Specific effects of drugs at pressure: animal investigations

The interactions of anaesthetics and other drugs with high pressure suggest that protection against the high pressure neurological syndrome (h.p.n.s.) can no longer be considered in terms of generalized non-specific mechanisms. The evidence from our work shows that anaesthetics may either protect, have no effect, or potentiate h.p.n.s. Structural analogues of the steroid anaesthetic Althesin have a protective effect against high pressure tremors in spite of the fact that they have no anaesthetic effects. Low doses of flurazepam are effective against tremor but can be antagonized by Ro 15-1788, which implies in this case a role for the benzodiazepine receptor complex. Pressure interactions with other drugs have included the classic anticonvulsants--which, in general, were relatively ineffective--and various agents perturbing the balance of specific neurotransmitter systems. Representative examples from different studies include 6-hydroxydopamine, muscimol, and sodium valproate. Finally, the potent protection against h.p.n.s. by 2-amino-phosphonoheptanoic acid, an antagonist with preferential action against excitation produced by aspartate and N-methyl-D-aspartate, provides the first evidence that enhanced excitatory amino acid neurotransmission may have an important role in the h.p.n.s.     

Metoclopramide-induced central nervous system depression in the chicken

Background

Metoclopramide is a dopamine D2-receptor antagonist used as an antiemetic and gastroprokinetic agent in man and animals. The drug causes sedation as a side effect in man. Such a sedative action of metoclopramide has not been documented in the chicken as the drug is not used clinically in this species. The present study examines the central nervous system depressant effects of metoclopramide in 7–14 days old broiler chicks.

Results

Injection of metoclopramide at 50, 100 and 200 mg/kg, subcutaneously (s.c.) induced sedation in the chicks in a dose dependent manner. The chicks manifested, within 3.6–19 minutes of metoclopramide injection, signs of sedation characterized by drooping of the head and wings, closed eyelids, reduced motility and decreased distress calls. The duration of sedation ranged between 37.2 to 163.4 minutes. Metoclopramide at 100 and 200 mg/kg induced, within 12.2 and 6.2 minutes, sleep (loss of righting reflex) for 43.8 and 158.6 minutes, respectively. The median effective doses of metoclopramide for induction of sedation and sleep in the chicks were 11 and 53 mg/kg, s.c., respectively. Lower doses of metoclopramide (5 and 10 mg/kg, s.c.) significantly decreased the open-field activity of the chicks and increased the durations of their tonic immobility. All treated-chicks recovered from the central nervous system depressant effect of metoclopramide without any observable adverse effects.

Conclusion

The data suggest that metoclopramide induces central nervous system depression in chicks, and the drug could have potential clinical applications as a sedative-hypnotic agent in avian species not intended for human consumptions.     

Vasopressin pressor antagonist injected centrally reverses behavioral effects of peripheral injection of vasopressin, but only at doses that reverse increase in blood pressure

Previous work in rats (Ader, R. and De Wied, D., Psychon. Sci., 29 (1972) 46-48) has established that subcutaneously (s.c.) injected arginine vasopressin (AVP) prolongs extinction of active avoidance and that this effect could be prevented by pretreatment with the vasopressin antagonist analog [1-deaminopenicillamine, 2-(O-methyl)tyrosine]-beta-arginine vasopressin (dPtyr(Me)AVP). The purpose of the present study was to determine if peripherally administered AVP acts via a peripheral blood pressure effect or by a direct action in the central nervous system. We therefore tested the effects of the antagonist injected intracerebroventricularly (i.c.v.) on the prolongation of active avoidance and on blood pressure effects of s.c. injected AVP. The antagonist (i.c.v.) blocked the behavioral effects of systemically injected AVP only at dose sufficient to block the peripherally mediated pressor response of systemically administered AVP. The results show that peripherally injected AVP acts on peripheral systems and support our hypothesis that the peripheral visceral action of AVP contributed significantly to its behavioral action.     

