Dermal lesions after post mortem petrol-exposure.

The effect of post mortem contact of the skin with petrol was investigated in 18 corpses with exposure times between 10 min and 24 h. The earliest onset of skin changes was observed within 2 h of exposure. They consisted of swelling and wrinkling with detachment of the upper layers of the skin (positive Nikolski's sign). Histologically the lesions appeared as non-vital acantholyses located in the prickle-cell layer with formation of intra-epidermal bullae. An influence of age and sex could be excluded, the earlier onset of lesions at 22 degrees C than at 4 degrees C was not statistically significant. These findings prove that post mortem petrol exposure may lead to dermal lesions.

Mammalian PASKIN, a PAS-serine/threonine kinase related to bacterial oxygen sensors.

The PAS domain is a versatile protein fold found in many archaeal, bacterial, and plant proteins capable of sensing environmental changes in light intensity, oxygen concentration, and redox potentials. The oxygen sensor FixL from Rhizobium species contains a heme-bearing PAS domain and a histidine kinase domain that couples sensing to signaling. We identified a novel mammalian PAS protein (PASKIN) containing a domain architecture resembling FixL. PASKIN is encoded by an evolutionarily conserved single-copy gene which is ubiquitously expressed. The human PASKIN and mouse Paskin genes show a conserved intron-exon structure and share their promoter regions with another ubiquitously expressed gene that encodes a regulator of protein phosphatase-1. The 144-kDa PASKIN protein contains a PAS region homologous to the FixL PAS domain and a serine/threonine kinase domain which might be involved in signaling. Thus, PASKIN is likely to function as a mammalian PAS sensor protein.

Investigations into the physiological role of muscarinic M2 and M4 muscarinic and M4 receptor subtypes using receptor knockout mice.

Determination of muscarinic agonist-induced parasympathomimetic effects in wild type and M2 and M4 muscarinic receptor knockout mice revealed that M2 receptors mediated tremor and hypothermia, but not salivation. The M4 receptors seem to play a modest role in salivation, but did not alter hypothermia and tremor. In the M2 knockout mice, agonist-induced bradycardia in isolated spontaneously beating atria was completely absent compared to their wild type litter mates, whereas agonist-induced bradycardia was similar in the M4 knockout and wild type mice. The potency of carbachol to stimulate contraction of isolated stomach fundus, urinary bladder and trachea was reduced by a factor of about 2 in the M2 knockout mice, but was unaltered in the M4 knockout mice. The binding of the muscarinic agonist, [3H]-oxotremorine-M, was reduced in cortical tissue from the M2 knockout mice and to a lesser extent from the M4 knockout mice, and was reduced over 90% in the brain stem of M2 knockout mice. The data demonstrate the usefulness of knockout mice in determining the physiological function of peripheral and central muscarinic receptors.

Low-affinity M(2) receptor binding state mediates mouse atrial bradycardia: comparative effects of carbamylcholine and the M(1) receptor agonists sabcomeline and xanomeline.

Carbamylcholine, a nonselective muscarinic receptor agonist, and sabcomeline and xanomeline, functional M(1) receptor-selective agonists with high M(2) receptor affinities, were used to explore the relationship of the M(2) receptor affinity of these agonists to mouse atrial bradycardia and to understand the relationship of the high and low M(2) receptor affinity states to carbamylcholine-induced mouse atrial bradycardia. All three agonists produced bradycardia with sabcomeline (pEC(50) = 6.7) more potent than either carbamylcholine (pEC(50) = 5.9) or xanomeline (pEC(50) = 5.1). Sabcomeline and carbamylcholine produced a rapid, concentration-related bradycardia, which was antagonized by atropine with pK(B) values of 8.6 and 8.9, respectively. In addition, sabcomeline antagonized carbamylcholine-induced bradycardia (pK(B) = 7.48), indicating that sabcomeline was a partial agonist at M(2) receptors. In contrast, xanomeline (up to 10(-5) M), did not antagonize carbamylcholine-induced bradycardia, and atropine (3.0 x 10(-8) M) did not antagonize xanomeline-induced bradycardia, suggesting that xanomeline-induced bradycardia was not mediated by M(2) receptors. Analysis of receptor occupancy curves indicated that bradycardia resulted from the interaction of carbamylcholine with the low- rather than high-affinity state of the M(2) receptor and that sabcomeline was a partial agonist at M(2) receptors in mouse atria. In contrast, similar analysis for xanomeline using the receptor affinity of xanomeline at M(2) receptors (1.8 x 10(-8) M) was not consistent with classical receptor theory. These data document that 1) the low-affinity state of the M(2) receptor is responsible for muscarinic-induced atrial bradycardia, 2) sabcomeline was an M(2) receptor partial agonist, and 3) xanomeline-induced bradycardia was not mediated by activation of M(2) muscarinic receptors.

