Downward Terrestrial Gamma-Ray Flash Observed in a Winter Thunderstorm.

During a winter thunderstorm on 24 November 2017, a strong burst of gamma rays with energies up to ∼10 MeV was detected coincident with a lightning discharge, by scintillation detectors installed at the Kashiwazaki-Kariwa Nuclear Power Station at sea level in Japan. The burst had a subsecond duration, which is suggestive of photoneutron production. The leading part of the burst was resolved into four intense gamma-ray bunches, each coincident with a low-frequency radio pulse. These bunches were separated by 0.7-1.5 ms, with a duration of ≪1 ms each. Thus, the present burst may be considered as a "downward" terrestrial gamma-ray flash (TGF), which is analogous to upgoing TGFs observed from space. Although the scintillation detectors were heavily saturated by these bunches, the total dose associated with them was successfully measured by ionization chambers, employed by nine monitoring posts surrounding the power plant. From this information and Monte Carlo simulations, the present downward TGF is suggested to have taken place at an altitude of 2500±500 m, involving 8_{-4}^{+8}×10^{18} avalanche electrons with energies above 1 MeV. This number is comparable to those in upgoing TGFs.

Genetic variation modulates susceptibility to aberrant DNA hypomethylation and imprint deregulation in naïve pluripotent stem cells.

Naïve pluripotent stem cells (nPSC) frequently undergo pathological and not readily reversible loss of DNA methylation marks at imprinted gene loci. This abnormality poses a hurdle for using pluripotent cell lines in biomedical applications and underscores the need to identify the causes of imprint instability in these cells. We show that nPSCs from inbred mouse strains exhibit pronounced strain-specific susceptibility to locus-specific deregulation of imprinting marks during reprogramming to pluripotency and upon culture with MAP kinase inhibitors, a common approach to maintain naïve pluripotency. Analysis of genetically highly diverse nPSCs from the Diversity Outbred (DO) stock confirms that genetic variation is a major determinant of epigenome stability in pluripotent cells. We leverage the variable DNA hypomethylation in DO lines to identify several trans-acting quantitative trait loci (QTLs) that determine epigenome stability at either specific target loci or genome-wide. Candidate factors encoded by two multi-target QTLs on chromosomes 4 and 17 suggest specific transcriptional regulators that contribute to DNA methylation maintenance in nPSCs. We propose that genetic variants represent candidate biomarkers to identify pluripotent cell lines with desirable properties and might serve as entry points for the targeted engineering of nPSCs with stable epigenomes. Highlights: Naïve pluripotent stem cells from distinct inbred mouse strains exhibit variable DNA methylation levels at imprinted gene loci.The vulnerability of pluripotent stem cells to loss of genomic imprinting caused by MAP kinase inhibition strongly differs between inbred mouse strains.Genetically diverse pluripotent stem cell lines from Diversity Outbred mouse stock allow the identification of quantitative trait loci controlling DNA methylation stability.Genetic variants may serve as biomarkers to identify naïve pluripotent stem cell lines that are epigenetically stable in specific culture conditions.

Chronic administration of DSP-7238, a novel, potent, specific and substrate-selective DPP IV inhibitor, improves glycaemic control and beta-cell damage in diabetic mice.