Possible involvement of 5-HT and 5-HT2 receptors in acceleration of gastrointestinal transit by escin Ib in mice

We have reported previously that escin Ib accelerated gastrointestinal transit (GIT) in mice, and that its effect may be mediated by the release of endogenous prostaglandins (PGs) and nitric oxide (NO). In this study, the possible involvement of 5-HT and 5-HT receptors in the GIT acceleration of escin Ib was investigated in mice. The acceleration of GIT by escin Ib (25 or 50 mg/kg, p.o.) was attenuated by pretreatment with ritanserin (0.5-5 mg/kg, s.c., a 5-HT(2A/2C/2B) receptor antagonist), but not with MDL 72222 (1 and 5 mg/kg, s.c.) and metoclopramide (10 mg/kg, s.c.) (5-HT3 receptor antagonists) or tropisetron (1 and 10 mg/kg, s.c., a 5-HT(3/4) receptor antagonist). Furthermore, pretreatment with ketanserin (0.05-5 mg/kg, s.c.), haloperidol (1-5 mg/kg, s.c.) and spiperone (0.5-5 mg/kg, s.c.) (5-HT2A receptor antagonists), as well as a bolus of dl-p-chlorophenylalanine methyl ester (PCPA, 1000 mg/kg, p.o., 1, 6 or 24 h before administration of the sample) (an inhibitor of 5-HT synthesizing enzyme tryptophan hydroxylase) and reserpine (5 mg/kg, p.o.) (a 5-HT depletor), but not 6-hydroxydopamine (80 mg/kg, i.p., a dopamine depletor) or repeated PCPA (300 mg/kg x2, p.o., 72 and 48 h before administration of the sample), also attenuated the effects of escin Ib. It is postulated that escin Ib accelerates GIT, at least in part, by stimulating the synthesis of 5-HT to act through 5-HT2, possibly 5-HT2A receptors, which in turn causes the release of NO and PGs.     

Inhibition of locus coeruleus neuronal activity by beta-phenylethylamine

The effect of beta-phenylethylamine (PEA) on brain noradrenaline (NA) neurons in the rat locus coeruleus (LC) was analyzed using single unit recording techniques including microiontophoretic methodology. Systemic injection of low doses of PEA consistently produced an instantaneous and dose-dependent inhibition of firing rate of the LC neurons. The effect was strongly antagonized by administration of the alpha 2-receptor antagonist yohimbine (1 mg/kg, i.v.) or by depletion of endogenous stores of NA by pretreatment with reserpine (10 mg/kg, i.p., 6 h), but unaffected by inhibition of tyrosine hydroxylase (alpha-met-hyl-p-tyrosine (alpha-MT), 250 mg/kg, i.p., 30 min). In contrast, the inhibitory effect of PEA on the LC neurons was strongly potentiated by pretreatment with the selective monoamine oxidase (MAO) - B inhibitor pargyline (2 mg/kg, i.p., 1 h), but, unexpectedly, also by pretreatment with the MAO-A selective inhibitors clorgyline (2 mg/kg, i.p., 1 h) or FLA 336 (2 mg/kg, i.p., 1 h). When microiontophoretically applied directly onto the LC neurons, PEA produced inhibition of a majority of the NA neurons. This action was prevented by intravenous injection of yohimbine (2.5 mg/kg). The results suggests that the action of PEA on NA neurons in the LC is an indirect effect, requiring availability of a reserpine-sensitive storage pool of NA, and mediated via activation of central alpha 2-receptors within the LC.     

