Search

We determined the ultracold neutron (UCN) production rate by superthermal conversion in the solid deuterium (sD$_2$) moderator of the UCN source at the Paul Scherrer Institute (PSI). In particular, we considered low amounts of less than $20\,$mol of D$_2$, deposited on the cooled moderator vessel surfaces in thin films of a few mm thickness. We measured the isotopic ($ c_\text{HD} < 0.2 \, \% $) and isomeric ($ c_\text{para} \le 2.7 \, \% $) purity of the deuterium to conclude that absorption and up-scattering at $5\,$K have a negligible effect on the UCN yield from the thin films. We compared the calculated UCN yield based on the previously measured thermal neutron flux from the heavy water thermal moderator with measurements of the UCN count rates at the beamports. We confirmed our results and thus demonstrate an absolute characterization of the UCN production and transport in the source by simulations.

Magnetic Johnson-Nyquist noise (JNN) originating from metal electrodes, used to create a static electric field in neutron electric-dipole-moment (nEDM) experiments, may limit the sensitivity of measurements. We present here the first dedicated study on JNN applied to a large-scale long-measurement-time experiment with the implementation of a co-magnetometry. In this study, we derive surface- and volume-averaged root-mean-square normal noise amplitudes at a certain frequency bandwidth for a cylindrical geometry. In addition, we model the source of noise as a finite number of current dipoles and demonstrate a method to simulate temporal and three-dimensional spatial dependencies of JNN. The calculations are applied to estimate the impact of JNN on measurements with the new apparatus, n2EDM, at the Paul Scherrer Institute. We demonstrate that the performances of the optically pumped $^{133}$Cs magnetometers and $^{199}$Hg co-magnetometers, which will be used in the apparatus, are not limited by JNN. Further, we find that in measurements deploying a co-magnetometer system, the impact of JNN is negligible for nEDM searches down to a sensitivity of $4\,\times\,10^{-28}\,e\cdot{\rm cm}$ in a single measurement; therefore, the use of economically and mechanically favored solid aluminum electrodes is possible.

The European Physical Journal A, 57 (7), ISSN:1434-6001, ISSN:1434-601X

Psychological bias towards, or away from, prior measurements or theory predictions is an intrinsic threat to any data analysis. While various methods can be used to try to avoid such a bias, e.g. actively avoiding looking at the result, only data blinding is a traceable and trustworthy method that can circumvent the bias and convince a public audience that there is not even an accidental psychological bias. Data blinding is nowadays a standard practice in particle physics, but it is particularly difficult for experiments searching for the neutron electric dipole moment (nEDM), as several cross measurements, in particular of the magnetic field, create a self-consistent network into which it is hard to inject a false signal. We present an algorithm that modifies the data without influencing the experiment. Results of an automated analysis of the data are used to change the recorded spin state of a few neutrons within each measurement cycle. The flexible algorithm may be applied twice (or more) to the data, thus providing the option of sequentially applying various blinding offsets for separate analysis steps with independent teams. The subtle manner in which the data are modified allows one subsequently to adjust the algorithm and to produce a re-blinded data set without revealing the initial blinding offset. The method was designed for the 2015/2016 measurement campaign of the nEDM experiment at the Paul Scherrer Institute. However, it can be re-used with minor modification for the follow-up experiment n2EDM, and may be suitable for comparable projects elsewhere., The European Physical Journal A, 57 (4), ISSN:1434-6001, ISSN:1434-601X

We present the result of an experiment to measure the electric dipole moment (EDM) of the neutron at the Paul Scherrer Institute using Ramsey’s method of separated oscillating magnetic fields with ultracold neutrons. Our measurement stands in the long history of EDM experiments probing physics violating time-reversal invariance. The salient features of this experiment were the use of a 199Hg comagnetometer and an array of optically pumped cesium vapor magnetometers to cancel and correct for magnetic-field changes. The statistical analysis was performed on blinded datasets by two separate groups, while the estimation of systematic effects profited from an unprecedented knowledge of the magnetic field. The measured value of the neutron EDM is dn=(0.0±1.1stat±0.2sys)×10−26 e.cm., Physical Review Letters, 124 (8), ISSN:0031-9007, ISSN:1079-7114