AIMS: The purpose of this study is to assess the in vitro enzyme inhibition profile of DSP-7238, a novel non-cyanopyrrolidine dipeptidyl peptidase (DPP) IV inhibitor and to evaluate the acute and chronic effects of this compound on glucose metabolism in two different mouse models of type 2 diabetes. METHODS: The in vitro enzyme inhibition profile of DSP-7238 was assessed using plasma and recombinant enzymes including DPP IV, DPP II, DPP8, DPP9 and fibroblast activation protein alpha (FAPalpha) with fluorogenic substrates. The inhibition type was evaluated based on the Lineweaver-Burk plot. Substrate selectivity of DSP-7238 and comparator DPP IV inhibitors (vildagliptin, sitagliptin, saxagliptin and linagliptin) was evaluated by mass spectrometry based on the changes in molecular weight of peptide substrates caused by release of N-terminal dipeptides. In the in vivo experiments, high-fat diet-induced obese (DIO) mice were subjected to oral glucose tolerance test (OGTT) following a single oral administration of DSP-7238. To assess the chronic effects of DSP-7238 on glycaemic control and pancreatic beta-cell damage, DSP-7238 was administered for 11 weeks to mice made diabetic by a combination of high-fat diet (HFD) and a low-dose of streptozotocin (STZ). After the dosing period, HbA1c was measured and pancreatic damage was evaluated by biological and histological analyses. RESULTS: DSP-7238 and sitagliptin both competitively inhibited recombinant human DPP IV (rhDPP IV) with K(i) values of 0.60 and 2.1 nM respectively. Neither vildagliptin nor saxagliptin exhibited competitive inhibition of rhDPP IV. DSP-7238 did not inhibit DPP IV-related enzymes including DPP8, DPP9, DPP II and FAPalpha, whereas vildagliptin and saxagliptin showed inhibition of DPP8 and DPP9. Inhibition of glucagon-like peptide-1 (GLP-1) degradation by DSP-7238 was apparently more potent than its inhibition of chemokine (C-X-C motif) ligand 10 (IP-10) or chemokine (C-X-C motif) ligand 12 (SDF-1alpha) degradation. In contrast, vildagliptin and saxagliptin showed similar degree of inhibition of degradation for all the substrates tested. Compared to treatment with the vehicle, single oral administration of DSP-7238 dose-dependently decreased plasma DPP IV activity and improved glucose tolerance in DIO mice. In addition, DSP-7238 significantly decreased HbA1c and ameliorated pancreatic damage following 11 weeks of chronic treatment in HFD/STZ mice. CONCLUSIONS: We have shown in this study that DSP-7238 is a potent DPP IV inhibitor that has high specificity for DPP IV and substrate selectivity against GLP-1. We have also found that chronic treatment with DSP-7238 improves glycaemic control and ameliorates beta-cell damage in a mouse model with impaired insulin sensitivity and secretion. These findings indicate that DSP-7238 may be a new therapeutic agent for the treatment of type 2 diabetes.

Hippocalcin protects hippocampal neurons against excitotoxin damage by enhancing calcium extrusion.

Hippocalcin, which is a member of the neuronal calcium-sensor protein family, is highly expressed in hippocampal pyramidal cells. Recently, it was demonstrated that hippocalcin deficit caused an increase in neuronal cell death in the field CA3 of Ammon's horn (CA3) region of the hippocampus following the systemic injection of kainic acid. Treatment with kainic acid results in seizure-induced cell death in CA3. In the present study, we injected quinolinic acid, which is an N-methyl-d-aspartate receptor agonist, into the hippocampal field CA1 of Ammon's horn (CA1) region in hippocalcin-knockout (-/-) mice, a procedure which mimics transient ischemia. Although significant pyknotic changes were observed at the injected site in wild-type (+/+) mice 24 h after injection, the area of pyknotic cells extended throughout the hippocampus in -/- mice. The quantification of cell numbers in Nissl-stained sections indicated that the cell damage in -/- mice was more severe than that in +/+ mice. The density of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling-positive cells roughly paralleled that of Nissl-stained pyknotic cells. Primary cultures of hippocampal neurons showed that the number of surviving neurons from -/- mice after 7 days in culture was smaller than the number from +/+ mice. The measurement of intracellular calcium concentrations in single cells revealed that the calcium extrusion from -/- neurons was slower than that from +/+ neurons. The involvement of hippocalcin in the upkeep of calcium extrusion was confirmed using hippocalcin-expressing COS7 cells. These results suggest that hippocalcin plays an important role in calcium extrusion from neurons and, in turn, helps to protect them against calcium-dependent excitotoxin damage in the hippocampus.

Increase in radioresponse of murine tumors by treatment with indomethacin.

