Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons.

Developmental programming studies indicate that glucocorticoids modify fetal development. We hypothesized that administration of the synthetic glucocorticoid (sGC) betamethasone to pregnant baboons at doses and stages of fetal life equivalent to human obstetric practice to decrease premature offspring morbidity and mortality, programs lipid metabolism. In 10-year-old male baboons (human equivalent 40) exposed in fetal life to betamethasone or saline, we quantified pericardial fat and hepatic lipid content with magnetic resonance imaging and spectroscopy. sGC offspring delivered at term as do most sGC-exposed human neonates. Pericardial fat thickness (7.7±3.6 mm vs 3.1±1.1 mm, M±s.d.; P=0.022; n=5) and hepatic fatty acids (13.3±11.0% vs 2.5±2.2%; P=0.046; n=5) increased following sGC without birth weight or current body morphometric differences. Our results indicate that antenatal sGC therapy caused abnormal fat deposition and adult body composition in mid-life primate offspring. The concern raised is that this degree of pericardial and hepatic lipid accumulation can lead to harmful local lipotoxicity. In summary, developmental programing by sGC produces a mid-life metabolically obese but normal weight phenotype. Prior studies show sexually dimorphic responses to some programming challenges thus female studies are necessary.

Cardiac magnetic resonance imaging: insights into developmental programming and its consequences for aging.

Cardiovascular diseases (CVD) are important consequences of adverse perinatal conditions such as fetal hypoxia and maternal malnutrition. Cardiac magnetic resonance imaging (CMR) can produce a wealth of physiological information related to the development of the heart. This review outlines the current state of CMR technologies and describes the physiological biomarkers that can be measured. These phenotypes include impaired ventricular and atrial function, maladaptive ventricular remodeling, and the proliferation of myocardial steatosis and fibrosis. The discussion outlines the applications of CMR to understanding the developmental pathways leading to impaired cardiac function. The use of CMR, both in animal models of developmental programming and in human studies, is described. Specific examples are given in a baboon model of intrauterine growth restriction (IUGR). CMR offers great potential as a tool for understanding the sequence of dysfunctional adaptations of developmental origin that can affect the human cardiovascular system.

Poor perinatal growth impairs baboon aortic windkessel function.

The ability of the aorta to buffer blood flow and provide diastolic perfusion (Windkessel function) is a determinant of cardiovascular health. We have reported cardiac dysfunction indicating downstream vascular abnormalities in young adult baboons who were intrauterine growth restricted (IUGR) at birth as a result of moderate maternal nutrient reduction. Using 3 T MRI, we examined IUGR offspring (eight male, eight female; 5.7 years; human equivalent 25 years) and age-matched controls (eight male, eight female; 5.6 years) to quantify distal descending aortic cross-section (AC) and distensibility (AD). ANOVA showed decreased IUGR AC/body surface area (0.9±0.05 cm2/m2 v. 1.2±0.06 cm2/m2, M±s.e.m., P<0.005) and AD (1.7±0.2 v. 4.0±0.5×10-3/mmHg, P<0.005) without sex difference or group-sex interaction, suggesting intrinsic vascular pathology and impaired development persisting in adulthood. Future studies should evaluate potential consequences of these changes on coronary perfusion, afterload and blood pressure.

Assessment of coronary arterial restenosis with phase-contrast magnetic resonance imaging measurements of coronary flow reserve.

BACKGROUND: After successful percutaneous coronary arterial revascularization, 25% to 60% of subjects have restenosis, a recurrent coronary arterial narrowing at the site of the intervention. At present, restenosis is usually detected invasively with contrast coronary angiography. This study was performed to determine if phase-contrast MRI (PC-MRI) could be used to detect restenosis noninvasively in patients with recurrent chest pain after percutaneous revascularization. METHODS AND RESULTS: Seventeen patients (15 men, 2 women, age 36 to 77 years) with recurrent chest pain >3 months after successful percutaneous intervention underwent PC-MRI measurements of coronary artery flow reserve followed by assessments of stenosis severity with computer-assisted quantitative coronary angiography. The intervention was performed in the left anterior descending coronary artery in 15 patients, one of its diagonal branches in 2 patients, and the right coronary artery in 1 patient. A PC-MRI coronary flow reserve value /=70% and >/=50%, respectively. CONCLUSIONS: Assessments of coronary flow reserve with PC-MRI can be used to identify flow-limiting stenoses (luminal diameter narrowings >70%) in patients with recurrent chest pain in the months after a successful percutaneous intervention.