Roles of neuropeptides in O,O,S-trimethylphosphorothioate (OOS-TMP)-induced anorexia in mice

O,O,S-Trimethylphosphorothioate (OOS-TMP), an impurity present in various organophosphorus insecticides, has previously been shown to induce hypophagia. The major goal of this study was to investigate its mechanism of action. Both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injection transiently induced hypophagia at a dose of 5mg/kg within 6h, without causing lung injury. Hypophagia was accompanied by up-regulation of corticotropin releasing factor (CRF) (2.92+/-0.45 vs. 1.7+/-0.5, at 2h after i.c.v., 3.40+/-1.38 vs. 1.76+/-0.41 at 6h after i.p., P<0.05) in the hypothalamus. After i.c.v. injection, hypophagia recovered by 6h after dosing. At doses higher than 5mg/kg, i.c.v. injection induced continuous hypophagia from 20min to 72h after dosing, accompanied by hypothermia and lung injury. OOS-TMP was considered to induce hypophagia through enhancing expression of CRF.     

Effect of aldosterone antagonists on aldosterone-induced activation of Mg2+ -HCO3- -ATPase and carbonic anhydrase in rat intestinal mucosa

In previous studies, Mg2+ -dependent, HCO3- -activated ATPase in the brush border and carbonic anhydrase in the cytoplasm of rat duodenal and jejunal mucosa decreased after adrenalectomy. Both enzyme activities increased to near normal levels 4 h after i.p. injection of aldosterone (40 micrograms/kg). These results suggest the possibility that both enzymes in the small intestinal mucosa may be mediators of the action of aldosterone. In the present studies, therefore, the effects of actinomycin D (500 micrograms/kg, i.p.), spironolactone (50 mg/kg, s.c.) and potassium canrenoate (50 mg/kg, s.c.) on aldosterone-induced activation of both enzymes in the upper small intestinal mucosa from adrenalectomized rats were examined to clarify the mechanism of action of aldosterone in enzyme levels. Actinomycin D inhibited carbonic anhydrase activity in small intestinal mucosa from normal rats 4 h after i.p. injection but had no effect on ATPase activity, while two other drugs had no effect on either enzyme activity in normal rats up to 4 h later. Pretreatment with these 3 drugs 1 h before aldosterone administration (40 micrograms/kg, i.p.) to adrenalectomized rats blocked the aldosterone-induced activation of ATPase and carbonic anhydrase in the upper small intestine. On the other hand, adrenalectomy and administration of aldosterone and its antagonists, alone or in combination, had no effect on kidney enzyme activities. These results confirm that Mg2+ -HCO3- -ATPase and carbonic anhydrase are mediators of the action of aldosterone in the upper small intestinal mucosa.     

Possible involvement of dopamine and dopamine2 receptors in the inhibitions of gastric emptying by escin Ib in mice

It was previously reported that escin Ib isolated from horse chestnut inhibited gastric emptying (GE) in mice, in which the capsaicin-sensitive sensory nerves (CPSN), the central nervous system and endogenous prostaglandins (PGs) were involved. In the present study, the possible involvement of dopamine and dopamine receptors in the inhibition of GE by escin Ib were investigated in mice. GE inhibition by escin Ib (25 mg/kg, p.o.) was attenuated after pretreatment with a single bolus of DL-alpha-methyl-p-tyrosine methyl ester (400 mg/kg, s.c., an inhibitor of tyrosine hydroxylase), reserpine (5 mg/kg, p.o., a catecholamine depletor), 6-hydroxydopamine (80 mg/kg, i.p., a dopamine depletor). Furthermore, pretreatment with spiperone (0.5-5 mg/kg, s.c., a dopamine2 receptor antagonist), haloperidol (0.5-10 mg/kg, s.c.) and metoclopramide (1-10 mg/kg, s.c.) (centrally acting dopamine2 receptor antagonists) attenuated the effect of escin Ib. Domperidone (0.1-5 mg/kg, s.c., a peripheral-acting dopamine2 antagonist) showed a weak attenuation, but SCH 23390 (1-5 mg/kg, s.c., a dopamine, receptor antagonist) did not. It is postulated that escin Ib inhibits GE, at least in part, mediated by CPSN, to stimulate the synthesis and/or release of dopamine, to act through central dopamine2 receptor, which in turn causes the release of PGs.     