Indomethacin, an inhibitor of prostaglandin (PG) synthesis, was investigated for its ability to increase radioresponse of two fibrosarcomas, FSA and NFSA, in C3Hf/Kam mice. In addition, the effect of indomethacin on radioresponse of hematopoietic tissue, jejunum, hair follicles, and tissues involved in the development of radiation-induced leg contractures was determined. Indomethacin greatly increased radioresponse of 8-mm tumors, as assessed by both tumor growth delay and TCD50 assays. Enhancement factors for tumor growth delay and tumor radiocurability (TCD50) were 1.55 and 1.39, respectively, for FSA, and 1.4 and 1.26, respectively, for NFSA tumors. Of four normal tissues assessed, two (hair follicles and tissues responsible for development of leg contractures) showed no change in radioresponse after treatment with indomethacin, one (hematopoietic tissue) exhibited radioprotection, and one (jejunum) exhibited slight radiosensitization (enhancement factor, 1.12). Therefore, indomethacin significantly augmented tumor radiocurability but had minimal effect on radioresponse of some normal tissues.

Prostaglandin production by murine tumors as a predictor for therapeutic response to indomethacin.

We investigated whether there is a relationship between the production of eicosanoids by murine solid tumors and their response to the prostaglandin H (PGH) synthase inhibitor indomethacin. Three sarcomas, designated FSA, NFSA, and SA-NH, and two carcinomas, designated MCA-K and HCA-I, syngeneic to C3Hf/Kam mice were used. In general, FSA and NFSA produced more PGH synthase products than lipoxygenase products, whereas HCA-I produced both types of metabolites in large quantities. All three tumors responded well to indomethacin treatment by slowing their growth. In contrast, MCA-K and SA-NH tumors produced insignificant quantities of PGH synthase products, but substantial amounts of lipoxygenase products. Their growth was not affected by treatment with indomethacin. Indomethacin did not influence tumor cell survival either in vitro or in vivo, but it reduced the proportion of S-phase cells in the tumors. The antitumor effect of indomethacin was not reduced by immunosuppression of the tumor host and was independent of tumor immunogenicity, implying that indomethacin acted through nonimmunological mechanisms. Thus, the effectiveness of indomethacin was directly related to the ability of tumors to produce PGs. Consequently, the eicosanoid profile of tumors could serve as a valuable way to select patients likely to respond to indomethacin and other PGH synthase inhibiting agents.

Dependence of indomethacin-induced potentiation of murine tumor radioresponse on tumor host immunocompetence.

In a previous study (Furuta, Y., Hunter, N., Barkley, H. T., Jr., Hall, E., and Milas, L., Cancer Res., 48:3008-3013, 1988), we demonstrated that inhibition of prostaglandins in murine tumors by indomethacin results in the augmentation of tumor response to single doses of ionizing radiation. The results of the present study show that indomethacin augmented tumor response to fractionated irradiation as well, the enhancement factor being more than 2. The effect of indomethacin on tumor growth and on tumor radioresponse was assayed in normal mice, mice deficient in T-cells (nude mice), and mice whose general immunocompetence was suppressed by whole-body irradiation. The antitumor activity of indomethacin was not significantly influenced by the immunocompetence of the tumor host. Since indomethacin inhibited tumor neoangiogenesis, we postulated that this inhibition is a major mechanism responsible for the antitumor activity of indomethacin. In contrast, potentiation of tumor radioresponse by indomethacin was greatly dependent on immunocompetence of tumor host: it was significantly reduced, or even abolished, when tumor grew in nude and whole-body irradiation mice. Thus, while immunocompetence of the tumor host has no significant effect on antitumor action by indomethacin, it plays a decisive role in the potentiation of tumor radioresponse by indomethacin.

Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK.

FAK is a unique non-receptor protein tyrosine kinase that was found in cellular focal adhesions. An increasing number of in vitro observations has suggested that FAK mediates signaling through integrins brought about by interactions with extracellular matrix (ECM). It is highly tyrosine-phosphorylated in v-src-transformed cells and during embryogenesis. To clarify the function of FAK in cell-ECM interactions, embryonic phenotype of its mutant was analysed. FAK-deficient embryos could implant and initiate gastrulation normally, but showed abnormalities in subsequent development. The abnormalities were characterized as a general deficiency in mesoderm, and the phenotype was quite similar to that caused by fibronectin-deficiency. The results suggest that FAK mediates fibronectin-integrin interactions uniquely at this stage of development, thereby playing an essential role in development of mesodermal cell lineages.