[Pancreatic excisions for chronic pancreatitis and cancer: their rationale for "factual" surgery. Evidence-based medicine]. / Exérèses pancréatiques pour pancréatite chronique et cancer: leur bien-fondé par la chirurgie "factuelle". Evidence-based medicine.

Despite significant improvement in the results of pancreatoduodenecomy over recent years, the Whipple procedure and its main modifications still has a poor reputation. Based on the principles of evidence-based medicine, we reviewed the current status of pancreatoduodenectomy for pancreatic cancer and chronic pancreatitis. Mortality of pancreatoduodenectomy has declined to less than 5% for chronic pancreatitis and to 3-5% for pancreatic cancer. In contrast, overall morbidity remains high, ranging from 20% to 70%. Delayed gastric emptying accounts for almost 50% of all complications. Major relief of pain is achieved in 70% to 100% of patients with chronic pancreatitis. Overall 5-year survival for patients with pancreatic cancer remains poor, ranging from 5% to 15%, with a median survival of 13 to 17 months. Mortality ad morbidity are not related to the type of pancreatoduodenectomy, however patients with pancreatic cancer tend to have a higher risk for complications. Extended lymph node dissection and portal vein resection can be performed with similar mortality and morbidity compared with standard procedures, however without any survival benefit in the long-term course.

Pharmacologic actions of the second generation leukotriene B4 receptor antagonist LY29311: in vivo pulmonary studies.

We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]pro poxy]phenoxy] benzoic acid sodium salt). Guinea pigs were used to evaluate the effect of this agent on (1) acute airway obstruction produced by intravenous leukotriene B4, (2) pulmonary granulocyte infiltration and delayed onset airway obstruction resulting from a 4-h leukotriene B4 inhalation and (3) lung inflammation after aerosol challenge with the divalent cationic ionophore A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid). Airway obstruction was quantitated using pulmonary gas trapping measurements and lung inflammation was evaluated by bronchoalveolar lavage (BAL) and histology. LY293111 sodium produced a dose-related inhibition of acute leukotriene B4-induced airway obstruction when administered i.v. (ED50=14 microg/kg) or p.o. (ED50=0.4 mg/kg). In contrast, LY293111 sodium did not inhibit the pulmonary gas trapping caused by aerosols of histamine, leukotriene D4, or the thromboxane mimetic U46619 (15 [(S)-hydroxy11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid]). Oral LY293111 sodium inhibited leukotriene B4-induced bronchoalveolar lavage granulocyte infiltration and delayed onset airway obstruction at doses as low as 0.3 mg/kg. In A23187-challenged animals, pulmonary inflammation was markedly inhibited at 1 h, but not 2 h and 4 h post-exposure. We conclude that LY293 11 sodium is a selective leukotriene B4 receptor antagonist with potent pulmonary anti-inflammatory activity.

M(2) and M(4) receptor knockout mice: muscarinic receptor function in cardiac and smooth muscle in vitro.

