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Volume 122 (2003)
- Issue 6 Pages 473-
- Issue 5 Pages 367-
- Issue 4 Pages 34A-
- Issue 3 Pages 192-
- Issue 2 Pages 111-
- Issue 1 Pages 5-
Volume 122, Issue 5
Displaying 1-10 of 10 articles from this issue
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Reviews: Receptor and Channel Gene Manipulation in Disease Models
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Teruyuki YANAGISAWA, Kazuo NUNOKI, Kunie HAGIWARAArticle type: Reviews
2003 Volume 122 Issue 5 Pages 367-374
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSThe heterologous expression system will provide clues for understanding the basic mechanism of arrhythmogenicity in both inherited and acquired long QT syndrome, which are reviewed here, with emphasis on the K+ channels. Endothelin is implicated in the morphological and electrical remodeling of cardiac muscles in heart failure. The effects of endothelin on the transient outward K+ currents (Ito) were compared between Kv1.4 (rich in endocardial muscle) and Kv4.3 (rich in epicardial muscle) channels in the Xenopus oocytes expression system. Both Itos were decreased by stimulation of endothelin receptor ETA coexpressed with the K+ channels. Ito of Kv1.4 was decreased by about 85% after 10−8 M ET-1, whereas that of Kv4.3 was decreased by about 60%. By mutagenesis experiments, we identified two phosphorylation sites of PKC and CaMKII in Kv1.4 responsible for the decrease in Ito by ET-1. In Kv4.3 we identified a PKC phosphorylation site that is partly responsible for the decrease. Differences in the suppression of Ito could be due to the differences in intracellular signaling including the number of phosphorylation sites. These findings show some of the molecular mechanisms of ventricular arrhythmias in heart failure, resulting in dispersion and prolongation of action potential which elicit reentry and afterdepolarization.
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Tetsushi FURUKAWAArticle type: Reviews
2003 Volume 122 Issue 5 Pages 375-383
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSCellular functions of Cl− channels are poorly understood, in contrast to well-established roles of cation channels. Recently, importants achievements in Cl− channel research have been sequentially reported, including cloning of many Cl− channel cDNAs, linkage of gene abnormalities to human inherited disorders, analysis of knock-out mouse phenotype, analysis of crystal structure, and regulation by protein-protein interaction. Intracellular membrane Cl− channels are important for acidification of intracellular vesicles: ClC-5 functions for re-absorption of low-molecular-weight proteins in renal proximal tubule, and ClC-7 for absorption of bone matrix by osteoclasts. Abnormal functions of these channels result in Dent's disease characterized by proteinuria and kidney stones and by osteopetrosis, respectively. Plasma membrane Cl− channels, ClC-K1, ClC-K2, and ClC-3B, are expressed predominantly in epithelical cells and are important for uni-directional Cl− transport across the epithelia. Abnormalities of these channels are also related to human diseases: abnormal ClC-K1 to diabetes insipidus and abnormal ClC-K2 to Bartter's syndrome.
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Akiyoshi HARA, Koh-ichi YUHKI, Takayuki FUJINO, Shuh NARUMIYA, Fumitak ...Article type: Reviews
2003 Volume 122 Issue 5 Pages 384-390
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSProstanoids, consisting of the prostaglandins (PGs) and thromboxanes (TXs), exert various actions through activation of their specific receptors. They include the DP, EP, FP, IP, and TP receptors for PGD2, PGE2, PGF2α, PGI2, and TXA2, respectively. Moreover, EP receptors are classified into four subtypes, the EP1, EP2, EP3 and EP4 receptors. Using mice lacking prostanoid receptors, we intended to clarify in vivo roles of prostanoids under pathophysiological conditions of the cardiovascular system, which include ischemia-induced cardiac injury, pressure overload-induced cardiac hypertrophy, renovascular hypertension, tachycardia during systemic inflammation and thromboembolism. The results demonstrated that 1) PGI2 plays an important role in attenuating the ischemic injury and the pressure overload-induced hypertrophy of the hearts, and also contributes to the development of renovascular hypertension; 2) PGE2 plays a cardioprotective role against the ischemic injury via both the EP3 and EP4, and also participates in acute thromboembolism via the EP3; and 3) both PGF2α and TXA2, which have been produced during systemic inflammation, are responsible for tachycardia.
