- 0.10 mEq/L [mean +/- SE], p less than 0.005), but was within normal limits in both groups. Urine potassium levels and excretion rates were significantly higher in the study group (potassium excretion rate after bypass: control 6.1 +/- 0.7 mEq/hr, study 11.3 +/- 0.9 mEq/hr [mean +/- SE], p less than 0.0025). We conclude that no special measures are required to facilitate potassium excretion when total potassium cardioplegia dose is not greater than 50 mEq.

Viral inclusion bodies in tracheobronchial epithelium of asymptomatic subjects.

During a survey conducted for the cytodiagnosis of early bronchogenic carcinoma, cytoplasmic viral inclusion bodies were found sporadically in tracheobronchial smears of asymtomatic patients of both sexes (ages ranging from 18 to 80 years) undergoing general endotracheal anesthesia for surgery. A review of 3,049 cases performed to assess the frequency of occurrence of this phenomenon showed a 1.1 percent incidence in all smears studied. There was no relationship between smoking habit, age, or sex and the presence of inclusion bodies; however, there was a marked seasonal incidence, with 60 percent of inclusion-bearing smears being found during the months of January through March.

Intracuff pressures in endotracheal and tracheostomy tubes. Related cuff physical characteristics.

This study compared intracuff pressure (ICP) during mechanical ventilation in a variety of currently used endotracheal (ET) and tracheostomy (trach) tube cuffs and related cuff physical characteristics. Tracheostomy tube physical characteristics were also measured. Variation was observed to exist between "just-seal" inspiratory and end-expiratory intracuff pressure during mechanical ventilation. Cuff diameter, thickness, compliance, geometry (shape), resting volume, and just-seal volume also varied. ICP varied with cuff diameter, thickness, compliance, geometry (shape), and trachea size, as well as tube curve and cuff position in the trachea. Thin, large-diameter, compliant cuffs generally "just seal" with relatively low ICPs. We recommend use of tracheal airways (endotracheal and tracheostomy) fitted with cuffs that seal in patients with low intracuff pressures. We also recommend nonrigid (soft) thermolabile tracheostomy tubes.

The hyperalgesic effect of naloxone is attenuated in streptozotocin-diabetic mice.

In mice with streptozotocin-induced hyperglycemia, nociception was tested after naloxone administration in hot plate and tail immersion tests. The choice of these two tests was to include a supra-spinal nociceptive reflex indicative of higher cognitive process (hot-plate test) as well as a reflex which predominantly represents lower spinal motor mechanisms (tail immersion test). Naloxone-induced hyperalgesia was attenuated in both tests in mice with streptozotocin-induced diabetes. In mice with hyperglycemia induced by intraperitoneal dextrose administration, naloxone hyperalgesia was significantly enhanced in the hot plate test. The basal nociceptive threshold in streptozotocin-treated animals was decreased in the immersion but not in the hot plate test. These results indicate that hyperglycemia per se does not adequately explain the changes in naloxone hyperalgesia in experimental models of diabetes. They also suggest that acute hyperglycemia may modify the interaction of endogenous opioid peptides with their receptors only at supra-spinal sites. However, chronic hyperglycemia appears to affect endogenous opioid peptides both at spinal and supra-spinal levels and their interaction with the opiate receptors.

Hand-held toy squeaker during carotid endarterectomy in the awake patient.

A toy squeaker held by the patient in the contralateral hand is used to monitor cerebral circulation during carotid endarterectomy. Regional anesthesia--cervical plexus block--allowed the patient to cooperate and give useful information, especially during the crucial period of test clamping. In a series of 300 cases, during a period of five years, it was instrumental in avoiding brain damage in 6% of the cases.

Influence of hypo and hyperthermia on disposition of morphine.