Peripheral muscarinic receptors play key roles in the control of heart rate and smooth muscle activity. In this study, bradycardic and smooth muscle contractile responses to the muscarinic agonist carbamylcholine were compared in isolated tissues from M(2) and M(4) muscarinic receptor knockout mice and their wild-type littermates. Carbamylcholine (1 x 10(-8)-3 x 10(-5) M) produced similar concentration-dependent bradycardia in spontaneously beating atria from M(4) receptor knockout and wild-type control mice. In contrast, carbamylcholine did not produce bradycardia in atria derived from M(2) receptor knockout mice, whereas such atria were responsive to adenosine-induced bradycardia. Carbamylcholine-induced contractile responses were similar in stomach fundus, urinary bladder, and tracheal preparations from M(4) receptor knockout mice and their wild-type littermates for each tissue (-logEC(50) values ranging from 6.20 +/- 0.10 to 6.76 +/- 0.08), suggesting that M(4) receptors do not participate in smooth muscle contraction in these tissues. In contrast, approximately 2-fold higher carbamylcholine concentration was required for contraction of stomach fundus, urinary bladder, and trachea from M(2) receptor knockout mice (-logEC(50) = 6.39 +/- 0.05, 6.07 +/- 0.06, and 6.27 +/- 0.12, respectively) than from wild-type littermates (-logEC(50) = 6.68 +/- 0.07, 6.27 +/- 0.07, and 6.56 +/- 0.06, respectively). Furthermore, the affinity of the M(2) "selective" receptor antagonist AF-DX116 in inhibiting carbamylcholine-induced smooth muscle contraction was significantly reduced in M(2) receptor knockout mice compared with tissues from wild-type littermates. Collectively, these results provide direct and unambiguous evidence that M(2) receptors mediate muscarinic receptor-induced bradycardia and play a role in smooth muscle contractility, whereas M(4) receptors are not involved in stomach fundus, urinary bladder, or tracheal contractility.

Shifts in lung lymphocyte profiles correlate with the sequential development of acute allergic and chronic tolerant stages in a murine asthma model.

T lymphocytes have a central regulatory role in the pathogenesis of asthma. We delineated the participation of lymphocytes in the acute allergic and chronic tolerant stages of a murine model of asthma by characterizing the various subsets of lymphocytes in bronchoalveolar lavage and lung tissue associated with these responses. Acute (10-day) aerosol challenge of immunized C57BL/6J mice with ovalbumin resulted in airway eosinophilia, histological evidence of peribronchial and perivascular airway inflammation, clusters of B cells and TCRgammadelta cells in lung tissue, increased serum IgE levels, and airway hyperresponsiveness to methacholine. In mice subjected to chronic (6-week) aerosol challenge with ovalbumin, airway inflammation and serum IgE levels were significantly attenuated and airway hyperresponsiveness was absent. The marked increases in lung B and T cell populations seen in the acute stage were also significantly reduced in the chronic stage of this model. Thus, acute ovalbumin challenge resulted in airway sensitization characteristic of asthma, whereas chronic ovalbumin challenge elicited a suppressed or tolerant state. The transition from antigenic sensitization to tolerance was accompanied by shifts in lymphocyte profiles in the lung and bronchoalveolar lavage fluid.

Pulmonary actions of anandamide, an endogenous cannabinoid receptor agonist, in guinea pigs.

Anandamide (arachidonylethanolamide), 5,8,11,14-eicosatetraenamide, (N-2-hydroxyethyl), was tested for bronchodilator and anti-inflammatory activities. Conscious guinea pigs were given cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) to assess its effect on dynamic compliance (Cdyn), total pulmonary resistance (RL), tidal volume (VT) and breathing frequency (f). Other guinea pigs were exposed to an aerosol of A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid) until Cdyn decreased by 50% (approximately 5 min) and at 20 min, cumulative i.v. doses of anandamide (1.0, 3.0, and 10.0 mg/kg) were administered and reversal of Cdyn examined. After the final dose of anandamide, the animals were killed and excised lung gas volumes (ELGV), i.e., pulmonary gas trapping, measured. Other animals were treated i.v. with anandamide (10.0 mg/kg), exposed to an aerosol of A23187 until labored breathing began, and then killed 1 h later. Anandamide did not significantly affect Cdyn, RL, VT and f. ELGV values of anandamide-treated guinea pigs were not different from those of vehicle-treated animals. Anandamide failed to reverse A23187-induced decreases in Cdyn and to reduce A23187-associated ELGV increases. Also, it did not prevent the prolonged airway obstruction caused by A23187. Histological evaluation revealed that anandamide significantly reduced A23187-related airway epithelial injury and pulmonary leukocytosis. However, it did not prevent A23187-induced peribronchiolar granulocytic accumulation. Our results suggest that in vivo anandamide has minimal direct airway smooth muscle-related actions, however it may possess modest anti-inflammatory properties.

Pharmacology of butylthio[2.2.2] (LY297802/NNC11-1053): a novel analgesic with mixed muscarinic receptor agonist and antagonist activity.