An array of 16 laser-pumped scalar Cs magnetometers was part of the neutron electric dipole moment (nEDM) experiment taking data at the Paul Scherrer Institute in 2015 and 2016. It was deployed to measure the gradients of the experiment's magnetic field and to monitor their temporal evolution. The originality of the array lies in its compact design, in which a single near-infrared diode laser drives all magnetometers that are located in a high-vacuum chamber, with a selection of the sensors mounted on a high-voltage electrode. We describe details of the Cs sensors' construction and modes of operation, emphasizing the accuracy and sensitivity of the magnetic-field readout. We present two applications of the magnetometer array directly beneficial to the nEDM experiment: (i) the implementation of a strategy to correct for the drift of the vertical magnetic-field gradient and (ii) a procedure to homogenize the magnetic field. The first reduces the uncertainty of the nEDM result. The second enables transverse neutron spin relaxation times exceeding 1500 s, improving the statistical sensitivity of the nEDM experiment by about 35% and effectively increasing the rate of nEDM data taking by a factor of 1.8. An array of sixteen laser-pumped scalar Cs magnetometers was part of the neutron electric dipole moment (nEDM) experiment taking data at the Paul Scherrer Institute in 2015 and 2016. It was deployed to measure the gradients of the experiment's magnetic field and to monitor their temporal evolution. The originality of the array lies in its compact design, in which a single near-infrared diode laser drives all magnetometers that are located in a high-vacuum chamber, with a selection of the sensors mounted on a high-voltage electrode. We describe details of the Cs sensors' construction and modes of operation, emphasizing the accuracy and sensitivity of the magnetic field readout. We present two applications of the magnetometer array directly beneficial to the nEDM experiment: (i) the implementation of a strategy to correct for the drift of the vertical magnetic field gradient and (ii) a procedure to homogenize the magnetic field. The first reduces the uncertainty of the new nEDM result. The second enables transverse neutron spin relaxation times exceeding 1500 s, improving the statistical sensitivity of the nEDM experiment by about 35% and effectively increasing the rate of nEDM data taking by a factor of 1.8.

We present the new spectrometer for the neutron electric dipole moment (nEDM) search at the Paul Scherrer Institute (PSI), called n2EDM. The setup is at room temperature in vacuum using ultracold neutrons. n2EDM features a large UCN double storage chamber design with neutron transport adapted to the PSI UCN source. The design builds on experience gained from the previous apparatus operated at PSI until 2017. An order of magnitude increase in sensitivity is calculated for the new baseline setup based on scalable results from the previous apparatus, and the UCN source performance achieved in 2016., Submitted as a web of conference proceedings paper

We report on the strategy used to optimize the sensitivity of our search for a neutron electric dipole moment at the Paul Scherrer Institute. Measurements were made upon ultracold neutrons stored within a single chamber at the heart of our apparatus. A mercury cohabiting magnetometer together with an array of cesium magnetometers were used to monitor the magnetic field, which was controlled and shaped by a series of precision field coils. In addition to details of the setup itself, we describe the chosen path to realize an appropriate balance between achieving the highest statistical sensitivity alongside the necessary control on systematic effects. The resulting irreducible sensitivity is better than 1 × 10−26e cm. This contribution summarizes in a single coherent picture the results of the most recent publications of the collaboration., EPJ Web of Conferences, 219, ISSN:2100-014X, ISSN:2101-6275

© 2019 American Physical Society. Magnetic-field uniformity is of the utmost importance in experiments to measure the electric dipole moment of the neutron. A general parametrization of the magnetic field in terms of harmonic polynomial modes is proposed, going beyond the linear-gradients approximation. We review the main undesirable effects of nonuniformities: depolarization of ultracold neutrons and Larmor frequency shifts of neutrons and mercury atoms. The theoretical predictions for these effects were verified by dedicated measurements with the single-chamber neutron electric-dipole-moment apparatus installed at the Paul Scherrer Institute. ispartof: Physical Review A vol:99 issue:4 status: published