Using morphine as a prototype opiate anesthetic, the dispositional changes and cardiovascular effects during hypothermia (30 degrees C) and hyperthermia (40 degrees C) in dogs under isoflurane anesthesia was assessed. Single intravenous bolus injection of 1 mg/kg morphine resulted in a significant and sustained decrease in mean arterial pressure in hypothermic, but not in hyperthermic or normothermic (37 degrees C) conditions. Hypothermic dogs showed significantly higher levels of morphine both in plasma and in cerebrospinal fluid. In contrast, hyperthermia did not affect these levels. Body temperature did not affect the t1/2 alpha, however t1/2 beta and mean residence time were significantly increased while volume of distribution at steady state and total body clearance were decreased during hypothermia. The results provide evidence that hypothermia is likely to be associated with a sustained increase in opiate levels and might be associated with a enhanced side effects. The results suggests the need for a controlled clinical trial to assess the dose of opiate anesthetics during hypothermia.

Effect of nitric oxide on mitogenesis and proliferation of cerebellar glial cells.

In the brain, nitric oxide (NO) has been identified as a messenger molecule and a mediator of excitatory amino acid-induced neurotoxicity. In this study, the effects of NO on serum-induced mitogenesis and cell proliferation of the cerebellar glial cells were assessed. NO-generating agent, S-nitroso-N-acetylpenicillamine (SNAP) increased intracellular cyclic guanosine monophosphate (cGMP) levels. Furthermore, 2 chemically dissimilar NO-generating agents, SNAP and sodium nitroprusside (SNP) inhibited serum-induced thymidine incorporation and cell proliferation. The antimitogenic effect of NO was mimicked by 8-bromo-cGMP and blocked by hemoglobin, a known inhibitor of NO. The effect of NO was not cytotoxic, since the cells were not stained with Trypan blue and did not show increased release of lactate dehydrogenase in the culture supernatants. However, NO-treated cells showed decreased conversion of tetrazolium to blue formazan suggesting that NO inhibited mitochondrial activity in the glial cells. These results demonstrate that NO inhibits serum-induced mitogenesis and cell proliferation of cultured rat cerebellar glial cells.

Pertussis and cholera toxins modulate kappa-opioid receptor agonists-induced hypothermia and gut inhibition.

In mice pretreated intracerebroventricularly (i.c.v.) with either saline (10 microliters/mouse), pertussis (1 microgram/mouse) or cholera (2.5 micrograms/mouse) toxins, effect of kappa-opioid receptor agonists on the colonic temperature and charcoal meal transit time were assessed. The kappa-opioid receptor agonist, trans-(+)-3,4-dichloro-N-methyl-[2-(1- pyrrolidinyl)cyclohexyl]-benzeneacetamide methane sulfonate hydrate (U-50488H, 50, 100 and 200 micrograms/mouse, i.c.v.) produced dose dependent hypothermia. Pertussis toxin pretreatment (72 and/or 144 h before) antagonized (P < 0.05) the hypothermic effect of U-50488H (100 micrograms/mouse) and (+)-trans-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl[benz[b]-thio-phene-4-acetamide (PD 117302, 30 micrograms/mouse). In contrast, cholera toxin pretreatment (48 and/or 96 h before) did not antagonize the hypothermic effect of the kappa-opioid receptor agonists. Moreover, both i.c.v. and intrathecal (i.t.) administration of kappa-opioid receptor agonists, U-50488H, }[5R-(5 alpha,7 alpha,8 beta)]-(+/-)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-benzeneacetamide¿ (U-69593) and PD 117302, produced dose dependent inhibition of the charcoal meal transit. Cholera toxin pretreatment (48 and 96 h before) augmented (P < 0.05) the antitransit effect of i.c.v. administered U-50488H (100 micrograms/mouse), U-69593 (100 micrograms/mouse) and PD 117302 (50 micrograms/mouse). However, pertussis toxin pretreatment did not affect the gastrointestinal inhibitory effect of the kappa-opioid receptor agonists. The present results extend our previous results on the effect of kappa-selective agonists on gastrointestinal motility and indicate, like the prototype opiate agonist morphine, kappa-opioid receptor agonists are effective in inhibiting the gastrointestinal motility when administered either by intrathecal or intracerebroventricular routes.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereospecific inhibition of gastrointestinal transit by kappa opioid agonists in mice.

