In the presence of arginine vasopressin (AVP), somatostatin increases [Ca2+]i, leading to a transient increase in insulin release from clonal β cells HIT-T15 via Gi/o and phospholipase C (PLC) pathway (Cheng et al., 2002a). The present study was to elucidate the mechanisms underlying somatostatin-induced [Ca2+]i increase in the presence of AVP. We found that the effect of somatostatin was mediated by βγ subunits but not by the α subunit of Gi/o. Because somatostatin alone failed to increase [Ca2+]i, we hypothesized that somatostatin increases phosphatidylinositol 4,5-bisphosphate (PIP2) synthesis, providing extra substrate for preactivated PLC-β to generate inositol 1,4,5-trisphosphate (IP3). Somatostatin alone did not increase IP3 levels, but AVP + somatostatin did. Somatostatin increased PIP2 levels but decreased phosphatidylinositol 4-phosphate levels. We further hypothesized that PLD mediates somatostatin-induced changes in PIP2 levels. Both the phospholipase D (PLD) inhibitors and antibody versus PLD1 antagonized AVP-somatostatin-induced increases in [Ca2+]i. PLD inhibitor also antagonized somatostatin-induced increase in PIP2 levels. In addition, somatostatin increased PLD activity. These results suggest that activation of somatostatin receptors that are coupled to the βγ dimer of Gi/o led to PLD1 activation, thus promoting the synthesis of phosphatidic acid. Phosphatidic acid activates PIP-5 kinase, which evokes an increase in PIP2 synthesis. The PIP2 generated by somatostatin administration increases substrate for preactivated phospholipase C-β, which hydrolyzes PIP2 to form IP3, leading to an increase in [Ca2+]i. The regulation of PIP2 synthesis by Gi/o-coupled receptors via PLD activation represents a novel signaling mechanism for somatostatin and a novel concept in the cross-talk between Gq- and Gi/o-coupled receptors in β cells.
Abstract Arginine vasopressin (AVP), released from the CNS, plays an important role in regulating several aspects of CNS functions including aggression, anxiety, and cognition. In this study, we report a novel finding that AVP induces glutamate release from astrocytes isolated from the cerebral cortex and hippocampus. We also investigated the types of AVP receptors involved in the AVP‐induced increase in glutamate release from astrocytes isolated from the hippocampus and cortex of neonatal rats. We showed that the AVP (0.1–1000 nmol/L) induced increase in glutamate release and [Ca 2+ ] i is brought about by two distinct subtypes of V 1 receptors (V 1a and V 1b ). Our results suggested that V 1b receptors are predominantly expressed in astrocytes isolated from the hippocampus and V 1a receptors are solely expressed in astrocytes isolated from the cerebral cortex of neonatal rats. The results of the western blot analyses confirmed these pharmacological data. In addition, the AVP‐induced increase in glutamate did not contribute to an increase in [Ca 2+ ] i , as blockade of metabotropic glutamate receptors did not alter the AVP‐induced increase in [Ca 2+ ] i . In addition, the administration of a phospholipase A 2 inhibitor failed to alter AVP‐induced [Ca 2+ ] i increase suggesting the lack of involvement of this enzyme.
Chapter 1: Principles of Drug Absorption, Disposition, and Action (Richard J. Martin and Walter H. Hsu). Chapter 2: Drugs Affecting Peripheral Nervous System (Walter H. Hsu). Chapter 3: Autacoids and Their Pharmacological Modulators (Anumantha G. Kanthasamy and Walter H. Hsu). Chapter 4: Drugs Acting on the Central Nervous System (Walter H. Hsu and Dean H. Riedesel). Chapter 5: Behavior Modifying Drugs (Arthi Kanthasamy). Chapter 6: Anesthetics (Dean H. Riedesel). Chapter 7: Nonsteroid Anti-inflammatory Drugs (NSAIDs) (Walter H. Hsu and Arthi Kanthasamy). Chapter 8: Drugs Acting on the Cardiovascular System (Wendy A. Ware). Chapter 9: Diuretics (Franklin A. Ahrens). Chapter 10: Respiratory Pharmacology (Dean H. Riedesel). Chapter 11: Drugs Acting on the Digestive System (Albert E. Jergens and Franklin A. Ahrens). Chapter 12: Endocrine Pharmacology (Walter H. Hsu). Chapter 13: Topical Dermatology Therapy (James O. Noxon). Chapter 14: Ocular Pharmacology (Daniel M. Betts). Chapter 15: Antimicrobial Drugs (Franklin A. Ahrens and Richard J. Martin). Chapter 16: Antiparasitic Agents (Walter H. Hsu and Richard J. Martin). Chapter 17: Antineoplastic Drugs (Dr. Leslie E. Fox). Chapter 18: Fluid and Blood Therapy (Walter H. Hsu). Chapter 19: Drug Interactions and Adverse Drug Reactions (Walter H. Hsu and Franklin A. Ahrens). Chapter 20: Legal Aspects of Medication Usage in Veterinary Medicine (Stephen D. Martin)
Abstract Objective —To evaluate baseline plasma cortisol and ACTH concentrations and responses to low-dose ACTH stimulation testing in ill foals. Design —Cross-sectional study. Animals —58 ill foals. Procedures —Baseline cortisol and ACTH concentrations and cortisol concentrations after administration of a low dose of cosyntropin were determined within 6 hours after admission. Foals were assigned to 4 groups on the basis of age (≤ 24 hours vs 1 to 56 days) and presence of septicemia (yes vs no). Values were compared among groups and with values previously reported for healthy foals. Results —Plasma cortisol concentrations 30 and 60 minutes after cosyntropin administration in foals ≤ 24 hours old were significantly higher than corresponding cortisol concentrations in older foals. In all 4 groups, plasma cortisol concentration 30 minutes after cosyntropin administration was significantly higher than baseline cortisol concentration or concentration 60 minutes after cosyntropin administration. No differences in baseline cor-tisol or ACTH concentration or in the ACTH-to-cortisol ratio were detected between groups or when ill foals were compared with healthy foals. A small number of ill foals had low baseline cortisol and ACTH concentrations or low responses to cosyntropin administration, compared with healthy foals. Conclusions and Clinical Relevance —Results indicated that most ill foals in the present study population had adequate responses to cosyntropin administration. However, a small subset of ill foals appeared to have dysfunction of the hypothalamic-pituitary-adrenal axis.