Butylthio[2.2.2], ((+)-(S)-3-(4-butylthio-1,2,5-thiadiazol-3-yl)-1-azabicyclo[2.2.2] octane; LY297802/NNC11-1053) is a muscarinic receptor ligand which is equiefficacious to morphine in producing antinociception. In vitro, butylthio[2.2.2] had high affinity for muscarinic receptors in brain homogenates, but had substantially less or no affinity for several other neurotransmiter receptors and uptake sites. In isolated tissues, butylthio[2.2.2] was an agonist with high affinity for M1 receptors in the rabbit vas deferens (IC50 = 0.33 nM), but it was an antagonist at M2 receptors in guinea pig atria (pA2 = 6.9) and at M3 receptors in guinea pig urinary bladder (pA2 = 7.4) and a weak partial agonist in guinea pig ileum, which contains a heterogeneous population of muscarinic receptors. In vivo, butylthio[2.2.2] was without effect on acetylcholine, dopamine and serotonin levels in rat brain. Moreover, butylthio[2.2.2] did not decrease charcoal meal transit in mice, nor did it significantly alter heart rate in rats. Further, butylthio[2.2.2] did not produce parasympathomimetic effects such as salivation or tremor in mice, but it antagonized salivation and tremor produced by the nonselective muscarinic agonist oxotremorine. The present data demonstrate that butylthio[2.2.2] is a novel muscarinic receptor mixed agonist/antagonist and its pharmacological profile suggests that it may have clinical utility in the management of pain as an alternative to opioids.

The non-peptide NK-1 receptor antagonist LY303870 inhibits neurogenic dural inflammation in guinea pigs.

LY303870 is a competitive, high affinity NK-1 receptor antagonist. It was tested in the trigeminal stimulation-induced neurogenic dural inflammation model of migraine. The neurogenic inflammation theory of migraine pain proposes that substance P, acting through NK-1 receptors, causes dural inflammation which enhances migraine pain. LY303870 administration potently inhibited neurogenic dural inflammation as measured by plasma protein extravasation caused by electrical stimulation of the trigeminal ganglion in guinea pigs. It was active in this model when administered via intravenous, oral or inhalation routes. LY306155, the enantiomer of LY303870 with lower affinity for the NK-1 receptor, was much less potent than LY303870 in this model. LY303870, at oral doses of 1, 10 and 100 microg/kg, produced a long, dose-dependent inhibition of dural inflammation, demonstrating a suitable duration of action for a potential use in acute migraine and migraine prophylaxis.

Aerosolized LTB4 produces delayed onset increases in pulmonary gas trapping.

Airway obstruction, as measured by increases in postmortem pulmonary gas trapping, and lung inflammatory changes were examined in guinea pigs exposed for up to 4 h to aerosols of leukotriene B4 (LTB4) or its non-chemotactic isomer, 6-trans-12-epi-LTB4. Airway obstruction and cytological responses in isomer-exposed animals were similar to those of unexposed control animals. LTB4-exposed animals had minimal inflammatory changes at 0.5 h but became dyspneic by 2 h and had increased airway obstruction, bronchoalveolar lavage neutrophils and eosinophils, and pulmonary tissue granulocyte scores. The LTB4-induced effects at 4 h were similar to those 2 h, except for further increase in BAL neutrophils and eosinophils. LTB4-induced airway obstructive and inflammatory changes were prevented by pretreatment with the LTB4 receptor antagonist SC-41930, but were unaffected by indomethacin. Thus, prolonged LTB4 inhalation can produce delayed onset airway obstruction that is stereospecific, cyclooxygenase-independent, and temporally associated with the influx of granulocytes into lung airways.

Folic acid and the prevention of neural tube defects: A position paper of the national society of genetic counselors.

Considerable scientific evidence demonstrates the reduction in risk for neural tube defects (NTDs) associated with maternal preconceptional folic acid supplementation. The National Society of Genetic Counselors (NSGC) endorses the U.S. Public Health Service recommendations for folic acid supplementation at the 0.4 mg level for women in the general population and at the 4.0 mg level for women at high or increased risk for NTD pregnancies for at least 4 weeks prior to active pursuit of conception. We encourage targeted educational efforts and surveillance to assess results of this dietary supplementation. The NSGC further urges the Food and Drug Administration to fortify staple foodstuffs with folic acid for a population-based approach to minimize the number of NTD births.