Perioperative Use of Clevidipine: A Systematic Review and Meta-Analysis

Background

Clevidipine is an ultrashort-acting drug for rapid reduction of blood pressure by selectively acting on the L-type Ca2+ channels on arteriolar smooth muscle. The drug’s ultrashort action in reducing the blood pressure is due to its rapid hydrolysis by blood and extravascular tissue esterases, which does not depend on hepato-renal metabolism and excretion. An analysis of the perioperative management of blood pressure should be considered to compare with other intravenous antihypertensive agents.

Methods

Analyses of the available evidence in randomized clinical trials following the PRISMA methodology as well as clinical significance according to the GRADE system were conducted. Placebo versus other antihypertensive drugs studies were included. Statistical assessments were done using the X2 and I2 tests.

Results

Clevidipine was more effective in maintaining the blood pressure within pre-specified ranges compared with other antihypertensive drugs (MD, -17.87 CI 95%: -29.02 to -6.72; p = 0.02). The use of Clevidipine versus placebo and rescue antihypertensive intravenous drug showed a clear reduction in rates of treatment failure (RR 0.10; IC 95%; 0.05–0.18; p <0.0001). There was no difference in the incidence of adverse events compared with placebo (RR 1.47; 95% CI 0.89 to 2.43, p = 0.14) and with other antihypertensive drugs (RR 0.78, 95% CI 0.45 to 1.35; p = 0.37). In addition, there was no difference in the incidence of atrial fibrillation (AF) between clevidipine and control groups (RR 1.09, IC del 95%: 0.65 a 1.83; p = 0.73).

Conclusions

Clevidipine is an ultrafast-acting drug that is highly effective for management of perioperative arterial hypertension. It is devoid of adverse effects associated with the use of other IV antihypertensives. Its favorable pharmacodynamic and pharmacokinetic properties make clevidipine the drug of choice for the management of acute perioperative hypertension. It is important to emphasize the need for further studies with a larger number of patients to confirm these findings and increase the degree of evidence.     

The anatomy of neurosecretory neurones in the pond snail Lymnaea stagnalis (L.).

The anatomy of three neurosecretory cell types in the central nervous system (c.n.s.) of the gastropod mollusc Lymnaea stagnalis (L.)- the Dark Green Cells, Yellow Cells and Yellow-green Cells-has been studied by using bright and dark field illumination of material stained for neurosecretion by the Alcian Blue-Alcian Yellow technique. The neuronal geometry of single and groups of neurosecretory cells of the various types has been reconstructed from serial sections, and the likely destination of most of their processes has been determined. Dark Green Cells are monopolar, occur exclusively within the central nervous system (c.n.s.), have few or no branches terminating in neuropile, and send axons to the surface of the pleuro-parietal and pleuro-cerebral connectives. The majority of Dark Green Cell axons however (80-85%), project down nerves which innervate ventral and anterior parts of the head-foot, the neck and the mantle. Dark Green Cell axons can be found in small nerves throughout these areas, and may terminate in a find plexus of axons on the surfaces of the nerves. Since previous experimental work has shown that the Dark Green Cells are involved in osmotic or ionic regulation, these results suggest that the target organ of the Dark Green Cells may be the skin. Yellow Cells occur both within and outside the c.n.s. They are usually monopolar, but can be bipolar. They have several axons which normally arise separately from a single pole of the cell body, or close to it. One or more processes leave the cell proximal to the point where separate axons arise, and may run unbranched for some distance through neuropile before terminating in fine brances and blobs of various sizes. These branches may release hormone inside the c.n.s. Yellow-green Cells are mono-, bi- or multi-polar, and like the Yellow Cells are found both within and outside the c.n.s. Some Yellow-green Cells, though not all, have projections which terminate in neuropile in fine branches and blobs. Yellow-green Cell bodies which occur in nerves can project back along the nerve into the c.n.s. The axons of Yellow Cells and Yellow-green Cells project to release sites in various ways. Some project into the connective tissue shealth of the c.n.s., which serves as a neurohaemal organ, either directly through the surface of a ganglion, or from the pleuro-cerebral or pleuro-parietal connectives. Other axons leave the c.n.s. via nerves leaving the left and right parietal and visceral ganglia; projections into the intestinal, anal, and internal right parietal nerves being most numerous. Axons which may be from either, or both Yellow Cells and Yellow-green Cells, can be found along the entire unbranched lengths of these nerves, and in subsequent branches which innervate organs lying in the anterior turn of the shell. All of these orgnas are closely associated with the lung cavity...     