Fyn expression during early neurogenesis in mouse embryos.

Fyn is a member of the Src family of tyrosine kinases which are thought to play important roles in cell to cell interactions during morphogenesis. The developmental profile of Fyn expression was examined using mutant mice in which lacZ gene was introduced into this locus. The expression was characteristic in the neural system. Though at low levels, it was detected in the headfold at embryonic day (E) 7.5 and in the luminal surface of neuroectoderm along the entire neural groove at E8.5. The expression appeared regional in rhombomeres at E8.5 and E9.5. Consistent expression was also found at a low level in the notochord. The expression was high in later stages of the neural tube which consists of three layers; it was in the marginal layer but not in the germinal layer. High expression was also found in developing dorsal root filaments of neural crest origin. Non-expression in dividing neuroepithelial cells and expression in developing neural fibers appeared ubiquitous features of Fyn expression throughout the entire brain.

Percutaneous angioplasty of stenosed gastroepiploic artery grafts.

OBJECTIVES: This report describes our early experience and results with percutaneous transluminal coronary angioplasty of gastroepiploic artery grafts in 12 patients. BACKGROUND: Angioplasty has been successfully performed in saphenous vein and internal thoracic artery grafts; however, experience with angioplasty in gastroepiploic artery/coronary artery bypass grafts is limited. METHODS: Balloon angioplasty was performed in 12 patients (11 men, 1 woman; mean age 58 +/- 8 years) with either total occlusion (6 patients) or severe stenosis (6 patients) of a gastroepiploic artery/coronary artery anastomosis. In seven patients, a guide wire/balloon catheter system was used through a 7F sheath inserted into the celiac trunk. In seven patients, including two who had unsuccessful wire/balloon angioplasty, an over the wire system was used through a 6.5F Cobra or 7F JR4 guide catheter, selectively inserted into the gastroduodenal artery. RESULTS: Angioplasty was successful in five (83%) of six patients with stenosis and in one of six patients with total occlusion (p = 0.08, 1 - beta = 0.68). The guide wire could not be advanced through the lesion in five patients, and the balloon catheter did not cross the lesion in one patient whose gastroepiploic artery was tortuous. Catheters exhibited better trackability and pushability when the over the wire system was used, and five of the six successes were achieved using this approach. Follow-up arteriography was performed in five patients, and all of the gastroepiploic artery grafts were patent without stenosis. CONCLUSIONS: Angioplasty can be safely performed in stenosed gastroepiploic artery grafts. An over the wire system that uses a thin balloon catheter inserted through a guide catheter in the gastroduodenal artery seems optimal.

Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo.

In mammals, 16 members of the Fgf family have so far been described with diverse roles in embryonic cell growth and differentiation. Here, we report the expression from early streak stage to midgestation of two newly-identified murine genes, Fgf17 and Fgf18, that are most closely related to Fgf8 (63.7% and 56.8% identical, respectively, at the amino acid level). Fgf17 is expressed during gastrulation but at lower levels than Fgf8, while Fgf18 RNA is not expressed until later, in paraxial mesoderm. In the developing tail bud, each Fgf gene shows a different pattern of transcription. Distinct and overlapping expression patterns are also described in the developing brain and limbs.

Experimental model for MDS-like myelodysplasia in transgenic mice harboring the SV40 large-T antigen under an immunoglobulin enhancer.