Visualization and functional assessment of proximal and middle left anterior descending coronary stenoses in humans with magnetic resonance imaging.

BACKGROUND: Coronary artery bypass grafting improves survival in patients with >70% luminal diameter narrowing of the 3 major epicardial coronary arteries, particularly if there is involvement of the proximal portion of the left anterior descending (LAD) coronary artery. Measurement of coronary flow reserve can be used to identify functionally important luminal narrowing of the LAD artery. Although magnetic resonance imaging (MRI) has been used to visualize coronary arteries and to measure flow reserve noninvasively, the utility of MRI for detecting significant LAD stenoses is unknown. METHODS AND RESULTS: Thirty subjects (23 men, 7 women, age 36 to 77 years) underwent MRI visualization of the left main and LAD coronary arteries as well as measurement of flow in the proximal, middle, or distal LAD both at rest and after intravenous adenosine (140 microgram/kg per minute). Immediately thereafter, contrast coronary angiography and when feasible, intracoronary Doppler assessments of coronary flow reserve, were performed. There was a statistically significant correlation between MRI assessments of coronary flow reserve and (a) assessments of coronary arterial stenosis severity by quantitative coronary angiography and (b) invasive measurements of coronary flow reserve (P<0.0001 for both). In comparison to computer-assisted quantitative coronary angiography, the sensitivity and specificity of MRI for identifying a stenosis >70% in the distal left main or proximal/middle LAD arteries was 100% and 83%, respectively. CONCLUSIONS: Noninvasive MRI measures of coronary flow reserve correlated well with similar measures obtained with the use of intracoronary Doppler flow wires and predicted significant coronary stenoses (>70%) with a high degree of sensitivity and specificity. MRI-based measurement of coronary flow reserve may prove useful for identification of patients likely to obtain a survival benefit from coronary artery bypass grafting.

Exercise-induced attenuation of alpha-adrenoceptor mediated vasoconstriction in humans: evidence from phase-contrast MRI.

OBJECTIVE: We recently provided evidence for contraction-induced attenuation of reflex sympathetic vasoconstriction in human skeletal muscle microcirculation. We now asked whether contraction-induced modulation of alpha-adrenoceptor mediated vasoconstriction in the human forearm (a) is evident in a large artery supplying the contracting skeletal muscle and (b) implicates a post-junctional site of action. METHODS AND RESULTS: To address these questions in humans, we used phase-contrast magnetic resonance imaging to measure blood flow velocity and cross-sectional area of the brachial artery during brachial-artery infusion of the alpha-adrenoceptor agonist norepinephrine (NE) (1.1 g/min for 5 min) at rest and during mild ipsilateral rhythmic handgrip (20% of maximum). At rest, brachial artery conductance decreased progressively during the entire 5 min period of infusion (baseline to first half to second half of infusion: 0.421 +/- 0.157 to 0.255 +/- 0.187 to 0.012 +/- 0.014 ml/min/mmHg, P < 0.05). When NE was superimposed on handgrip, conductance at first decreased sharply (1.205 +/- 0.127 to 0.330 +/- 0.097 ml/min/mmHg, P < 0.05). However, during the second half of the infusion, conductance did not decrease further but rather returned progressively toward baseline (0.476 +/- 0.199 ml/min/mmHg at the end of the exercise, P < 0.05 vs. NE alone). CONCLUSION: These data provide new evidence in humans that alpha-adrenoceptor mediated vasoconstriction is sensitive to modulation by skeletal muscle contraction. Such modulation is evident at the level of a large conduit artery and it involves a post-junctional mechanism of action.