Changes induced in adrenergic lipolysis by the administration of diethylstilboestrol, oestradiol and clomiphene

The authors studied changes in adrenergic lipolysis in the epididymal adipose tissue of rats to which diethylstilboestrol and oestradiol combined with the anti-oestrogen clomiphene were administered. The maximum lipid-mobilizing effect of isoprenaline was increased not only by subcutaneously administered diethylstilboestrol, but also by the highest dose of the antioestrogen clomiphene used (p.o., 200 micrograms.kg-1 b.w.). Under the given experimental conditions, with 4 1/2 h incubation of adipose tissue, clomiphene was also effective when added in vitro. Its own oestrogenic effect probably stimulated the lipid-mobilizing action of isoprenaline. On combining the administration of increasing doses of clomiphene (p.o., 1-5 days) with a constant dose of oestradiol (200 micrograms.kg-1, s.c. on the 8th day, i.e. 24 h before the actual experiment), changes in isoprenaline lipolysis depended on the dose of clomiphene. In low doses clomiphene inhibited the stimulating effect of subsequently administered oestradiol on isoprenaline-induced lipolysis, but in large doses (100 and 200 micrograms.kg-1 daily) it potentiated, together with oestradiol, the lipid-mobilizing effect of isoprenaline. The results show that the non-steroid oestrogen diethylstilboestrol and the antioestrogen clomiphene may be included among the hormones capable of altering the response of adipose tissue to sympathomimetics (isoprenaline). We attribute the fact that clomiphene acted either as an antagonist or as an agonist of oestradiol to its combined oestrogenic and anti-oestrogenic effects.     

Pharmacological characterisation of anti-inflammatory compounds in acute and chronic mouse models of cigarette smoke-induced inflammation

Background

Candidate compounds being developed to treat chronic obstructive pulmonary disease are typically assessed using either acute or chronic mouse smoking models; however, in both systems compounds have almost always been administered prophylactically. Our aim was to determine whether the prophylactic effects of reference anti-inflammatory compounds in acute mouse smoking models reflected their therapeutic effects in (more clinically relevant) chronic systems.

Methods

To do this, we started by examining the type of inflammatory cell infiltrate which occurred after acute (3 days) or chronic (12 weeks) cigarette smoke exposure (CSE) using female, C57BL/6 mice (n = 7-10). To compare the effects of anti-inflammatory compounds in these models, mice were exposed to either 3 days of CSE concomitant with compound dosing or 14 weeks of CSE with dosing beginning after week 12. Budesonide (1 mg kg^-1; i.n., q.d.), roflumilast (3 mg kg^-1; p.o., q.d.) and fluvastatin (2 mg kg^-1; p.o., b.i.d.) were dosed 1 h before (and 5 h after for fluvastatin) CSE. These dose levels were selected because they have previously been shown to be efficacious in mouse models of lung inflammation. Bronchoalveolar lavage fluid (BALF) leukocyte number was the primary endpoint in both models as this is also a primary endpoint in early clinical studies.