The SV40 large T gene under the control of immunoglobulin enhancer induced hyperproliferation of multi-lineage hematopoiesis in transgenic mice. Hence the disease has been considered to be an appropriate experimental model for MDS-like myelodysplasia, sequential pathological changes in the development of the disease are introduced in the report. Huge splenomegaly was the major gross abnormality, which developed with 100% frequency; neither hepato-renal, nor other thymico-lymphatic involvement was common. During the progressive increase in splenic weight, extensive proliferation of multi-lineage hemopoiesis was prominent, although no differences were apparent in the cellular proportions of each hematopoietic element compared with normal spleens, either in flow-cytometric analysis using markers for each subset of hematopoietic elements, or in the histological findings. In the later phases of the disease, the proliferating cell type tended to shift to a variety of single to oligo-lineage hemopoiesis, but the majority of mice still showed the presence of multi-lineage hemopoiesis; histologically, such hemopoiesis was somewhat dysplastic, but had no apparent nature of leukemic infiltration. Several transplantation-assays essentially supported the low neoplastic potential of proliferating cells even in later phase. A long-term observation was made aiming to induce more frequent transition of this abnormal hemopoiesis into a single-lineage neoplasm by transplantation of pre-onset spleen cells, as well as bone-marrow cells from transgenic mice at an early phase of the disease, into lethally irradiated C57BL/6 mice. This trial resulted in a variety of neoplastic growths in the recipients; not only was myelodysplastic hypercellularity seen, but also, single-lineage hemopoietic malignancies, such as B-cell lymphomas/leukemias, histiocytic malignancies, and even myeloid leukemias. The transition from multi-lineage myelodysplasia into single lineage hemopoiesis at some frequency is reminiscent of myelodysplastic syndromes (MDS) in humans. Higher frequency of transition into lymphoid malignancies may be due partly to the immunoglobulin enhancer used as a promoter unit. The results that the SV40 large T antigen was expressed in every proliferating cells, there was no apparent increase in multi-CSFs activity; together with the results of the transplantation assays suggest that the hyperproliferation of the cells is directly induced by the expression of SV40 large T antigen in the hemopoietic cells themselves.

Prognostic significance of clinical parameters and biological markers in patients with squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy.

Concurrent chemoradiotherapy is reported to have a fair clinical outcome with organ preservation for patients with squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to determine whether biological markers are related to proliferative activity or apoptosis of tumor cells and whether clinical factors are associated with a clinical outcome in SCCHN patients treated with concurrent chemoradiotherapy. Immunostaining with antibodies specific for p53, bcl-2, bax, and MIB-1 was performed to evaluate expression of these proteins in formalin-fixed, paraffin-embedded specimens of 111 SCCHN patients treated with concurrent chemoradiotherapy (carboplatin, 100 mg/m2, four to six times every week; total radiation therapy dose of 40-65 Gy over 4-6.5 weeks). Multivariate analysis indicated that nodal status was a significant indicator of overall survival (OS; P = 0.001) and locoregional control (LRC; P = 0.002). In a univariate analysis, patients with a low MIB-1-positive index (< 40%) had better OS than those with a high MIB-1-positive index (> or = 40%; P = 0.013), although the difference was not statistically significant in a multivariate analysis (P = 0.060). Patients with bcl-2-positive tumors had better LRC than those with bcl-2-negative tumors, based on a multivariate analysis (P = 0.017). No statistically significant association was found between p53 or bax expression and clinical outcome. These results indicate that nodal status is the major prognostic factor in SCCHN patients treated with concurrent chemoradiotherapy. In addition, our findings suggest that bcl-2 positivity is associated with better LRC and that the proliferative activity of tumor cells might be prognostic for OS.

MDS-like experimental myelodysplasia: multilineage abnormal hematopoiesis in transgenic mice harboring the SV40 large T antigen under an immunoglobulin enhancer.