NK3 receptor blockade prevents hyperalgesia and the associated spinal cord substance P release in monoarthritic rats.

Previous studies in vitro have shown that NK3 receptors exist on primary afferent terminals in rat spinal cord and mediate potentiation of the depolarisation-evoked substance P (SP) release. In the present study we have investigated the role of the NK3 receptor-mediated SP release system in a model of inflammatory pain. Monoarthritis was induced in rats by unilateral injection of complete Freund's adjuvant (CFA); withdrawal latencies to a thermal stimulus were subsequently measured at various times following CFA. The CFA-treated paw displayed hyperalgesia as early as 4 h after CFA injection and hyperalgesia was maintained until day 4 but had disappeared by day 21. The thermal hyperalgesia was associated with an increase in basal SP release from spinal cord synaptosomes. The possible involvement of endogenous neurokinin B acting at NK3 receptors was tested by using SB 223412-A [(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carbo xamide hydrochloride], a novel, potent (Ki=30 nM) and selective (Ki>10,000 nM for NK1 and NK2 receptors), non-peptidic NK3 receptor antagonist. In vitro SB 223412-A antagonised the potentiation of SP release produced by senktide in spinal cord synaptosomes. Administered systemically to monoarthritic rats (50 mg/kg, p.o., b.i.d., for 4 days), the NK3 receptor antagonist SB 223412-A significantly reduced thermal hyperalgesia and normalised the basal release of SP from spinal cord synaptosomes. The data suggest that neurokinin B acting at NK3 receptors that mediate SP release within the spinal cord play a role in inflammation. These NK3 receptors may represent, therefore, appropriate targets in the therapy of inflammatory pain.

(2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: novel, highly selective kappa opioid analgesics.

This paper describes the synthesis and structure-activity relationships as kappa opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives. The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60 degrees, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and kappa affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl )piperidine hydrochloride and (2S)-1-[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1-ylmet hyl) piperidine hydrochloride are the most kappa/mu selective (respectively 6500:1 and 4100:1) and among the most potent (Ki kappa 0.24 and 0.57 nM, respectively) kappa ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard kappa ligand U-50488.

Synthesis and structure-activity relationships of bafilomycin A1 derivatives as inhibitors of vacuolar H+-ATPase.

The macrolide antibiotic bafilomycin A1 is a highly potent and selective inhibitor of all the vacuolar ATPases (V-ATPases). With the aim of obtaining novel analogues specific for the osteoclast subclass of vacuolar ATPase, 31 derivatives of bafilomycin A1 were synthesized and tested for their ability to inhibit differentially the V-ATPase-driven proton transport in membrane vesicles derived from chicken osteoclasts (cOc) and bovine chromaffin granules (bCG). Although none of the new analogues were more potent than the parent compound, the obtained data provided a significant amount of information about the structural requirements for the inhibitory activity of bafilomycin A1. The different effects of a few analogues on the two enzymes could also suggest the possibility of a selective modulation of the V-ATPases in different tissues.

(1S)-1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: members of a novel class of very potent kappa opioid analgesics.

The synthesis and structure-activity relationship (SAR) of a novel class of kappa opioid analgesics, 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4- tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines+ ++, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60 degrees was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of kappa receptor selectivity was a feature of this novel class of antinociceptive agents (mu/kappa ratio from 44 to 950 according to the nature of the basic moiety). SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 microM/kg sc) and kappa ligands (Ki(kappa) ca. 0.20 nM) identified so far.

Substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines: a novel class of very potent antinociceptive agents with varying degrees of selectivity for kappa and mu opioid receptors.