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Kazuhiko YANAI, Jalal Izadi MOBARAKEH, Atsuo KURAMASU, Shinobu SAKURAD ...Article type: Reviews
2003 Volume 122 Issue 5 Pages 391-399
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSTo study the participation of histamine H1- and H2-receptors in pain perception, H1 and H2 receptor knockout (KO) mice were examined for pain threshold by means of three kinds of nociceptive tasks. These included assays for thermal, mechanical, and chemical nociception. H1KO mice showed significantly fewer nociceptive responses to the hot-plate, tail-flick, tail-pressure, paw-withdrawal, formalin, capsaicin, and abdominal constriction tests. Sensitivity to noxious stimuli in H1KO mice was significantly decreased when compared to wild-type mice. The antinociceptive phenotypes of H2KO were relatively less prominent when compared to H1KO mice. We also examined the antinociceptive effects of intrathecally-, intracerebroventricularly-, and subcutaneously-administered morphine in H1KO and H2KO mice. In these nociceptive assays, the antinociceptive effects produced by morphine were more enhanced in both H1KO and H2KO mice. The effects of histamine H1- and H2-receptor antagonists on morphine-induced antinociception were studied in ICR mice. The intrathecal, intracereborventricular and subcutaneous co-administrations of d-chlorpheniramine enhanced the effects of morphine in all nociceptive assays examined. In addition, intrathecal co-administrations of cimetidine enhanced the antinociception of morphine in the hot plate tests. These results suggest that existing H1 and H2 receptors play an inhibitory role in morphine-induced antinociception in the spinal and supra-spinal levels.
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Lectures: Pharmacology in Undergraduate Education - in Relation to the So-called Core-Curriculum
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Toshimasa YOSHIOKAArticle type: Lectures
2003 Volume 122 Issue 5 Pages 402-406
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSThe objectives of undergraduate medical education have been shifted drastically during the last decades. As the world standard, basic medical knowledge, skill, and attitude to practice patient-centered medical care became main objectives in undergraduate medical education. In response to these changes in the environment of medical practice and education, the Medical Education Model Core Curriculum (MEMCC), was published in 2001. MEMCC describes general and specific behavioral objectives in an integrated form to be used in the practice of medicine. The achievement of MEMCC will be evaluated by the Nationwide Common Achievement Test. The test examines knowledge, skill, and attitude that is required for clinical clerkship. Pharmacological teachers in medical schools should discuss, study, and evaluate MEMCC based on their experience in the use of the curriculum. MEMCC and the Nationwide Common Achievement Test will enhance intra- and inter-disciplinary, as well as inter-institutional informational exchange in the context and strategies in pharmacological education.
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Ian HughesArticle type: Lectures
2003 Volume 122 Issue 5 Pages 411-418
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSChanges in pharmacology teaching are being driven by various pressures. These originate: from changes in the discipline itself; from government; from professional bodies; from students; from changes in teaching styles and opportunities; from academic staff; from ethical/animal rights considerations; from employers and from higher education institutions. These changes will require an alteration in the knowledge, skills and attitudes of academic pharmacologists as much as they will require changes in the way teaching is delivered and learning is facilitated. Pharmacology courses will be provided in a changed environment and must prepare students to work in a changed discipline as well as being appropriate for students who will take employment in non-pharmacology areas. Change is likely to centre around the curriculum, problem based learning, simulated practicals, peer assessment, use of the internet, information technology and interactive computer based learning, virtual learning environments and integrated medical courses. The most effective strategy to achieve the necessary changes is likely to involve collaboration between pharmacology teachers on a global scale and a general consciousness among current academic pharmacologists that we need to ensure tomorrow's academics are well prepared for the changed environment in which they will have to work.