Results

To start, we confirmed that the inflammatory phenotypes were different after acute (3 days) versus chronic (12 weeks) CSE. The inflammation in the acute systems was predominantly neutrophilic, while in the more chronic CSE systems BALF neutrophils (PMNs), macrophage and lymphocyte numbers were all increased (p < 0.05). In the acute model, both roflumilast and fluvastatin reduced BALF PMNs (p < 0.01) after 3 days of CSE, while budesonide had no effect on BALF PMNs. In the chronic model, therapeutically administered fluvastatin reduced the numbers of PMNs and macrophages in the BALF (p ≤ 0.05), while budesonide had no effect on PMN or macrophage numbers, but did reduce BALF lymphocytes (p < 0.01). Roflumilast''s inhibitory effects on inflammatory cell infiltrate were not statistically significant.

Conclusions

These results demonstrate that the acute, prophylactic systems can be used to identify compounds with therapeutic potential, but may not predict a compound''s efficacy in chronic smoke exposure models.     

Novel 8 alpha-ergolines with inhibitory and stimulatory effects on prolactin secretion in rats

Four derivatives of the ergot dopamine (DA) agonist lisuride (LIS), namely 6-n-propyl-lisuride (6-n-propyl-LIS), transdihydrolisuride (TDHL), 6-n-propyl-transdi-hydrolisuride (6-n-propyl-TDHL) and 2-bromolisuride (2-Br-LIS) were investigated in female rats with regard to their influence on hyperprolactinaemia induced by pretreatment with reserpine (2 mg/kg i.p., 24 h) at various intervals following their subcutaneous or oral administration (0.05 mg/kg). Two hours after administration, LIS, 6-n-propyl-LIS, and 6-n-propyl-TDHL caused a statistically significant inhibition of reserpine-induced hyperprolactinaemia of about the same extent. Eight hours after administration 6-n-propyl-LIS and 6-n-propyl-TDHL were as active as after 2 h in inhibiting prolactin (PRL) secretion whereas LIS was almost ineffective in this respect. TDHL caused a statistically significant inhibition of PRL secretion at 2 and 8 h after oral administration; this effect was less pronounced after s.c. administration. In contrast to the aforementioned derivatives 2-Br-LIS further increased the reserpine-induced hyperprolactinaemia. In normal male rats pretreatment with 2-Br-LIS (0.025-6.25 mg/kg s.c., 2 h) dose-dependently stimulated PRL secretion. The present data support the assumption of the longlasting DA agonistic action of 6-n-propyl-LIS and 6-n-propyl-TDHL and of the antidopaminergic properties of 2-Br-LIS recently derived from behavioural studies.     

Biological activities of sarcosine1-angiotensin I in man

In order to examine whether substrate specificity of angiotensin-converting enzyme (ACE) exists or not for N-terminal substituted angiotensin I (ANG I) in man, biological activities of sarcosine1-angiotensin I (Sar1-ANG I) and the effects of an ACE inhibitor, captopril, on the Sar1-ANG I activities were studied in 5 normal men. The following 3 experiments were done at 1 week intervals. Sarcosine1-angiotensin II (Sar1-ANG II) was infused iv at a rate of 5 pmol/kg X min from 0900 h to 0930 h in 5 normal men in a recumbent position. Blood pressure rose remarkably and the average increment was 38/31 mmHg at 30 min (p less than 0.001). Average duration of the pressor action after the cessation of the infusion (T) was 40 min for systolic and 50 min for diastolic and much longer than T of isoleucine5-angiotensin II. Plasma renin activity (PRA) decreased (p less than 0.01) and plasma aldosterone (PA) increased significantly (p less than 0.01). Sar1-ANG I was infused iv at a rate of 5 pmol/kg X min from 0900 h to 0930 h. Blood pressure rose to the same extent as in (1) (p less than 0.001). T was 40 min for both systolic and diastolic and much longer than T of ANG I in man. PRA decreased (p less than 0.01) and PA increased (p less than 0.01) significantly. Oral 100 mg captopril was given at 08:00 h and Sar1-ANG I was infused iv at a rate of 5 pmol/kg X min from 09:00 h to 09:30 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of 125I-GST-TatdMt, a recombinant fusion protein possessing potent anti-obesity activity, after intravenous, nasal, oral, and subcutaneous administration