This study describes the synthesis of a series of novel substituted 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinolines, and discusses their structure-activity relationships (SARs) using binding affinity for opioid receptors and antinociceptive potency as the indices of biological activity. The introduction of a hydroxy substituent in position 5 of the isoquinoline nucleus generated a compound, 40, which is 2 times more potent than the previously disclosed unsubstituted analogue 39 in mouse models of antinociception. A QSAR analysis of the 5-substitution clearly demonstrates that antinociceptive activity is inversely associated with the lipophilicity of the substituents. The substituted compounds described herein are less selective for the kappa opioid receptors than the unsubstituted isoquinoline 39. For example, the 5-hydroxy-substituted compound 59 shows high affinity for kappa opioid receptors (Ki kappa = 0.09 nM) and a Ki mu/Ki kappa ratio of only 5. However, a multiple linear regression analysis demonstrates a lack of correlation between antinociceptive activity and affinity for the mu opioid receptor. On the other hand, the correlation between binding affinity to kappa opioid receptor and antinociceptive activity was statistically significant.

Selective kappa-opioid agonists: synthesis and structure-activity relationships of piperidines incorporating on oxo-containing acyl group.

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.

Discovery of a novel class of substituted pyrrolooctahydroisoquinolines as potent and selective delta opioid agonists, based on an extension of the message-address concept.

This paper describes the design and synthesis of compounds belonging to a novel class of substituted pyrrolooctahydroisoquinolines which are potent and selective delta opioid agonists. Molecular modeling studies performed on known, selective delta ligands such as (+)-3 and the potent delta agonists SNC 80 led to the identification of the carboxamido moiety of the latter as a putative nonaromatic delta address. Insertion of this moiety onto the octahydroisoquinoline opioid message resulted in (+/-)-5b, a potent and selective delta ligand. The active enantiomer, (-)-5b, displayed nanomolar affinity for the delta receptor (Ki = 0.9 nM) with good mu/delta and kappa/delta binding selectivity ratios (140 and 1480, respectively). In addition, (-)-5b behaved as a full delta agonist in the mouse vas deferens bioassay having an IC50 = 25 nM and being antagonised in the presence of 30 nM naltrindole (NTI). These studies, based on the message-address concept, indicated that the nonaromatic (N,N-diethylamino)carbonyl moiety is a viable alternative to the classical benzene ring as a delta opioid address. Preliminary in vivo studies showed that (+/-)-5b produced a dose-related antinociception in the mouse abdominal constriction test after intracerebroventricular administration (ED50 = 1.6 micrograms/mouse).

Synthesis, biological evaluation, and quantitative receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as novel tifluadom-like ligands with high affinity and selectivity for kappa-opioid receptors.

The synthesis and biological evaluation of a series of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), the only benzodiazepine that acts simultaneously as a kappa-opioid agonist and a cholecystokinin-A (CCK-A) antagonist, are reported. The radioligand binding models used in these studies were [(125)I](BH)-CCK-8 in rat pancreas (CCK-A), [(3)H]-(MENLE(28,31))-cck-8 in guinea pig cerebral cortex (CCK-B), and [(3)H]U-69593 (kappa(1)), [(3)H]DAMGO (mu), and [(3)H]DADLE (delta) in guinea pig brain. All the title compounds were devoid of significant affinity for both CCK-A and CCK-B receptors, while some of them bound with nanomolar affinity and high selectivity for kappa-opioid receptors. In particular, the 2-thienyl derivative 7A(X = H) with a K(i) = 0.50 nM represents a clear improvement with respect to tifluadom, showing a comparable potency but higher selectivity. The application of computational simulations and linear regression analysis techniques to the complexes between guinea pig kappa (kappa(1))-receptor and the title compounds allowed the identification of the structural determinants for recognition and quantitative elucidation of the structure-affinity relationships in this class of receptors.

5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides: novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity.