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Technical Note
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Norimichi NAKAHATA, Satoko OHKUBOArticle type: Technical Note
2003 Volume 122 Issue 5 Pages 419-425
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSMicrodomains in cell membranes consist of caveolae and lipid rafts, in which cholesterol, glycolipids, and sphingomyelin are concentrated. While caveolae are relatively stable because caveolin, an integral protein, supports the structure, lipid rafts are unstable, being dynamically produced and degraded. In lipid rafts, flotillin is assumed to be one of the specifically located proteins. Since microdomains contain several signaling molecules, such as transmembrane receptors, they have an important role in receptor-medicated signal transduction. Caveolae or lipid rafts are known to be resistant to non-ionic detergents, such as Triton X-100. Because of this property, they are separated as the detergent-resistant membranes when the Triton X-100-treated cell lysate is subjected to sucrose gradient centrifugation. On the other hand, cholesterol is an essential molecule to maintain microdomain structure. When the cells are treated with cholesterol removing agents, such as methyl-β-cyclodextrin and filipin, the microdomain in cell membranes is disrupted. Thus, the cholesterol removing agents are utilized to determine whether the microdomain is involved in certain cellular/physiological responses. Recently, green fluorescent protein-tagged protein is used to analyze the localization of the protein in lipid rafts in intact cells. Research on lipid rafts will be helpful for understanding the detailed mechanism of signal transduction and to clarify the molecular basis of several diseases.
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Hitoshi HASHIMOTO, Norihito SHINTANIArticle type: Technical Note
2003 Volume 122 Issue 5 Pages 427-435
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSMutant strains of mice with precise genetic mutations generated by gene-targeting technology have proved to be useful tools for linking specific genes with biological processes in vivo and serve as models for human diseases. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved neuropeptide that is widely expressed in the mammalian brain, and it has been implicated in a broad variety of physiological and pathophysiological processes. To assess the function of PACAP in vivo, recently, we have generated PAC1 receptor- and PACAP-targeted mice and transgenic mice overexpressing PACAP in the pancreatic β-cells. The phenotypes of these mutant mice revealed both expected and unexpected roles of PACAP in the brain and pancreatic functions. A significant contribution of genetic background as well as environmental factors to the knockout phenotypes was also observed. In this article, we briefly describe the technique of gene targeting and discuss how this method was used to generate PACAP and its receptor deficient mice. We also analyze how these mutants can contribute to our understanding of the molecular mechanism underlying higher nervous functions.
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Hitoshi ISHIBASHI, Mari UMEZUArticle type: Technical Note
2003 Volume 122 Issue 5 Pages 437-442
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSIt is generally considered that dominant excitatory control of the airway is exerted by the parasympathetic nervous system. In the lower airway, there are a number of parasympathetic ganglia on the serosal surface of the dorsal tracheal wall. The dissociation of these paratracheal ganglion neurons facilitates the ability to visualize and patch-clamp single-neurons and to control the surrounding solutions. This article describes technical procedures to obtain the single paratracheal neurons and its application to neuropharmacology. The single paratracheal neurons can be isolated with adherent functional synaptic terminals using a weak enzyme treatment. This will allow investigations of the mechanisms and modulation of neurotransmitter release from vagal preganglionic nerve terminals with unprecedented ease and accuracy.
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Review on New Drug
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Nobuo NAGANO, Naoshi FUKUSHIMAArticle type: Review on New Drug
2003 Volume 122 Issue 5 Pages 443-453
Published: 2003
Released on J-STAGE: October 21, 2003
JOURNAL FREE ACCESSHyperphosphatemia is one of the major complications of hemodialysis patients and plays a key role in the pathogenesis of cardiovascular calcification and secondary hyperparathyroidism. Dietary phosphate restriction and removal of phosphate by dialysis are insufficient to control hyperphosphatemia. Therefore, almost all patients undergoing hemodialysis should take oral phosphate binders. Sevelamer hydrochloride (sevelamer) is a novel phosphate-binding polymer that contains neither aluminum nor calcium, and it is not absorbed from the gastrointestinal tract. In rat models with progressive chronic renal insufficiency, in addition to lowering effects on serum levels of phosphorus, calcium × phosphorus product, and parathyroid hormone, dietary treatment of sevelamer can prevent parathyroid hyperplasia, vascular calcification, high turnover bone lesion, and renal functional deterioration. In clinical studies with hemodialysis patients, sevelamer lowers serum phosphorus and calcium × phosphorus product without any incidence of hypercalcemia. Switching calcium-containing phosphate binders to sevelamer can decrease the percentage of hypoparathyroidism and hyperparathyroidism by negative calcium balance and increased dosage of vitamin D, respectively. Sevelamer also decreases serum low-density lipoprotein cholesterol levels by its bile acid-binding capacity. A long-term clinical study has demonstrated that the progression of coronary and aortic calcification in hemodialysis patients is attenuated by sevelamer. Thus, sevelamer offers the promise of impacting cardiac calcification and thereby reducing morbidity and mortality of hemodialysis patients.
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