Methacholine-induced pulmonary gas trapping in guinea pigs, hamsters, mice, and rats.

Postmortem pulmonary gas trapping was investigated as an index of in vivo airway obstruction following methacholine inhalation in four different rodent species. Male guinea pigs (Hartley), hamsters (golden Syrian), mice (A/J, BALB/c, and ICR), and rats (Brown-Norway, Fischer 344, Lewis, and Sprague-Dawley) were exposed to aerosols of methacholine or sodium chloride. Maximum excised lung gas volumes (ELGV) of methacholine-exposed guinea pigs, hamsters, mice, and rats were 2.3-8.7 times those of sodium chloride-treated animals. Mean ELGV values of sodium chloride-exposed animals ranged from 1.50 +/- 0.20 ml/kg for guinea pigs to 2.75 +/- 0.20 ml/kg for Brown-Norway rats. Although all species responded to methacholine, guinea pigs were the most responsive, with approximately 1.6 microgram/kg of inhaled methacholine needed to increase ELGV to 200% of control. Compared with guinea pigs, hamsters, mice, and rats were 11- to 1,395-fold less responsive. Although hamsters, mice, and rats are less sensitive than guinea pigs to the airway-obstructive effects of methacholine, pulmonary gas trapping appears useful as a measure of airway responses in these species.

Pharmacological characterization of LY303870: a novel, potent and selective nonpeptide substance P (neurokinin-1) receptor antagonist.

LY303870 [(R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]propane] is a new, potent and selective nonpeptide neurokinin-1 (NK-1) receptor antagonist. LY303870 bound selectively and with high affinity to human peripheral (Ki = 0.15 nM) and central (Ki = 0.10 nM) NK-1 receptors. LY303870 inhibited [125I]substance P (SP) binding to guinea pig brain homogenates with similar affinity; however, it had approximately 50-fold lesser affinity for rat NK-1 sites. The less active enantiomer, LY306155 [(S)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4- (piperidin-1-yl)piperidin-1-yl)acetyl)amino]-propane], was 1,000- to 15,000-fold less potent in all the species examined. LY303870 antagonized in vitro NK-1 receptor effects as demonstrated by blockade of SP-stimulated phosphoinositide turnover in UC-11 MG human astrocytoma cells (Ki = 1.5 nM) and interleukin-6 secretion from U-373 MG human astrocytoma cells (Ki = 5 nM). In addition, LY303870 inhibited SP-induced rabbit vena cava contractions (pA2 = 9.4) with high (50,000-fold) selectivity vs. NK-2 or NK-3 receptor-mediated responses. In vivo, LY303870 inhibited [Sar9,Met(O2)11]-SP induced guinea pig bronchoconstriction (ED50 = 75 micrograms/kg i.v.) and pulmonary microvascular leakage in the bronchi (ED50 = 12.8 micrograms/kg i.v.) and trachea (ED50 = 18.5 micrograms/kg i.v.). Therefore, LY303870 is a potent and selective NK-1 receptor antagonist in vitro and in vivo. The use of LY303870 will facilitate a better understanding of NK-1 receptors in physiological processes.

Effect of bronchoconstrictive aerosols on pulmonary gas trapping in the A/J mouse.

We exposed A/J mice to several challenge aerosols and measured gas trapped within excised lungs by quantitating their buoyancy in saline (Archimedes' principle). The temporal stability of the excised lung gas volume (ELGV) measurement was also examined. ELGV increased in a dose proportional manner with increasing concentrations of methacholine and reached a maximum of 338 +/- 33% above vehicle-exposed controls. The A/J mice were 100 times more responsive to aerosol methacholine compared to hyporesponsive C3H/HeJ mice. Aerosol challenges of U-46619, a thromboxane A2 mimetic, and serotonin resulted in a 40% and 135% increase in ELGV's versus their controls, respectively. ELGV's were not increased after aerosols of leukotriene C4, histamine, substance P, N-formyl-methionyl-leucyl-phenyl-alanine and platelet activating factor. Both normal (filtered air-exposed) and hyperinflated (methacholine-exposed) excised lungs lost about 10% of their initial volume by 30 min and 40-65% of initial volume by 4 h. Occlusion of the trachea in either group did not affect the total gas lost, suggesting that majority of the gas loss was via transpleural diffusion. We conclude that determination of ELGV in mice, when performed soon after challenge testing, is a simple, rapid and reliable estimate of airway obstruction.

