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1 We investigated the effects of N0-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, on the performance of rats in a radial arm maze and in habituation tasks, and on monoamine metabolism in the brain. 2 Daily administration of L-NAME (10-60 mg kg-') resulted in a dose-dependent impairment of performance during the acquisition of the radial arm maze task, while it failed to affect performance in those rats that had previously acquired the task. 3 The rate of decrease in locomotor activity in the habituation task in the L-NAME-treated rats was significantly less than that in control rats. 4 N -nitro-D-argimne methyl ester (D-NAME, a less active inhibitor of NO synthase) showed no effects in the above behavioural tasks. 5 NO synthase activity was significantly decreased in both the L-NAME and D-NAME-treated rats, with the magnitude of inhibition being greater in the L-NAME-treated animals. 6 The content of 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus and the 5-HIAA/5-hydroxytry_, tamine ratio in the hippocampus and cortex were significantly decreased in the L-NAME (60 mg kg )-treated rats compared with these values in the controls. 7 Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) content was significantly increased in the L-NAME (60 mg kg-l)-treated rats compared with the values in the controls, while the DOPAC/dopamine ratio was not changed. 8 These results suggest that: (i) NO may play an important role in performance during the acquisition, but not retention, of the radial arm maze task, and (ii) that endogenous NO may be involved in the regulation of monoamine metabolism. Keywords: Nitric oxide; nitric oxide synthase; learning and memory; radial arm maze; habituation task; dopamine; 5-hydroxytryptamine IntroductionNitric oxide (NO) plays an important role in several biological systems Ignarro, 1990;Garthwaite, 1991). In the central nervous system, this free radical gas acts as a diffusible intercellular signalling molecule (Bredt & Snyder, 1992;Snyder, 1992). NO is synthesized from L-arginine, in a NADPH-dependent reaction, by NO synthase. Neuronal and endothelial NO synthases appear to be constitutive calcium-dependent enzymes, whereas other NO synthase isozymes, i.e., those found in smooth muscle and macrophages, are expressed as a result of activation by various cytokines and are calcium-independent (Garthwaite, 1991;Dawson & Snyder, 1994). The localization of a brain-specific isozyme of NO synthase suggests that NO has widespread action in the central nervous system (Vincent & Kimura, 1992;Southam & Garthwaite, 1993). Activation of N-methyl-D-aspartate (NMDA) receptors has been shown to induce NO synthesis (Garthwaite et al., 1988), which then activates soluble guanylate cyclase (Knowles et al., 1989) and leads to the formation of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in the brain (Bredt & Snyder, 1989; Garthwaite et al., 1989, East & Garthwaite, 1991.Further, recent studies have demonstrated the feedback inhibition of NMDA receptors by NO (Lei et a...

The heparin-binding dimeric hypotensive factor (HF) was purified from Vipera aspis aspis (Aspic viper) venom [Komori, Y. and Sugihara, H. (1990) Toxicon 28, 359-369]. In this study, the amino acid sequence, and structure and function of HF, were elucidated. By electrospray ionization mass spectrometry (ESI-MS), the molecular weight of HF was determined to be 25 072.1. The complete amino acid sequence of HF was determined by Edman sequencing of the S-pyridylethylated HF and its peptides derived from enzymatic digestion. The theoretical molecular mass calculated from the primary structure agrees well with the molecular weight determined by ESI-MS. HF consists of two homogeneous monomers bound covalently. The monomer with an N-terminal blocked by pyroglutamic acid contains 110 amino acid residues, including eight cysteine residues, two of which are considered to be involved in intermolecular disulfide bonds. Sequential homology search revealed that the primary structure of HF is similar to that of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) with a sequential homology of 45 and 22%, respectively. When injected intradermally into a rat, an increase in capillary permeability was observed with HF or VEGF. On the other hand, only HF exerted a strong hypotensive effect after intravenous injection of samples into a rat. Purified HF has a mitogenic effect on endothelial cells. Through the use of bovine aortic endothelial cells (BAEC), the half-maximal mitogenic concentration of HF was determined to be 5-5. 5 nM (125-138 ng/mL). Similarly, VEGF had a mitogenic concentration at 0.5-1 nM. When incubated with HF and cycloheximide or HF and heparin, the cell growth was inhibited, suggesting that the mechanism of action of HF is similar to that of VEGF.

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