The neutron and its hypothetical mirror counterpart, a sterile state degenerate in mass, could spontaneously mix in a process much faster than the neutron β-decay. Two groups have performed a series of experiments in search of neutron – mirror-neutron (n − n′) oscillations. They reported no evidence, thereby setting stringent limits on the oscillation time τnn′. Later, these data sets have been further analyzed by Berezhiani et al.(2009–2017), and signals, compatible with n − n′ oscillations in the presence of mirror magnetic fields, have been reported. The Neutron Electric Dipole Moment Collaboration based at the Paul Scherrer Institute performed a new series of experiments to further test these signals. In this paper, we describe and motivate our choice of run configurations with an optimal filling time of 29 s, storage times of 180 s and 380 s, and applied magnetic fields of 10 μT and 20 μT. The choice of these run configurations ensures a reliable overlap in settings with the previous efforts and also improves the sensitivity to test the signals. We also elaborate on the technique of normalizing the neutron counts, making such a counting experiment at the ultra-cold neutron source at the Paul Scherrer Institute possible. Furthermore, the magnetic field characterization to meet the requirements of this n − n′ oscillation search is demonstrated. Finally, we show that this effort has a statistical sensitivity to n − n′ oscillations comparable to the current leading constraints for B′ = 0., EPJ Web of Conferences, 219, ISSN:2100-014X, ISSN:2101-6275

Pumpkins are one of the most important Cucurbitaceae vegetables in Taiwan, and Cucurbita pepo Tung Ying is the primary cultivar planted by farmers. In December 2015, about 5% pumpkin fruits with circular, corky, and tan lesions were seen in a 20 ha field in Yilan County, Taiwan. Later in January 2016, approximately 20% of the pumpkin plants in Fenglin (23.756844, 121.469782) nearby Hualien County also developed the typical symptoms which were diamond-shaped white to cream-colored lesions on their stems, petioles, and leaves. After 5 to 10 seconds surface disinfected with 0.5% sodium hypochlorite, 3 to 4 excised leaf, stem and fruit samples were placed on potato dextrose agar (PDA) and incubated at 22°C with a 12-h photoperiod. A single-spore was isolated pale pink colonies with appressed and slimy mycelium grew on PDA. Aerial mycelium growth was occasionally detected. Moreover, aseptate or single-septate, hyaline, symmetric spores (sized 6.0 × 2.0 to 9.0 × 2.8 μm dimension) were observed microscopically. ...

The influence of kidney function on interleukin-10 (IL-10) pharmacokinetics was assessed by comparing the disappearance of IL-10 from the circulation in the intact and acutely nephrectomized mice over 1 h following a single bolus injection of E. coli-derived recombinant h IL-10 at 250 micrograms/kg i.v. The intact mice demonstrated a C(max) of 1,172 ng/ml and an AUC(tf) of 385 n g.h/ml. By comparison, there was a 4-fold elevation in C(max) and a 7-fold increase in AUC(tf) in the anephric mice. The serum IL-10 concentration at 1 h post-injection was 87 ng/ml in the intact vs 1,684 ng/ml in the anephric mice. The results imply that IL-10, in common with other cytokines, is eliminated through the kidney.

Platelets have been implicated in the pathophysiology of ischemia-reperfusion injury. In this study, antiplatelet effects of cyclic GMP (cGMP)- and cyclic AMP (cAMP)-mediated agents were evaluated in renal ischemia in pentobarbital-anesthetized rats. Renal ischemia was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion (30 min) with the contralateral kidney serving as control. 111Indium-labeled platelets, drugs or vehicle were administered 30 min before induction of renal ischemia. Occlusion of the left renal artery for 20, 40 or 60 min resulted in a 100, 300 and 600% increase (over contralateral right kidney) in the platelet-associated 111indium activity in the ischemic kidney. In all subsequent studies the kidney was occluded for 40 min to test the antiplatelet activity of individual agents. 8-Br-cGMP (0.1 and 0.3 mg/kg/min i.v.), zaprinast (0.1 mg/kg/min i.v.) and sodium nitroprusside (0.003 and 0.01 mg/kg/min i.v.) significantly attenuated platelet accumulation in renal ischemia, whereas 8-Br-cAMP (0.3 mg/kg/min i.v.) or milrinone (0.1 mg/kg i.v. bolus, plus 0.01 mg/kg/min) did not. Minoxidil (0.01 and 0.03 mg/kg/min i.v.), a vasodilator which produced equihypotensive effects as the cGMP-mediated agents, and milrinone failed to prevent platelet accumulation. These results demonstrate that modulation of the platelet function by cGMP agents can be dissociated from their blood pressure lowering effects. cGMP is known to inhibit both platelet adhesion and aggregation, whereas cAMP is only active against aggregation. The present findings provide further evidence that cGMP-mediated drugs may afford effective antiplatelet action in an in vivo model of ischemia-reperfusion injury.