The vacuolar H+-ATPase (V-ATPase), located on the ruffled border of the osteoclast, is a proton pump which is responsible for secreting the massive amounts of protons that are required for the bone resorption process. With the aim to identify new agents which are able to prevent the excessive bone resorption associated with osteoporosis, we have designed a novel class of potent and selective inhibitors of the osteoclast proton pump, starting from the structure of the specific V-ATPase inhibitor bafilomycin A1. Compounds 3a-d potently inhibited the V-ATPase in chicken osteoclast membranes (IC50 = 60-180 nM) and were able to prevent bone resorption by human osteoclasts in vitro at low-nanomolar concentrations. Notably, the EC50 of compound 3c in this assay was 45-fold lower than the concentration required for half-maximal inhibition of the V-ATPase from human kidney cortex. These results support the validity of the osteoclast proton pump as a useful molecular target to produce novel inhibitors of bone resorption, potentially useful as antiosteporotic agents.

Evaluation of the potassium channel activator cromakalim (BRL 34915) as a bronchodilator in the guinea-pig: comparison with nifedipine.

1. The potential of the potassium channel activator, cromakalim (BRL 34915), as a bronchodilator has been evaluated in guinea-pig models in comparison with nifedipine. Some effects of the compounds on guinea-pig tracheal spirals have been studied in an attempt to elucidate their different efficacies in vivo. 2. When given by the intraduodenal route to anaesthetized guinea-pigs, cromakalim (3 and 10 mg kg-1) inhibited 5-hydroxytryptamine (5-HT)-induced bronchospasm for at least 60 min. When given by the i.v. route, the dose of cromakalim producing 50% inhibition of the 5-HT response was 84 micrograms kg-1. Nifedipine failed to show any protective effect up to 100 micrograms kg-1, i.v. and was lethal at higher dose levels. 3. Cromakalim protected conscious guinea-pigs from asphyxic collapse in response to histamine aerosol. The maximal effect occurred 60 min following oral dosing, with 2.5 mg kg-1 providing complete protection for almost half of the animals. Nifedipine had only a weak protective effect even at a high dose level of 50 mg kg-1, p.o. 4. Cromakalim prolonged the time before convulsive cough in response to an antigen challenge in actively sensitized guinea-pigs. Its minimum protective dose was 1 mg kg-1, p.o. Nifedipine (50 mg kg-1, p.o.) was ineffective. 5. Cromakalim inhibited both spontaneous and prostaglandin E2-induced tone in guinea-pig isolated tracheal spirals with IC50 values, relative to the maximum inhibition achieved by isoprenaline (10(-3)M), of 1.1 x 10(-6)M and 8.9 x 10(-7)M, respectively. Its maximal effect was 89% of that produced by isoprenaline. Removal of the epithelium did not influence its activity. Studies using the two enantiomers showed that the activity of cromakalim resided almost entirely in the (-)-enantiomer. 6. Nifedipine (2 x 10-SM) achieved only 49% of the relaxant effect of 10 -3M isoprenaline in isolated tracheal spirals. Addition of cromakalim (10- 5 M) at the end of the nifedipine concentrationresponse experiment caused further relaxation to 94% of the effect of isoprenaline. 7. It is concluded that cromakalim has greater potential than nifedipine as a bronchodilator. It appears that opening of potassium channels, with consequent hyperpolarization and stabilization of the membrane potential, prevents calcium entering the cytosol through routes that are unaffected by calcium entry blockers.

Cerebral blood flow and cranial magnetic resonance imaging in eclampsia and severe preeclampsia.

