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Volume 119 (2002)
- Issue 6 Pages 319-
- Issue 5 Pages 273-
- Issue 4 Pages 201-
- Issue 3 Pages 135-
- Issue 2 Pages 65-
- Issue 1 Pages 7-
Volume 119, Issue 2
Displaying 1-6 of 6 articles from this issue
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Review
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Tetsuhiro HISAYAMA, Koichi NAKAYAMA, Naoaki SAITO, Yasuki KIHARA, Shig ...Article type: Review
2002 Volume 119 Issue 2 Pages 65-78
Published: 2002
Released on J-STAGE: December 24, 2002
JOURNAL FREE ACCESSProtein kinase C (PKC) is a superfamily of lipid-dependent protein Ser/Thr kinases consisting of at least 10 isozymes. The present article summarizes the papers presented at the congress symposium of the 74th Annual Meeting of the Japanese Pharmacological Society, in which six special topics regarding PKC isozyme-dependent cellular functions and pathological disorders were discussed. Using a GFP-tagged PKC expression technique, each PKC subtype was suggested to vary its targeting-site in each cell in response to each stimulus and that the targeting to the specific compartment is necessary for the specific cellular responses (NS). A cardioprotective agent, JTV519, was shown to attenuate post-ischemic myocardial injury by mimicking ischemic preconditioning through specific activation of PKCδ (YK). Using an antisense technique, PKCα and δ/ε were shown to be necessary for gene expression of inducible NO synthase by interleukin-1, one of the proinflammatory cytokines, by a stimulated transactivation of NF-κB (TH). In canine cerebral artery, PKCδ and PKCα play important roles in the development and the maintenance of vasospasm induced by subarachnoid hemorrhage, respectively (SN); and stretch-induced MLC20 phosphorylation involves MLCK and PKCα but not PKCδ activities facilitated by inactivation of myosin phosphatase through Rho activity (KO & KN). To clarify the role of PKC isozymes in insulin resistance, the effects of insulin on glucose uptake, PKC isozyme activation and PI3K activation in rat adipocytes were shown and then platelet PKCβ activation in diabetic patients with various diabetic complications, including diabetic retinopathy, was reported (TI). These studies will promisingly open the way to a new era for the development of novel drugs controlling an isozyme-specific activity of the protein kinase C superfamily and improvement in the knowledge about the role of the protein kinase in health and disease.
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Hiroshi UEDA, Wakako HAMABEArticle type: Review
2002 Volume 119 Issue 2 Pages 79-88
Published: 2002
Released on J-STAGE: December 24, 2002
JOURNAL FREE ACCESSThe brain has various in vivo neuroprotective mechanisms that allow it to survive for an entire lifetime. As well as neurotrophic factor-mediated inhibition of in vivo apoptotic mechanisms through various protein kinases including Akt and MAP kinase, we propose adding the neuronal death mode switch mechanism observed under the brain ischemic stress to the list of neuroprotective mechanisms. Necrosis occurs when energy or ATP levels are markedly reduced. Lowered ATP levels cause a Na+-K+-ATPase failure, leading to an osmolysis. On the other hand, sufficient ATP is required for the apoptosome activation. Under the serum-free condition, cortical neurons rapidly die in necrosis. High-glucose treatment converted the cell death mode to apoptosis through an elevation of cellular ATP levels. This treatment also rescued the cell from death due to retinal ischemic injury. These findings suggest the possibility that ischemia-induced neuronal death could be inhibited by some drugs to elevate cellular ATP levels. Neurogenesis in the adult brain is now an important topic in neuroscience. As brain injury is reported to enhance the neurogenesis, this might be also included in the ways of in vivo neuroprotection. As lysophosphatidic acid has various activities to drive neurogenesis, the neurogenesis could also be managed by other drugs to compensate for functions lost by neuronal death.
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Osamu KOZAWA, Haruhiko TOKUDAArticle type: Review
2002 Volume 119 Issue 2 Pages 89-94
Published: 2002
Released on J-STAGE: December 24, 2002
JOURNAL FREE ACCESSPhysiological stresses such as heat stress, chemical stress and mechanical stress induce the expression of heat shock protein (HSP) families in cells, which affects cell function. In the present review, we describe HSP27, a small HSP in osteoblasts, especially the regulatory mechanism of the induction of HSP27 stimulated by physiological bone agents. Chemical stress by sodium arsenite (arsenite) induces HSP27 coupled to the metabolic activity of the arachidonic acid cascade, and the HSP27 induction by arsenite is negatively regulated by activation of protein kinase C (PKC). On the contrary, physiological regulators of bone such as endothelin-1, prostaglandin F2α (PGF2α), PGD2, and basic fibroblast growth factor (bFGF) induce HSP27 via protein kinase C (PKC) activation. In addition, the mitogen-activated protein (MAP) kinase superfamily takes part in the HSP27 induction. Thus, not only stress but also physiological agonists induce HSP27 in osteoblasts, and PKC or MAP kinases play important roles in the induction of HSP27.