The SV40 large T gene under the control of immunoglobulin enhancer induced hyperproliferation of multilineage hematopoiesis in transgenic mice. Huge splenomegaly was the major gross abnormality; mice were rather anemic, and neither leukoerythroblastosis nor invasion into tissues such as liver, kidneys or lymph nodes was common. In the latter phases of the disease, the proliferating cell type tended to shift to a variety of single-lineage hematopoiesis, but the majority of mice still showed the presence of multilineage hematopoiesis; such cells were somewhat dysplastic but low in neoplastic potential. A long-term observation by transplantation of the hematopoietic cells into lethally irradiated C57BL/6 mice resulted in a variety of neoplastic growths in the recipients; not only was myelodysplastic hypercellularity seen, but also single-lineage hematopoietic malignancies such as B cell lymphomas/leukemias, histiocytic malignancies and even myeloid leukemias. The disease bore the proliferative feature solely in the spleen and bone marrow, and the transition from multilineage myelodysplasia into single-lineage hematopoiesis at some frequency is reminiscent of myelodysplastic syndromes (MDS) in humans. The results that the SV40 large T antigen was expressed in every proliferating cell, and that there was no apparent increase in any colony-stimulating cytokine(s), together with the results of the transplantation assays, suggested that the hyperproliferation of the hematopoietic cells was a direct consequence of the expression of SV40 large T antigen in these cells themselves.

Effect of oral calcium on blood pressure response in salt-loaded borderline hypertensive patients.

To clarify the mechanism of the antihypertensive effect of oral calcium loading, we studied the effect of low versus high calcium intake on salt-induced blood pressure elevations in patients with borderline hypertension. After a 7-day period of dietary salt restriction (50 meq/day), 27 patients were placed on a high salt (300 meq/day), low calcium (250 mg/day) diet for 7 days; 14 of these patients were given 2,160 mg/day of supplementary calcium (Ca group), and 13 patients were given placebo (non-Ca group). With a high salt intake, the percent increase in mean blood pressure was smaller in the Ca group than in the non-Ca group (+2.85 +/- 1.22% vs. +8.63 +/- 1.66%, respectively, p less than 0.01). The Ca group showed a smaller weight gain (p less than 0.05) and a greater urinary excretion of sodium (p less than 0.005) than the non-Ca group. In the Ca group, but not in the non-Ca group, high salt intake resulted in an increase in intraerythrocyte magnesium content (p less than 0.01), which was correlated inversely with the salt-induced changes in mean blood pressure (r = -0.54, p less than 0.05). While the increase in cellular magnesium was greater in the Ca group, the changes in red blood cell sodium and sodium/potassium ratio were not different between the two groups. The results suggest that oral calcium supplementation may prevent a rise in blood pressure in patients on a high salt, low calcium diet by attenuating the sodium retention.(ABSTRACT TRUNCATED AT 250 WORDS)

Genomic structure and chromosomal mapping of the human and mouse hippocalcin genes.

In an attempt to elucidate the possible relationship of hippocalcin to neurological disorders, we isolated and analyzed the human and mouse hippocalcin genes. The human and mouse hippocalcin genes contain three exons and two introns, and span approximately 7 and 8kb, respectively. The exon/intron splice junctions of the human and mouse genes are all situated in exactly the same position and are not consistently placed with respect to the coding regions of the tandemly repeated EF-hand motifs. The amino acid sequences of human and mouse hippocalcins deduced from the genes are 100% identical. Within the 2-kb 3'-flanking sequences of the human and mouse genes, one conserved polyadenylation signal was identified at positions 762 and 823bp downstream from TAG, respectively. Within the 2.6-kb 5'-flanking sequences of the human and mouse genes, neither a canonical 'TATA' box nor a 'CAAT' box was found. Southern blot analysis of the human and mouse genomic DNAs demonstrated that the positive bands coincide exactly with those expected from the sequence of the cloned genes, indicating that the human and mouse hippocalcin genes are present as a single-copy gene. Fluorescence in-situ hybridization revealed that the human hippocalcin gene is located at chromosome 1 p34.2-35 and the mouse hippocalcin gene at chromosome 4 D2-D3.

Early diagnosis of zoster sine herpete and antiviral therapy for the treatment of facial palsy.

The effect of antiviral agents on recovery from facial palsy in patients with zoster sine herpete (ZSH; varicella zoster virus reactivation without zoster) has not been evaluated because ZSH is difficult to diagnose early after onset. In this study, all 13 patients who received acyclovir-prednisone treatment within 7 days of onset, as confirmed by a positive PCR result, showed complete recovery. PCR-based early diagnosis of ZSH and antiviral therapy elicited an excellent outcome for recovery from facial palsy due to ZSH.