Endothelin (ET)-1 is a potent vasoactive peptide elaborated by the vascular endothelial cells. In the present study we examined the effects of ischemia-hypoxia (I/H) on ET-1 release from isolated perfused guinea pig lungs and heart. Guinea pig lungs subjected to 15 min I/H followed by reperfusion and reventilation significantly (P less than .05) augmented ET-1 release from 14.1 +/- 2.7 to 30.4 +/- 5.6, 27.3 +/- 4.0 and 28.0 +/- 5.0 pg/g of dry weight of lung at 15, 30 and 45 min after I/H, respectively. Pretreatment of guinea pigs with phosphoramidon (10 mg/kg i.v.), an ET converting enzyme inhibitor, 10 min before the removal of lungs abrogated the I/H-induced increases in ET-1 release without affecting the base-line values of ET-1. Phosphoramidon also attenuated the elevations in pulmonary insufflation pressure (PIP) produced by I/H. Moreover, infusion of big ET-1 (BET-1; 30 micrograms/over 15 min) into isolated perfused guinea pig lungs enhanced PIP that was abolished by phosphoramidon. Isolated guinea pig hearts subjected to 15 or 30 min of global ischemia exhibited no disturbances in ET-1 release or mechanical activity. In addition, the increases in perfusion pressure elicited by BET-1 infusion (12 micrograms/over 30 min) into isolated guinea pig hearts was unaffected by phosphoramidon. In a separate study in anesthetized guinea pigs, phosphoramidon significantly attenuated the increases in blood pressure and PIP elicited by BET-1 (10 micrograms/kg i.v.); the pressor and PIP responses to ET-1 (4 micrograms/kg i.v.) were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

The possible role of sympathoadrenal stimulation and endothelin release in cyclosporine (CS)-induced hypertension was ascertained in intact and pithed rats. CS (20 and 40 mg/kg), administered by i.v. infusion over 10 min, produced a dose-dependent increase in blood pressure: 19 +/- 5 and 31 +/- 2 mm Hg in intact rats and 13 +/- 4 and 18 +/- 2 mm Hg in pithed rats. In intact rats, pretreatment with reserpine (5 mg/kg, i.p.) or hexamethonium (10 mg/kg, i.v.) greatly blunted the pressor responses to CS (40 mg/kg) (7 +/- 3 and 11 +/- 2 mm Hg, respectively). In pithed rats, the blood pressure responses to CS (40 mg/kg) were significantly impaired, but were not further modified by phenoxybenzamine (3 mg/kg, i.v.), whereas adrenalectomy completely abolished the CS-induced pressor responses (0 +/- 1 mm Hg). CS (40 mg/kg) did not potentiate pressor responses to sympathetic nerve stimulation (0.1 and 0.3 Hz) or vasoconstrictors, including angiotensin II (0.03 microgram/kg, i.v.), phenylephrine (1 microgram/kg, i.v.) and arginine vasopressin (0.075 microgram/kg) in pithed rats. In addition, CS (40 mg/kg, i.v.) did not cause elevation of plasma immunoreactive endothelin-1 and -3. Furthermore, phosphoramidon (0.25 mg/kg/min x 30) abolished pressor response to big endothelin-1 (5 micrograms/kg, i.v.) but failed to affect CS-induced hypertension. It is concluded that the acute blood pressure response to CS manifests great dependence on sympathetic nervous system but appears independent of endothelin release.