The mechanisms underlying AVP‐induced increase in [Ca 2+ ] i and glucagon release in clonal α‐cells In‐R1‐G9 were investigated. AVP increased [Ca 2+ ] i and glucagon release in a concentration‐dependent manner. After the administration of AVP, glucagon was released within 30 s, quickly reached the maximum within 2 min, and maintained a steady‐state concentration for at least 15 min. In Ca 2+ ‐containing medium, AVP increased [Ca 2+ ] i in a biphasic pattern; a peak followed by a sustained plateau. In Ca 2+ ‐free medium, the Ca 2+ response to AVP became monophasic with lower amplitude and no plateau. Both the basal and AVP‐induced glucagon releases were lower in the absence than in the presence of extracellular Ca 2+ . When [Ca 2+ ] i was stringently deprived by BAPTA, a Ca 2+ chelator, AVP still significantly increased glucagon release. Pretreatment with thapsigargin, a microsomal Ca 2+ ATPase inhibitor, abolished both the Ca 2+ peak and sustained plateau. AVP increased intracellular concentration of IP 3 . U‐73122 (8 μ M ), a phospholipase C inhibitor, abolished AVP‐induced increases in [Ca 2+ ] i , but only reduced AVP‐induced glucagon release by 39%. Pretreatment with nimodipine, an L‐type Ca 2+ channel blocker failed to alter AVP‐induced glucagon release or increase in [Ca 2+ ] i . The results suggest that AVP causes glucagon release through both Ca 2+ ‐dependent and ‐independent pathways. For the Ca 2+ ‐dependent pathway, the G q protein activates phospholipase C, which catalyzes the formation of IP 3 . IP 3 induces Ca 2+ release from the endoplasmic reticulum, which, in turn, triggers Ca 2+ influx. Both Ca 2+ release and Ca 2+ influx may contribute to AVP‐induced glucagon release. British Journal of Pharmacology (2000) 129 , 257–264; doi: 10.1038/sj.bjp.0703037
A study of amoxicillin pharmacokinetics was conducted in healthy goats and goats with chronic lead intoxication.The intoxicated goats had increased serum concentrations of liver enzymes (alanine aminotransferase and γ-glutamyl transferase), blood urea nitrogen, and reactivated δ-aminolevulinic acid dehydratase compared to the controls.Following intravenous amoxicillin (10 mg/kg bw) in control and lead-intoxicated goats, elimination half-lives were 4.14 and 1.26 h, respectively.The volumes of distribution based on the terminal phase were 1.19 and 0.38 L/kg, respectively, and those at steady-state were 0.54 and 0.18 L/kg, respectively.After intramuscular (IM) amoxicillin (10 mg/kg bw) in lead-intoxicated goats and control animals, the absorption, distribution, and elimination of the drug were more rapid in lead-intoxicated goats than the controls.Peak serum concentrations of 21.89 and 12.19 μg/mL were achieved at 1 h and 2 h, respectively, in lead-intoxicated and control goats.Amoxicillin bioavailability in the lead-intoxicated goats decreased 20% compared to the controls.After amoxicillin, more of the drug was excreted in the urine from lead-intoxicated goats than the controls.Our results suggested that lead intoxication in goats increases the rate of amoxicillin absorption after IM administration and distribution and elimination.Thus, lead intoxication may impair the therapeutic effectiveness of amoxicillin.
The LD50 from subcutaneous administration of levamisole in castrated male pigs (15 to 25 kg) was established as 39.8 mg/kg. Oral administration of dichlorvos (60 mg/kg, 3 times the anthelmintic dosage level) 1 hour before levamisole injection lowered blood cholinesterase activity to approximately 60% that of the controls, but did not change the LD50 of levamisole. In contrast, oral administration of pyrantel tartrate (25 mg/kg, an anthelmintic dosage level) did not lower blood cholinesterase activity, but rather, increased the toxicity by lowering the LD50 of levamisole from 39.8 mg/kg to 27.5 mg/kg. The data supported the hypothesis that levamisole toxicity was enhanced by nicotine-like compounds (ie, pyrantel), but was not affected by organophosphates (ie, dichlorvos).
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