Plasma concentrations of platelet-specific proteins in different stages of essential hypertension: interactions between platelet aggregation, blood lipids and age.

Plasma beta-thromboglobulin (beta TG) and platelet factor 4 (PF4) were significantly higher in a group of 116 hypertensive men than in a normotensive group of 142 men. They increased with the stage of hypertension but the level did not correlate with the age of the subjects. Platelet aggregation was similar in the two groups and positively correlated with the age of the subjects in the normotensive group but not in the hypertensive group. A strong positive correlation was observed between the levels of plasma beta TG and PF4 and between platelet aggregation to ADP and that to epinephrine in both the hypertensive and normotensive groups. However, there was no correlation between the level of plasma beta TG or PF4 and platelet aggregation. Plasma antithrombin III was lower in the hypertensive group than in the normotensive group. These studies suggest that plasma levels of beta TG and PF4 are closely related to the stage of hypertension and are better indicators than aggregation of in vivo platelet activation in hypertensive subjects. Enhanced platelet activation may be involved in the acceleration of hypertensive arteriovascular damage and atherosclerosis.

beta-Adrenoceptor stimulation of exocrine secretion from the rat pancreas.

1 Effects of catecholamines given intravenously on exocrine secretion from the pancreas were investigated in anaesthetized rats. The flow rate of pancreatic juice under resting conditions was 11.1 +/- 3.2 microliter per hour in 100 animals. 2 Dopamine (0.3--3 mg/kg) and isoprenaline (1--10 microgram/kg) induced almost the same increase in the pancreatic secretion, so that dopamine was 300 times less potent than isoprenaline. The relative potency of the two amines for stimulation of pancreatic secretion was equivalent to that for beta-stimulation of the contractile force of the left ventricle in vivo. 3 Propranolol (0.5 mg/kg) antagonized completely the dopamine- and isoprenaline-induced stimulation of the pancreatic secretion. 4 Haloperidol (10 mg/kg) failed to suppress the secretory effect of dopamine on the exocrine pancreas but abolished the dopamine-induced hypotension. 5 The dopamine-induced secretion was not modified by atropine (3 mg/kg), phenoxybenzamine (3 mg/kg), vagotomy or pithing. 6 Adrenaline and noradrenaline (10 microgram/kg) induced secretion after phenoxybenzamine treatment (3 mg/kg). 7 It is suggested that the rat pancreas has a stimulatory beta-adrenoceptor mechanism of exocrine secretion.

Modification by drugs of the secretagogue effect of dopamine on the pancrease.

1 The specific stimulating action of dopamine and L-DOPA on exocrine pancreatic secretion was further investigated in the isolated blood-perfused canine pancreas.2 6-Hydroxydopamine (100 mug, i.a.) stimulated the secretion but was far less potent than dopamine. Epinine (0.3-1 mg. i.a.), alpha-methyldopamine (10-300 mug, i.a.) and octopamine (10-300 mug, i.a.) were ineffective.3 alpha-Methyldopa (30 mg, i.a.) inhibited the stimulating effect of L-DOPA (1-3 mg) on pancreatic secretion.4 Apomorphine (1 mg, i.a.) attenuated dopamine-induced (1-30 mug) pancreatic secretion but did not antagonize secretin-induced (0.03-0.3 units) or pancreozymin-induced (0.3-1 units) secretion.5 These observations suggest that L-DOPA is probably converted to dopamine to stimulate the exocrine pancreas, and that dopamine interacts with the specific receptors.6 The noradrenaline and dopamine content of the canine pancreas was estimated in controls and in dogs treated with secretin, reserpine, L-DOPA or alpha-methyldopa. The values for dopamine and noradrenaline in controls were 139 +/- 6 and 375 +/- 40 ng/g tissue (n=13), respectively. Reserpine reduced the noradrenaline content of the pancreatic tissue without affecting the dopamine content. L-DOPA or secretin caused a significant increase in the dopamine, but not in the noradrenaline content. It is suggested that dopamine has a physiological function in the pancreas which is independent of that of the noradrenaline-containing nerve fibres.