Inhibition of the enzyme neutral metalloendopeptidase (NEP) potentiates responses to atrial natriuretic factor (ANF) and elicits reductions in blood pressure in deoxycorticosterone acetate sodium (DOCA Na) hypertensive rats. The present study evaluated the role of ANF and bradykinin in the antihypertensive response to NEP inhibition through the use of antibodies and antagonists, respectively. In addition, the pharmacokinetic mechanism by which NEP inhibition interferes with ANF metabolism was explored. The antihypertensive response to the NEP inhibitors SCH 34826 and 42495 was abruptly reversed by an intravenous injection of a polyclonal antiserum to ANF. In contrast, the antihypertensive response to SCH 34826 was unaffected by injection of the bradykinin antagonist [thi5,8-D-phe7] bradykinin, indicating that ANF, but not bradykinin, affects this response. The NEP inhibitor SCH 39370 significantly delayed the disappearance of trichloroacetic acid (TCA)-precipitable radioactivity and the appearance of TCA-soluble radioactivity in plasma following an intravenous bolus dose of 125I-ANF(99-126). The effects were enhanced in the presence of the C-receptor ligand des[gln18,ser19,gly20,leu21,gly22]r ANF(4-23)-NH2. These data suggest that the two clearance mechanisms interact to govern plasma levels of ANF.

Prostaglandin E2 and carbenoxolone, putative cytoprotective agents, were tested in cysteamine, reserpine and stress ulcers in rats. In cysteamine-induced duodenal ulcer, PGE2 was inactive at 0.1 and 0.5 mg/kg p.o.; carbenoxolone at 100 mg/kg p.o. decreased the incidence but not the severity of the ulcer. PGE2 at 5.0 mg/kg p.o. and carbenoxolone at 300 mg/kg p.o. showed moderate effects, but the dosage also inhibited cysteamine-stimulated acid secretion. PGE2 (0.1 and 0.3 mg/kg p.o.) was inactive and carbenoxolone (100 and 300 mg/kg p.o.) further aggravated the gastric ulceration caused by reserpine or cold-restraint stress. In contrast, atropine (3 and 10 mg/kg p.o.) and cimetidine (30, 100 and 300 mg/kg p.o.) were active in all three ulcer models. But the results with cimetidine in stress ulcer were somewhat variable. 2-methyl-8-(phenylmethoxy) imidazo [1,2-a] pyridine-3-acetonitrile (Sch 28 080), a novel structure with both cytoprotective and antisecretory activity, was highly efficacious in cysteamine, reserpine and stress ulcers (1-30 mg/kg p.o.), which was presumably adequately accounted for by its potent antisecretory activity. It is concluded that cysteamine, reserpine and stress ulcers may not be appropriate models for testing the potential antiulcer effect of primarily cytoprotective compounds.

This report describes the gastric antisecretory properties of SCH 32651 (3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a] pyrazine HCl . 1/3 H2O). In the pyloric ligated rat, SCH 32651 inhibited gastric acid secretion; the oral ID50 (95% confidence limits) was 23.7 (13.8-39.2) mg/kg. In Heidenhain pouch dogs, SCH 32651 antagonized histamine-stimulated acid secretion with an ID50 of 1.44 (0.55-3.91) mg/kg p.o. SCH 32651 was also active against secretory responses to dimaprit, pentagastrin and feeding in dogs. In all test models SCH 32651 showed similar potency to cimetidine. Chronic administration of SCH 32651 or cimetidine caused slight tolerance and its antisecretory effect was readily reversible on cessation of dosing. The data indicate that SCH 32651 is an orally effective novel antisecretory drug.

SCH 39370 (N-[N-[1-(S)-carboxyl-3-phenylpropyl]-(S)-phenyl-alanyl]-(S)-isoserin e) is a potent and specific inhibitor of neutral metalloendopeptidase (NEP) from rabbit kidney (IC50 = 11.2 +/- 1.9 nM) and is devoid of angiotensin-converting enzyme inhibitory activity at 1 microM. We evaluated the effect of NEP inhibition with SCH 39370 on the inactivation of atrial natriuretic factor (ANF) and on cardiovascular function in rats. SCH 39370 effectively prevented in vitro degradation of ANF (99-126) by a purified rabbit kidney NEP. SCH 39370 (30 mg/kg s.c) significantly delayed the disappearance of immunoreactive (ir) ANF from plasma in rats after an i.v. infusion of ANF (1 microgram/kg/min for 30 min): the plasma ir ANF level at 15 min postinfusion was 1.5 +/- 0.3 ng/ml vs. 0.3 +/- 0.04 ng/ml in the control. SCH 39370 also delayed the disappearance of ir ANF after infusion of the peptide (0.1 microgram/kg/min for 30 min) which increased plasma levels to those observed during volume expansion. This effect was accentuated markedly in rats with bilateral nephrectomy. The hypotensive response to injection of ANF (30 micrograms/kg i.v.) in spontaneously hypertensive rats (-38 +/- 6 mm Hg vs. -13 +/- 2 mm Hg in the control) and the diuretic and natriuretic responses to ANF in normal rats were potentiated by SCH 39370 (30 mg/kg s.c.), respectively. The results suggest that NEP can play a role in ANF disposition in vivo and that potentiation of the biological activities of high doses of ANF by SCH 39370 may be consequent to its inhibitory effect on ANF degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

