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Volume 119, Issue 1
Displaying 1-6 of 6 articles from this issue
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Reviews: Pathophysiological Roles of NO -Progress Towards the Development of Novel Medicines-
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Toshio NAKAKI, Keiichi HISHIKAWA2002 Volume 119 Issue 1 Pages 7-14
Published: 2002
Released on J-STAGE: December 10, 2002
JOURNAL FREE ACCESSL-Arginine has attracted major interest because it has been identified as the natural substrate of nitric oxide synthase and is now recognized as a major player in the regulation of biological function. The arginine paradox refers to the phenomenon that exogenous L-arginine causes NO-mediated biological effects despite the fact that nitric oxide synthases (NOS) are theoretically saturated with the substrate L-arginine. There have been several explanations for this phenomenon, although none of them can explain the arginine paradox fully: (1) L-arginine-induced insulin, which has vasodilatory actions. (2) Neither extracellular nor intracellular concentration determines the NOS activity but rather the L-arginine amount transported across the plasma membrane may do so. (3) Endogenous NOS inhibitors reduce the enzyme sensitivity to L-arginine. These inhibitors include, NG, NG-dimethyl-L-arginine, L-citrulline, argininosuccinic acid and agmatine. (4) Intracellular L-citrulline, an NOS product, is a potent inhibitor of NOS so that the cells may need extra L-arginine to compete with L-citrulline inhibition.
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Akinori AKAIKE, Hiroshi KATSUKI, Toshiaki KUME2002 Volume 119 Issue 1 Pages 15-20
Published: 2002
Released on J-STAGE: December 10, 2002
JOURNAL FREE ACCESSThe prominent pathological feature of the brain in Parkinson's disease is selective degeneration of dopaminergic neurons in the substantia nigra of the midbrain. Glutamate and nitric oxide (NO) are the major effectors of the radical stress that may induce selective loss of dopaminergic neurons. It has been postulated that neurotoxicity induced by glutamate and NO in dopaminergic neurons is regulated by certain endogenous factors. We have reported that estradiol protects dopaminergic neurons against NO-mediated glutamate neurotoxicity by reducing intracellular reactive oxygen species (ROS) levels. We further searched for a candidate for neuroprotective substances with unique structure. From the ether extract of fetal calf serum (FCS), we isolated a novel substance possessing protective activity against neurotoxicity induced by glutamate NO. The compound was a sulfur-containing diterpenoid and showed hydroxyl radical scavenging activity. We further analyzed the change of resistance to excitotoxicity in midbrain dopaminergic neurons in co-culture with the striatum by using a slice culture technique. The results suggested that the generation of NO is involved in NMDA cytotoxicity on dopaminergic neurons and that increased activity of SOD in co-culture renders dopaminergic neurons resistant to NMDA cytotoxicity by preventing peroxynitrite formation. Those findings suggest that regulation of intracellular ROS levels plays a critical role in protecting neurons against NO-mediated radical stress in neurodegenerative disorders.
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Kazuhide AYAJIKI, Noboru TODA, Tomio OKAMURA2002 Volume 119 Issue 1 Pages 21-28
Published: 2002
Released on J-STAGE: December 10, 2002
JOURNAL FREE ACCESSIn vascular tissues including the corpus cavernosum, the organ function is reciprocally regulated by noradrenergic and non-adrenergic, non-cholinergic (NANC) nerves. NANC nerves innervating the corpus cavernosum is thought to be nitroxidergic (nitrergic) nerves which liberate nitric oxide (NO) produced by neuronal NO synthase, and liberated NO activates soluble guanylate cyclase (sGC) in cavernous smooth muscle cells. Intracellular increase in cyclic (c) GMP by activation of sGC dilates cavernous smooth muscle and then induces penile erection. Nitroxidergic (nitrergic) vasodilator nerves also innervate cavernous arteries and veins which regulate the blood volume in the corpus cavernosum. The order of potency of nitroxidergic nerve functions in these tissues (cavernosum>artery>>vein) may be suitable for producing the erection. Therefore, obstruction of the arteries and impairment of nitroxidergic (nitrergic) nerve function are speculated to be one of the causes for erectile dysfunction (ED). On the other hand, NO derived from the cavernous endothelium may partly contribute to erectile function. Sildenafil (Viagra) is one of the potent therapeutics for ED. The agent is a selective phosphodiesterase type 5 (PDE-V) inhibitor that inhibits degradation of cGMP elevated by NO mainly derived from the nerves. To develop more selective and safer therapeutics for ED, further systematic investigations are required.