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Hiroaki MATSUBARAArticle type: Review
2002 Volume 119 Issue 2 Pages 95-102
Published: 2002
Released on J-STAGE: December 24, 2002
JOURNAL FREE ACCESSDue to the discovery of nonpeptidic ligands, the receptors for angiotensin (Ang) II are classified into two subtypes (AT1-R and AT2-R). AT1-R mediates most of the cardiovascular actions of Ang II. AT2-R is expressed at very high levels in the developing fetus. Its expression is very low in the cardiovascular system of the adult. The expression of AT2-R can be modulated by pathological states associated with tissue remodeling or inflammation. In failing hearts or neointima formation after vascular injury, AT2-R is re-expressed in cells proliferating in interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular matrix proteins, resulting in attenuation of the tissue remodeling. An extreme form of cell growth inhibition ends in programmed cell death, and this process, which is initiated by the withdrawal of growth factors, is also enhanced by AT2-R. Cardiac myocyte- or vascular smooth muscle-specific mice that overexpress AT2-R display an inhibition of Ang II-induced chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells and the maintenance of vascular resistance. AT2-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal systems, resulting in AT2-R-mediated cardioprotection, vasodilation and pressure natriuresis. These effects, transmitted by AT2-R, are mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in a Gi-protein-dependent manner. The expression level of AT2-R is much higher in human hearts than in rodent hearts, and the AT2-R-mediated actions are likely enhanced, especially by clinical application of AT1-R antagonists. Thus, in this review, the regulation of AT2-R expression, its cellular localization, its pathological role in cardiovascular and kidney diseases, and pharmacotherapeutic effects of AT2-R stimulation are discussed.
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Review on New Drug
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Akihiro OYABE, Hidetoshi SANOArticle type: Review on New Drug
2002 Volume 119 Issue 2 Pages 103-109
Published: 2002
Released on J-STAGE: December 24, 2002
JOURNAL FREE ACCESSNifekalant (shinbit®, MS-551) is a pure class III antiarrhythmic drug (Vaughan Williams' classification), which was approved in Japan in June 1999. This drug prolongs the action potential duration (APD) and the effective refractory period (ERP) in cardiac myocytes mainly by blocking the IKr (the rapid component of delayed rectifier K+ current). The antiarrhythmic efficacy depends on prolongation of ERP. The importance of this drug is to save patients from the life-threatening arrhythmias ventricular tachycardia (VT) and fibrillation (VF). Nifekalant was effective against reentrant arrhythmias such as VT and VF in postinfarction dogs. This drug does not have the negative inotropic effect that has been observed with other antiarrhythmic drugs. In clinical therapy, this drug was remarkably effective on patients who were unresponsive to therapy with other drugs or who were not able to receive other drugs due to decreased cardiac function. There has been no case of drug-induced worsening of the cardiac function. The significant adverse reaction is proarrhythmia such as ventricular tachycardia including TdP. Nifekalant is expected to be a useful drug for patients who could not be rescued from life-threatening arrhythmia by conventional therapies.
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Kiyoharu SHIRAKAWAArticle type: Review on New Drug
2002 Volume 119 Issue 2 Pages 111-118
Published: 2002
Released on J-STAGE: December 24, 2002
JOURNAL FREE ACCESSZolpidem is a non-benzodiazepine hypnotic agent with a chemical structure of imidazopyridine. In vitro and in vivo binding studies, zolpidem exhibits selectivity to ω1 receptors (GABAA-receptor subtypes containing α1 subunits). Unlike benzodiazepines, zolpidem produces sedative effects in preference to anxiolytic, anticonvulsant and myorelaxant effects in behavioral experiments using mice. Double-blind comparative studies with reference drugs such as triazolam and zopiclone show that zolpidem is an effective and highly safe drug for the treatment of insomnia. In addition, zolpidem does not produce next-day residual effects, rebound insomnia and tolerance. This clinical profile of zolpidem may be related to its selectivity and high intrinsic activity for ω1 receptors.
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