By using aprotinin, a potent kallikrein inhibitor, the role of kinin formation in the cardiovascular and renal effects of captopril was assessed in pentobarbital-anesthetized dogs previously undergoing hydrochlorothiazide treatment (2.5 mg/kg, p.o., b.i.d.) for 5 days. A fall in mean arterial pressure (MBP) from 117 +/- 8 to 94 +/- 6 mmHg followed i.v. administration of captopril, 1 mg/kg. A concomitant rise in renal blood flow (RBF) from 168 +/- 18 to 205 +/- 20 ml/min occurred without changes in glomerular filtration rate (GFR) and with cardiac output tending to decrease. Urine flow (V) tended to rise while Na+ and K+ excretion were variable. With i.v. infusion of aprotinin (900 KIU/min) the hypotensive response to captopril was unaffected (from 103 +/- 5 to 75 +/- 8 mmHg) suggesting that captopril decreases BP independent of kinin accumulation. However, aprotinin completely abolished the renal vasodilator response to captopril (from 163 +/- 25 to 143 +/- 22 ml/min). In addition, there was a concomitant fall in GFR, V and electrolyte excretion. In comparison, the cardiovascular and renal effects of saralasin (3 micrograms/kg/min, i.v.) were not altered by aprotinin. It is, therefore, concluded that, in dogs with stimulated renin-angiotensin system, the plasma kinins do not contribute to the hypotensive action of captopril but play an important role in inducing renal vasodilatation and supporting kidney function.

Phorbol esters activate protein kinase C and induce contraction in vascular smooth muscle. The role of Ca and the sensitivity of this response to nitrovasodilators were evaluated in rabbit aortic rings. Phorbol dibutyrate (PDB) (0.01-10 microM) elicited a concentration-dependent contraction of rabbit aortic rings. Responses to PDB in a salt solution (SS) containing 2.54 mM CaCl2 were not significantly different from those in SS containing 0 Ca and 2 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. Contractions to PDB (1 microM) in zero Ca SS were not reduced by depletion of the norepinephrine-sensitive pool of intracellular Ca. The Ca entry blockers verapamil (100 microM) and nifedipine (100 microM) did not affect PDB (1 microM) responses. Nitroprusside (0.1-10 microM) and nitroglycerin (0.1-10 microM) inhibited PDB contractions in both normal SS and Ca-free SS. 8-Br-cyclic GMP (100 microM) also inhibited PDB responses. Effects of PDB on 45Ca fluxes were evaluated in separate experiments. PDB (1 and 10 microM) elicited contraction, but no change in 45Ca uptake or efflux. In contrast KCl (80 mM) and norepinephrine (10 microM) elicited an increase in both influx and efflux, reflecting a rise in cytosolic Ca. The data suggest that PDB-induced contractions in rabbit aorta are independent of extracellular Ca and are not associated with a rise in cytosolic Ca as detected by calcium flux studies.(ABSTRACT TRUNCATED AT 250 WORDS)

The gastrointestinal protective action of SCH 12223 [3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one hydrate, sodium salt] against various noxious stimuli was characterized in rats. SCH 12223 inhibited the ethanol-induced gastric lesions when given p.o. (0.3-3 mg/kg) or i.v. (1 and 3 mg/kg). Indomethacin pretreatment (10 mg/kg p.o.) did not interfere with this effect. SCH 12223 was also active p.o. in five gastric erosion models: aspirin (1-10 mg/kg), aspirin + acid (1-30 mg/kg), indomethacin (1-10 mg/kg), stress (1 and 3 mg/kg) and reserpine (0.3-10 mg/kg)-induced erosions. The compound lacked antisecretory activity in the pylorus-ligated rats (10 mg/kg p.o.) but increased total gastric mucus (N-acetylneuraminic acid measurements) (1-10 mg/kg p.o.). SCH 12223 (10 and 30 mg/kg p.o.) attenuated intestinal lesions provoked by indomethacin (20 mg/kg p.o. or s.c.) and the protected animals showed better weight gain and food intake than controls. In a 38-day study, SCH 12223 also improved survival from indomethacin lethality (6 of 16 vs. 16 of 16 in the control, P less than .05). The protection cannot be attributed to changes in biliary excretion and plasma levels of indomethacin. We conclude that SCH 12223 is a unique agent which protects both gastric and intestinal epithelia from noxious stimuli, a feature shared by prostaglandins.