OBJECTIVE: To measure cerebral blood flow in women with eclampsia and severe preeclampsia using phase-contrast magnetic resonance imaging (MRI). METHODS: Women with eclampsia and severe preeclampsia were studied and compared with normotensive cohorts. Magnetic resonance imaging studies were performed initially in hypertensive women after seizure treatment or prophylaxis was given. Magnetic resonance imaging flow measurements were made using a phase contrast velocity imaging technique in each middle and posterior cerebral artery. Conventional brain MRI and magnetic resonance angiography of the circle of Willis were performed at the time of flow measurement. Women with preeclampsia and eclampsia served as their own controls and were matched with normotensive cohorts. All of the hypertensive women were studied again 4-5 weeks postpartum. Paired t test analysis and an analysis of variance were performed. Considering a 20% minimum detectable difference in flow, the power was 0.80, 0.92, 0.86, and 0.96 for the left and right middle cerebral arteries and the left and right posterior cerebral arteries, respectively. RESULTS: All 28 women enrolled were studied initially within 24 hours of delivery or of their most recent seizure. There were no significant differences in blood flow in either the posterior or middle cerebral arteries in women with eclampsia or severe preeclampsia between the initial studies and those 4-5 weeks postpartum, or compared with their normal counterparts. No findings of vasospasm were seen. T2-weighted brain images were markedly abnormal in all eight women with eclampsia, mildly abnormal in two of ten with severe preeclampsia, and normal in all ten controls. CONCLUSIONS: No flow changes were seen in the posterior or middle cerebral arteries of women with eclampsia and severe preeclampsia despite the presence of remarkable brain lesions in all women with eclampsia. These findings question the role of vasospasm and cerebral hypoperfusion, although a vasodilatory effect of magnesium could not be excluded.

Characterization of species-specific genes using a flexible, web-based querying system.

We describe a query-based web-accessible system (www.neurogadgets.com/bws.php) for facilitating comparative microbial genomics. A variety of query pages are available, each with numerous options, that allow a biologist to pose relevant questions of genomic data. We illustrate with a characterization of species-specific protein-coding genes (so-called "ORFans"), finding that they are on average smaller, faster evolving, and less G+C-rich, and that they encode proteins more basic in their predicted isoelectric point, compared with non-species-specific genes. Using a dual-threshold approach, we conclude that these are characteristics of true species-specific genes, rather than artifacts of mis-annotation.

Inhibition of mammalian 5-lipoxygenase by 2-benzylaminophenols.

A number of 2-benzylaminophenols, prepared from the corresponding 2-aminophenols by reductive alkylation, have been identified as highly potent inhibitors of 5-lipoxygenase with IC50 values in the nanomolar range. Most compounds were also shown to inhibit the release of the peptidoleukotrienes when administered intraperitoneally in a rat model of peritoneal anaphylaxis. Two compounds evaluated for their effects on anaphylactic contractions in isolated human lung were shown to attenuate the leukotriene-induced component of the response.

Comparative effects of selective kappa-opioid receptor agonists on dopamine levels in the dorsal caudate of freely moving rats.

Microdialysis was utilized to evaluate the effects of selective kappa-opioid receptor agonists on dopamine levels in the dorsal caudate of conscious rats. Subcutaneous administration of equivalent antinociceptive doses of spiradoline--(+/-)-(5 alpha, 7 alpha, 8 beta)-3, 4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl] benzeneacetamide--(U62066; 12 mg/kg), BRL 52656--(2S)-1-[(4- trifluoromethylphenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperidine--(2 mg/kg) and enadoline--(-)-(5 beta, 7 beta, 8 alpha)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzo[b]furan-4-acetamide-- (CI-977; 0.1 mg/kg) produced similar, statistically significant decreases in dorsal caudate dopamine levels; BRL 53001--(2S)-2- (dimethylaminomethyl)-1-[(5,6,7,8-tetrahydro-5-oxo-2-naphthyl)ace tyl] piperidine--(12 mg/kg) was, however, without effect. At a higher dose (36 mg/kgP, BRL 53001 also caused a significant reduction in dopamine levels. BRL 52974--4-(1-pyrrolidinylmethyl) 5-[(3,4-dichlorophenyl)acetyl]-4,5,6,7-tetrahydroimidazo[4,5-c] pyridine, a selective kappa-opioid receptor agonist with limited ability to cross the blood brain barrier or produce antinociceptive effects, had no effect on dopamine levels at 10 mg/kg s.c. Overall, these findings suggest that selective kappa-opioid receptor agonists decrease dopamine levels in the dorsal caudate of rats via a central locus of action. Furthermore, compared to other kappa-opioid receptor agonists, BRL 53001 appears to have a reduced propensity to decrease dopamine levels at equianalgesic doses.