Multiple factors alter the interaction of muscle relaxants with the neuromuscular (NM) junction. This review focused on the aberrant responses caused, principally, by alterations in acetylcholine receptor (AChR)s. It should be emphasized that prejunctional and post AChR factors also may alter sensitivity to muscle relaxants and also cause functional changes, including muscle weakness. The pharmacokinetic and pharmacogenetic factors which cause aberrant responses have not been discussed. Many pathological states increase or decrease AChRs and this has been enumerated in Table 1. Increased AChRs is associated with resistance to the NM effects of nondepolarizing (ND)MR. With proliferation of AChR, the exaggerated release of potassium with depolarization from succinylcholine (SCh) can be attributed to increased AChR number; qualitative changes in AChR number may also play a role. Preliminary studies using potassium channel inhibitors indicate that potassium channels do not play a major role in the hyperkalimic response to SCh. During acute organophosphorus poisoning, SCh should be avoided because its metabolic breakdown would be impared;¹ the requirement for NDMR may be increased because of increased competition with high leels of ACh at the neuromuscular junction. With the chronic presence of ACh at the neuromuscular junction there would be down regulation and the responses would be similar to that seen in myasthenia gravis. All of these responses to SCh and NDMR which are associated with concomitant changes in AChR are analogus to drug-receptor interactions observed in other biological systems.

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Certain aspects of current progress in melanin biology and its possible clinical relevances are reviewed with emphasis on some of our recent research activities. The important aspects discussed are (a) the biological properties of melanin pigments and their relevance to biological functions, (b) functional interaction of melanogenic/melanogenesis-associated genes in melanin biosynthesis process (melanogenesis, and (c) the targeting of proteins involved in melanogenesis and assembly by melanosomal proteins. Upon exposure to UV light radiation (UVR), melanin pigments revealed two distinct photobiological reactions, i.e. photoprotective and phototoxic reactions. The precursor intermediate of brown-black eumelanin, 5-6-dihydroxyindole, appears to possess the most potent photoprotective (antioxidant) property. Eumelanin pigment also had some antioxidant property. Similarly, yellow-red pheomelanin and its precursor intermediate, 5-S-cysteinyldopa also revealed some antioxidant property, but they became prooxidant in the presence of the ferric iron upon exposure to UVR. Melanosomes are known to possess several metal ions including Fe²⁺, Fe³⁺, Cu²⁺ and Zn²⁺. In addition, upon exposure to UV-light, there is an increase in ferric/ferrous iron in the skin. Therefore, in the in vivo system, pheomelanin intermediate, 5-S-cysteinyldopa, may show significant prooxidant property in conjunction with metal ions (e.g. Fe²⁺, Fe³⁺). When atypical moles (previously called dysplastic nevi) were analysed chemically for quantitative and qualitative properties of melanin pigment, they revealed a high ratio of pheomelanin/eumelanin content. This finding may partly explain our clinical observation that these moles are frequently the precursors of malignant melanoma and that the intermittent heavy exposure of UVR can be the major direct cause of their transformation. How, then, the melanosomal compartment, where active new melanin synthesis occurs after exposure to UVR, is protected from the cytotoxicity of melanin precursor intermediates. To study this question, two major experiments were conducted; (a) expression of melanogenesis-associated genes upon exposure of melanocytes to UVR and (b) transfection of cDNAs from the melanogenesis associated genes. There was coordinated gene expression (mRNA) of tyrosinase and tyrosinase-related protein, TRP-1 and this coordinated gene expression was also accompanied by the upregulation of LAMP-1 (lysosome-associated membrane protein-1). Furthermore, human tyrosinase and TRP-1 mRNAs were expressed successfully in individual transfectants or co-transfectants of cDNAs from the two genes. Co-transfectants of human tyrosinase and TRP-1 cDNAs produced many lysosomal granules and melanin-containing granules, melanosomes. LAMP-1 gene was upregulated simultaneously in co-transfectants of tyrosinase and TRP-1, but not in individual transfectants of the two genes. TRP-1 and LAMP-1 gene products were transferred from Golgi complexes to melanosomes. LAMP-1 gene products stimulated by TRP-1 and tyrosinase genes may prevent programmed death of melanocytes due to cytotoxic melanin precursor intermediates by coating the inner surface of melanosomal membrane through the N- and O-linked oligosaccharide moieties of LAMP-1 which have been suggested to protect lysosomes from the action of hydrolytic enzymes.

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The present study was designed to determine the effects of intravenous infusion of L-arginine (ARG), an endogenous precursor of nitric oxide (NO), on the cerebral circulation in the rat. Systemic arterial blood pressure (ABP) was continuously recorded, and local cerebral blood flow (LCBF) was measured by the iodo[¹⁴C]antipyrine method at a point of time as follows: In Saline group (n=12); at 3min after an intravenous injection of saline. In N^G-monomethyl-L-arginine (L-NMMA) group (n=7); at 3min after an injection of L-NMMA (30mg/kg/30 see). In L-NMMA+L-ARG group (n=7); at 3min after an infusion of L-ARG free base (300mg/kg/1min) 3min after prior injection of L-NMMA (30mg/kg/ 30 sec). In L-ARG-1 group (n=7); during an infusion of L-ARG free base (300mg/kg/1min). In L-ARG-2 group (n=8); at 3min after an administration of L-ARG free base (300mg/kg/1min). In D-ARG group (n=5); at 3min after an infusion of D-ARG free base (300mg/kg/1min). (1) The diffuse reduction in LCBF and increase in ABP induced by L-NMMA were almost completely reversed by excess L-ARG. (2) During the administration of L-ARG, a sustained decrease in ABP was observed, but LCBF revealed no significant change. (3) At 3min after the infusion of L-ARG, LCBF was significantly decreased in several regions, while ABP recovered. (4) The infusion of D-ARG also induced a transient decrease in ABP, but did not alter LCBF. The effect of L-ARG on ABP may not be entirely due to an increase in substrate availability for NO synthase, since the D-enantiomer also had some vasodilatory property. Regarding the therapeutic application of L-ARG, further investigations on its actions should be performed under various conditions.

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Malignant tumors arising from trachea are not common. This paper presents an example of primary tracheal adenoid cystic carcinoma treated by surgical resection with good prognosis. A 46-yearold woman presented with a short history of dyspnea. Five months before the onset of dyspnea, the patient had mild wheezing. She had no history of smoking. Physical examination suggested primary tracheal tumor. The patient underwent a V-shaped resection of 3.5cm of trachea followed by reconstruction with the trough method. Histological examination revealed adenoid cystic carcinoma. Adjuvant chemotherapy was indicated with 50mg of adriamycin postoperatively. The patient has done well for 12 years with no further treatment. The tumor was an adenoid cystic carcinoma that was slow-growing, infiltration of mucus membrane was few and growth fraction (mitotic index was less than 1%) was low. Those were considered the reason for good prognosis.

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