Systemic administration of highly selective kappa opiate agonists, U-50488H and U-69593 (3, 10 and 30 mg/kg i.p.) produced significant inhibition of the gastrointestinal transit in mice as assessed by charcoal meal test. In contrast, the (+) stereoisomer of U-50488H, U-53455E did not inhibit the gastrointestinal motility. Furthermore, the kappa-selective antagonist, Mr 2266 (3 mg/kg) when administered along with the agonists, reversed the effects of the agonists. These results suggest that stereospecific kappa opiate receptors are involved in inhibition of gut motility in mice.

Effects of the benzomorphan kappa-opiate, MR 2266 and its (+) enantiomer MR 2267, on thermonociceptive reactions in different strains of mice.

The effects of the benzomorphan kappa opiate MR 2266 and its dextro enantiomer MR 2267 were assessed on thermonociception in Swiss Webster, C57BL/6, BALB/c and DBA/2 strains of mice. In the hot plate (60 +/- 0.5 degrees C, cut-off time 120 s and tail immersion tests, MR 2266 (10 mg/kg, s.c., 15 min before) decreased, while MR 2267 (10 mg/kg s.c., 15 min before) increased the reaction latencies. In the hot plate test, the sensitivities for the effects of MR 2266 and MR 2267 on jump latency in different strains of mice were as follows: MR 2266; BALB greater than Swiss greater than C57BL greater than DBA and MR 2267; DBA greater than BALB = Swiss greater than C57BL. In the immersion test, for the hyperalgesic response of MR 2266, the rank order of strains was; BALB greater than C57BL and DBA greater than or equal to Swiss while the rank order for the analgesic effect of MR 2267 was; Swiss greater than DBA and BALB. The results indicate the presence of tonic kappa-receptor-mediated regulation of the spinal and supra-spinal thermonociceptive reactions which is stereospecific and strain dependent.

Intracerebroventricular administration of kappa-agonists induces convulsions in mice.

Intracerebroventricular (ICV) administration of kappa-agonists (PD 117302, U-50488H and U-69593) induced convulsions in a dose-related manner in mice. The dose at which 50% of animals convulsed (CD50) was in nmol ranges for all opioids. Among the opioids used, PD 117302 was the most potent convulsant. ICV administration of either vehicle alone or U-53445E, a non-kappa-opioid (+) enantiomer of U-50488H did not induce convulsions. The convulsive response of kappa-agonists was differentially susceptible for antagonism by naloxone and/or MR 2266. Collectively, these findings support the view that convulsions induced by kappa-agonists in mice involve stereospecific opioid receptor mechanisms. Furthermore, the convulsant effect of kappa-agonists could not be modified by pretreatment with MK-801, ketamine, muscimol or baclofen. It is concluded that kappa-opioid but not NMDA or GABA receptor mechanisms are involved in convulsions induced by kappa-agonists. These results are the first experimental evidence implicating stereospecific kappa-receptor mechanisms in opioid-induced convulsions in mice.

Methodological variables during analysis of in vivo cerebellar cyclic GMP, an indirect marker of nitric oxide release.

In light of the recent recognition of the physiological significance of nitric oxide, there is considerable interest in the methodological variables that can confound the results of the cerebellar cGMP analysis from in vivo experiments. In this study, using male Swiss Webster mice, the effect of such methodological variables as 1) weight of the animals; 2) tissue extraction procedures used in radioimmunoassay for cGMP; and 3) the commercial source of the assay kit on, harmaline-, pentylenetetrazole- or SNAP-induced increase in cerebellar cGMP in vivo were evaluated. Results indicate that mice in the 15- to 19-g weight range are most sensitive and best suited for in vivo drug effects on cerebellar cGMP. Furthermore, for the extraction of cerebellar cGMP, use of ice-cold 0.5N hydrochloric acid and subsequent dilution of the sample in assay buffer is the simplest and fastest method. Present data also indicate that the source of the radioimmunoassay kit has a significant effect on the cerebellar cGMP results. Based on the present results, the protocol developed and the guidelines drawn are timely and of high practical significance for research in the area of pharmacology of nitric oxide.