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Hitoshi MASUDA, Hiroshi AZUMA2002 Volume 119 Issue 1 Pages 29-35
Published: 2002
Released on J-STAGE: December 10, 2002
JOURNAL FREE ACCESSProtein arginine N-methyltransferases (PRMTs) catalyse the methylation of guanidinonitrogen(s) of arginine to produce NG-monomethyl-L-arginine (L-NMMA), asymmetric NG,NG-dimethyl-L-arginine (ADMA) and symmetric NG,NG-dimethyl-L-arginine (SDMA), which are subsequently released into the cytoplasm following proteolysis. Free intracellular L-NMMA and ADMA, but not SDMA, are inhibitors of all three isoforms of nitric oxide synthases (nNOS, eNOS and iNOS). L-NMMA and ADMA, but not SDMA, are actively metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and methylamine (and dimethylamine). Free methylarginines are detectable in cell cytosol, plasma and tissues. Elevated ADMA has been detected in the plasma of patients or experimental animals with hypercholesterolemia, renal failure, atherosclerosis, hypertension, thrombotic microangiopathy, peripheral arterial occlusive disease and in the regenerated endothelial cells after angioplasty. Moreover, in the non-cardiovascular field, ADMA was increased in the urethral tissue following ischemia and in the plasma of patients with schizophrenia and multiple sclerosis. Altered biosynthesis of NO has been implicated in the pathogenesis of these diseases, and it is possible to consider that the accumulation of endogenous L-NMMA and ADMA underlies the impaired NO generation and increased O2− production. We described herein the biosynthesis, transmembrane transport, metabolic pathway and possible pathophysiological roles of endogenous methylarginines.
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Technical Note
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Tomie KAWADA, Mikio NAKAZAWA, Teruhiko TOYO-OKA2002 Volume 119 Issue 1 Pages 37-44
Published: 2002
Released on J-STAGE: December 10, 2002
JOURNAL FREE ACCESSThe hereditary form of dilated cardiomyopathy (DCM) accounts for about 20% of human DCM and is a major cause of heart failure. TO-2 strain hamsters show DCM, a gene deletion of δ-sarcoglycan (SG), loss of all four SGs, α-, β-, γ- and δ-SG proteins, and are useful for developing gene therapy of the hereditary DCM. The δ-SG is a component of dystrophin-associated glycoprotein complex that stabilizes sarcolemma. Four familial and sporadic DCM cases have been reported in human patients with the same δ-SG gene mutation. To establish the potential gene therapy of DCM, efficient and long-lasting transduction of the responsible gene is mandatory, especially for improving the functional defect. Recombinant adeno-associated virus (rAAV) vector with δ-SG gene was intramurally transfected to the TO-2 hearts at 5-weeks-old. The transfected myocardium revealed robust expression of both transcript and transgene after 10 and 20 weeks. Immunohistological analyses demonstrated re-expression of not only δ-SG but also the other three SGs and normalization of the diameter of transduced cardiomyocytes without the pathogenicity. Hemodynamic studies revealed preferential amelioration of the diastolic indices. It suggests a novel strategy for the treatment of DCM and the rAAV vector is available for the treatment of several human diseases because of its safety and efficacy.
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Drug Development Now
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Yoshitaka HIRAYAMA, Hiroshi KAYAKIRI2002 Volume 119 Issue 1 Pages 45-53
Published: 2002
Released on J-STAGE: December 10, 2002
JOURNAL FREE ACCESSThe kallikrein-kinin system plays an important role in many physiological and pathophysiological conditions such as homeostasis of circulation, inflammation/allergy, pain, shock, etc. Two types of kinin receptor are known, bradykinin (BK) B1 receptor and BK B2 receptor. B2 receptors are constitutively expressed and mediate most physiological actions of kinins, whereas B1 receptors are highly inducible upon inflammatory stimulation or tissue injury, suggesting that they are involved in inflammation and/or nociception. Only three peptide type B2 antagonists, NPC 567, CP-0127 and HOE-140, have been evaluated in clinical studies so far, and some beneficial effects of B2 antagonists have been shown for rhinitis, asthma, systemic inflammatory response syndrome/sepsis and brain injury. However, the results were less convincing than expected. Now several potent and orally active nonpeptide B2-receptor antagonists have been found, which are expected to overcome the weak point of the peptide type antagonists and clarify the therapeutic potential of the B2-receptor antagonist for novel indications as well as those mentioned above. As for B1 receptors, no antagonist has been tested in a clinical trial. The important role of B1 receptors is just being elucidated by use of peptide type antagonists or B1 receptor gene knockout mice. The further development of newer B1 antagonists and clinical evaluation is desired.
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