Pulmonary actions of the neurokinin1-specific agonist [Sar9,Met(O2)11]-substance P.

We examined the relationship between airway obstruction and plasma extravasation produced by the intravenous administration of the selective NK1 receptor agonist [Sar9, Met(O2)11]-substance P(SP). Conscious guinea-pigs were injected with Evans' blue dye followed by intravenous [Sar9,Met(O2)11]-SP. Animals were killed 3 min later and airway obstruction, determined via excised lung gas volumes, and plasma extravasation in the trachea, mainstem bronchi and intrapulmonary airways quantitated. Maximal plasma protein extravasation occurred at a dose about 30 times less than that required to elicit airway obstruction. Neither the neutral endopeptidase (NEP) inhibitor, thiorphan, or the angiotensin-converting enzyme (ACE) inhibitor, captopril, altered the extravasation response to [Sar9,Met(O2)11]-SP. However, thiorphan alone or combined with captopril produced a small but significant potentiation of the airway obstructive response. The marked difference between pulmonary gas trapping and Evans' blue extravasation responses suggest that [Sar9,Met(O2)11]-SP-induced airway obstruction is not secondary to increased pulmonary edema.

Effect of dexamethasone on A23187-induced airway responses in the guinea pig.

We examined the effect of dexamethasone on A23187-induced bronchospasm, pulmonary inflammation and airway responses to substance P. Guinea pigs, dosed orally once a day for 4 days with dexamethasone (3.0, 10.0 or 30.0 mg/kg) or saline, were exposed to an aerosol of A23187 for 12 min or until labored breathing began. Postmortem pulmonary gas trapping was used as an indicator of in vivo airway obstruction and changes in bronchial responses. Dexamethasone did not alter airway obstruction or inflammation 1 h after A23187 exposure. However, dexamethasone reduced the enhanced airway responses to substance P and bronchiolar/peribronchiolar inflammation 24 h post-A23187. It is possible that glucocorticosteroid suppression of A23187-induced pulmonary inflammation was important in reducing the increased airway responses to substance P.

Bronchopulmonary actions of 1-(1,2,3,4-tetrahydro-1-naphthylenyl)-1H-imidazole, nitric acid salt (LY150310), a substituted imidazole, in the guinea pig.

1-(1,2,3,4-tetrahydro-1-naphthylenyl)-1H-imidazole, nitric acid salt (LY150310), was examined for bronchodilator activity in the guinea pig. In guinea pig tracheal preparations, LY150310 competitively antagonized the contractile effects of exogenous histamine and blocked the histamine-mediated component of contractions produced by ovalbumin challenge. LY150310 had little effect on the nonhistamine component of ovalbumin-induced contractions of lung parenchymal strips, but it enhanced the production of prostaglandin (PG) E2 and PGF2 alpha although it partially inhibited thromboxane B2 formation. In other studies, in which postmortem pulmonary gas trapping was used as an index of in vivo airway obstruction, i.v. LY150310 dose-dependently inhibited the bronchospasm produced by aerosols of the divalent cationic ionophore A23187, histamine, 5-hydroxytryptamine, leukotriene D4, methacholine, ovalbumin or platelet activating factor. LY150310 was equal to or more potent than aminophylline in all test systems. Also, orally administered LY150310 inhibited the airway obstruction produced by selected challenge aerosols. In ex vivo studies, LY150310 elevated PGE2 and tended to decrease thromboxane B2 in sodium arachidonate-stimulated whole blood. However, PGE2 and other cyclooxygenase products did not appear to account for in vivo bronchodilation, because combining LY150310 and piroxicam did not alter inhibition of A23187-induced airway obstruction. Our results demonstrate that LY150310 reduces airway obstruction caused by a variety of bronchoconstrictive agents, including A23187 and ovalbumin. Although this substituted imidazole appears to have activity as a histamine H1-receptor antagonist and can alter prostanoid concentrations in vitro and in vivo, its mode of bronchodilation is unclear.