This study first reports the absorption kinetics of GST-TatdMt, a recombinant Tat protein possessing potent anti-obesity activity, in rats after nasal, s.c., and p.o. administration. GST-TatdMt was over-expressed in E. coli, purified, and radioiodinated using the IODO-GEN method. The radioiodinated 125I-GST-TatdMt was administered to rats by nasal, s.c., and oral routes at doses of 7.3 microg (420.7 nCi), 146.5 microg (8413.8 nCi), and 146.5 microg (8413.8 nCi), respectively. For the determination of absolute bioavailability, 125I-GST-TatdMt was also given to rats by i.v. injection (73.2 microg, 4206.9 nCi). Following administration by extravascular routes, the systemic absorption of radioactivity was prolonged, with Cmax being attained within 4.2-8.0 h. The absolute bioavailability calculated as dose-normalized AUC(extravascular)/AUC(i.v.) was 98.0, 75.8, and 87.1% after nasal, s.c., and oral administration, respectively. The majority of administered radioactivity was excreted in urine (57.5-64.7%), with fecal excretion being less (2.5-12.7%). The distribution of 125I-GST-TatdMt to various tissues was also determined at 4 and 72 h after s.c. injection. The findings of this study suggest that this protein may be absorbed into the systemic circulation when given by extravascular administration.     

Mechanical Intestinal Obstruction in a Porcine Model: Effects of Intra-Abdominal Hypertension. A Preliminary Study

Introduction

Mechanical intestinal obstruction is a disorder associated with intra-abdominal hypertension and abdominal compartment syndrome. As the large intestine intraluminal and intra-abdominal pressures are increased, so the patient’s risk for intestinal ischaemia. Previous studies have focused on hypoperfusion and bacterial translocation without considering the concomitant effect of intra-abdominal hypertension. The objective of this study was to design and evaluate a mechanical intestinal obstruction model in pigs similar to the human pathophysiology.

Materials and Methods

Fifteen pigs were divided into three groups: a control group (n = 5) and two groups of 5 pigs with intra-abdominal hypertension induced by mechanical intestinal obstruction. The intra-abdominal pressures of 20 mmHg were maintained for 2 and 5 hours respectively. Hemodynamic, respiratory and gastric intramucosal pH values, as well as blood tests were recorded every 30 min.

Results

Significant differences between the control and mechanical intestinal obstruction groups were noted. The mean arterial pressure, cardiac index, dynamic pulmonary compliance and abdominal perfusion pressure decreased. The systemic vascular resistance index, central venous pressure, pulse pressure variation, airway resistance and lactate increased within 2 hours from starting intra-abdominal hypertension (p<0.05). In addition, we observed increased values for the peak and plateau airway pressures, and low values of gastric intramucosal pH in the mechanical intestinal obstruction groups that were significant after 3 hours.

Conclusion

The mechanical intestinal obstruction model appears to adequately simulate the pathophysiology of intestinal obstruction that occurs in humans. Monitoring abdominal perfusion pressure, dynamic pulmonary compliance, gastric intramucosal pH and lactate values may provide insight in predicting the effects on endorgan function in patients with mechanical intestinal obstruction.     

Functional opioid pathways are necessary for hypocretin-1 (orexin-A)-induced feeding

We investigated the interaction of the orexigenic neuropeptide, hypocretin-1 (Hcrt-1, also known as orexin-A), with endogenous opioids (also orexigenic neuropeptides). Rats were injected with naltrexone (NTX, nonspecific opioid antagonist) i.p., i.c.v., in the lateral hypothalamus (LH), and in the accumbens shell (AcbSh), and naloxone methiodide (nonspecific opioid antagonist unable to cross the blood brain barrier) was injected i.p. Rats were then injected with Hcrt-1 in the LH. Food intake was measured for up to 4h thereafter. Rats were also pretreated with NTX in the LH, with Hcrt-1 injected in the AcbSh. NTX suppressed Hcrt-1-induced feeding only when injected i.p., i.c.v., and in the AcbSh. These studies reveal the necessity for functional central opioidergic pathways involving the AcbSh, but not the LH in Hcrt-1-induced feeding.     