The antisecretory activity of SCH 32651 (3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a] pyrazine HCl . 1/3 H2O) has been described in a preceding paper. This report describes its gastric cytoprotective properties. SCH 32651 inhibited the gastric lesions due to ethanol in a dose-dependent manner (ID50 = 5 mg/kg p.o.) and exerted its maximal effect when given 30 min before ethanol and had a duration of at least 90 min at 30 mg/kg p.o. The activity of SCH 32651 against ethanol was unaffected by indomethacin pretreatment. Furthermore, SCH 32651 produced significant increases in gastric mucus release (10-100 mg/kg p.o.) and rapidly reversed ethanol-induced (30-100 mg/kg p.o.) fall in gastric potential difference (PD). SCH 32651 displayed significant antiulcer activity in indomethacin-(30-100 mg/kg p.o.), aspirin - (30-100 mg/kg p.o.), "aspirin + acid" - (10-100 mg/kg p.o.), reserpine - (10-100 mg/kg p.o.), stress - (30-100 mg/kg p.o.), and cysteamine (10-100 mg/kg p.o.) ulcers. The present data in conjunction with those reported in a preceding paper indicate that SCH 32651 is an orally effective novel antiulcer drug with both gastric antisecretory and cytoprotective properties.

The role of renal prostaglandin (PG) and kallikrein-kinin systems in the renal effects of furosemide was assessed indirectly by using known inhibitors of synthetic pathways in conscious rats supplemented with physiological saline (2.0% body wt.). In normal rats oral pretreatment of indomethacin or meclofenamic acid (cyclooxygenase inhibitors) each at 10 mg/kg failed to alter the diuretic and natriuretic responses to furosemide (10 and 30/kg, p.o.). In contrast, the natriuretic and diuretic actions of furosemide in sodium-deficient rats were greatly inhibited by indomethacin and by meclofenamic acid independent of changes in endogenous creatinine excretion. Aprotinin (2..0 x 10(5) KIU/kg, s. c.), an inhibitor of kallikrein formation, did not impair the natriuretic and diuretic responses to furosemide in either normal or low-sodium rats. Additionally aprotonin did not influence the antagonistic effects of indomethacin against furosemide in low-sodium rats. These results suggest that the renal PG system but not the kallikreinkinin system is necessary for furosemide to produce optimal diuretic and natriuretic effects during sodium restriction.

SCH 28080 (2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile) is a novel antiulcer agent which has both antisecretory and cytoprotective activities. The antisecretory ED50 values in the pylorus-ligated rat were 3.7 mg/kg p.o. and 2.8 mg/kg i.p., being 7 and 10 times more potent than cimetidine, respectively. In dogs, SCH 28080 was effective in inhibiting acid secretion stimulated by histamine (ED50 of 0.09 mg/kg i.v. and 4.4 mg/kg p.o.), dimaprit, pentagastrin, insulin and feeding. The cytoprotective activity of SCH 28080 was demonstrated by inhibition of ethanol-induced gastric lesions in a dose-dependent manner in rats (ED50:3.0 mg/kg p.o.). SCH 28080 was active in similar dose ranges (1-10 mg/kg) by both p.o. and i.v. routes of administration. This gastric cytoprotective activity was not affected by indomethacin pretreatment. Furthermore, the gastric potential difference was effectively sustained by SCH 28080 (3, 10 and 30 mg/kg p.o.) after intragastric ethanol. SCH 28080 (1-30 mg/kg p.o.) also inhibited gastric ulcers provoked by aspirin, aspirin + acid, indomethacin and stress (cold-restraint) in rats. The data support the concept that it is possible to have combined antisecretory and cytoprotectant actions in a single molecule which is not a prostaglandin.