The effects of ouabain in the medullary site of the hypotensive action of clonidine

Blood pressure was studied in pentobarbital anesthetized rats and cats after central administration of ouabain. Intracerebroventricular (i.c.v.) injections caused a classical biphasic effect, a short lasting hypotension followed by a hypertensive phase. When injected directly into the nucleus reticularis lateralis region (NRL), ouabain (0.01–2 μg/kg) caused a dose-dependent pressor effect. In the same region, kryptofix 221, a sodium complexing agent, produced a fall in blood pressure. Moreover, central administration of ouabain prevented the hypotensive effect of i.v. clonidence whereas the central hypotensive effect of muscimol was not affected. It is concluded that sodium movements play an important role in the blood pressure regulation within the NRL region. We also report here that ouabain antagonizes the hypotensive effect of clonidine suggesting that sodium movement might be the essential link of this action.     

Evidence that the acidic polysaccharide secreted by Agrobacterium radiobacter (ATCC 53271) has a seventeen glycosyl-residue repeating unit.

The extracellular anionic polysaccharide produced by the bacterium Agrobacterium radiobacter (ATCC 53271) contains D-galactose, D-glucose, and pyruvic acid in the molar ratio 2:15:2. Analysis of the methylated polysaccharide indicated the presence of terminal, non-reducing glucosyl, 3-, 4-, 6-, 2,4-, and 4,6-linked glucosyl residues, 3-linked 4,6-O-[(S)-1-carboxyethylidene]glucosyl residues, and 3-linked galactosyl residues. Partial acid hydrolysis of the methylated polysaccharide, followed by reduction with NaB2H4 and then O-ethylation, gave a mixture of alkylated oligoglycosyl alditols that were separated by reversed-phase h.p.l.c. and analyzed by 1H-n.m.r. spectroscopy, g.l.c.-m.s., and glycosyl-linkage composition analysis. Smith degradation of the polysaccharide gave three diglycosyl alditols that were separated by semi-preparative, high-pH anion-exchange chromatography, and were analyzed by 1H-n.m.r. spectroscopy, g.l.c.-m.s., and glycosyl-linkage composition analysis. The polymer obtained by NaBH4 reduction of the periodate-oxidized polysaccharide was methylated, and the noncyclic acetals were hydrolyzed with aq. 90% formic acid to generate a mixture of partially O-methylated mono- and di-glycosyl alditols. The partially O-methylated oligoglycosyl alditols were O-ethylated. The resulting alkylated oligoglycosyl alditols were separated by reverse-phase h.p.l.c. and then characterized by 1H-n.m.r. spectroscopy, g.l.c.-m.s., and glycosyl-linkage composition analysis. The results from the studies described here provide strong evidence that the acidic polysaccharide secreted by A. radiobacter (ATCC 53271) has a heptadecasaccharide repeating unit.     

Hydrostatic pressure effects on the central nervous system: perspectives and outlook

The high pressure neurological syndrome (h.p.n.s.) represents a complex of behavioural changes observed in all vertebrates when exposed to progressively increasing pressures. The general characteristics of the syndrome will be described and discussed in the light of alternative hypotheses about its aetiology and biophysical characteristics. Recent investigations in this area have dealt with the problem of the discretion of the several stages of the h.p.n.s. in their dependence on compression parameters; with the problem of individual variability in sensitivity to h.p.n.s. development, the genetic basis thereof, and its implications from the point of view of personnel selection; and with exploration of the characteristics and nature of the antagonism between high pressure and general anaesthetics in the production of h.p.n.s. symptoms. A final part of the discussion will deal with the current status of investigations into the problem of hazard assessment, and with the several possible approaches to controlling the h.p.n.s. associated hazards encountered in deep diving operations.