It is known that serotonin is widely distributed in the body; its receptors are located in various tissues and organs. It has been reported that serotonin receptors without apparent synaptic structure exist in the peripheral nervous system. These serotonin receptors might be the target of circulatory serotonin. In particular, serotonin has a potent depolarizing action on vagal afferent nerves. This stimulation causes various autonomic reflexes, so-called von Bezold-Jarisch reflex, that consist of bradycardia, hypotension and apnea. The peripheral 5-HT₃-receptor subtype seems to be responsible for the initiation of these reflexes. The physiological and pathophysiological significance of these serotonin-induced modulations have not, however, been established. The present study was designed to examine the effects of exogenous serotonin on the chemosensitive afferent nerves including carotid sinus nerves, cervical vagus nerve, and efferent motor nerves, such as phrenic nerves and pharyngeal nerves. Because little is known about the involvement of the serotonergic system in the pulmonary reflex and pulmonary-related reflexes (swallowing or vomiting), the distribution of the motor component of these nerves within the brain stem of the rat was also determined.

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Recent cDNA cloning of pharmacological receptors revealed their primary structures, and the following functional studies with those cloned receptors enabled us to discover the existence of various receptor subtypes. Each receptor has three characteristic properties: 1)ligand binding, 2)effector coupling and 3) desensitization. Delineation of precise domains of a receptor involved in these functions is now an important matter. The molecular mapping of receptors would give us not only a rationale for designing selective drugs, but also new insight about the genotypephenotype relationships of a certain kinds of hereditary diseases caused by a mutation of receptor genes. A mutagenesis study is a powerful approach for elucidating the structure-function relationships of pharmacological receptors. In contrast to a peptide, a protein is impossible to engineer in vitro. However, modulation of a specific codon in a given cDNA could bring about a substitution of a corresponding amino acid in the protein expressed in vivo. In this article, the popular strategies for generating artificially mutated receptors are discussed. This review will focus on three types of mutant receptors: 1)point mutation, 2)chimeric and 3)truncated receptors. The annotated bibliographies will also come in handy when devising experimental protocols.

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We investigated the effects of the combination of idebenone, an energy metabolism enhancer, and manidipine 2HCl, a dihydropyridine-derivative calcium antagonist, on neurological deficits and histological changes in the brain and kidneys of stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions (stroke). The SHRSP were kept on a 1 % NaCl solution as their drinking water to synchronize the onset of stroke. After the onset of stroke symptoms, the salt solution was replaced with tap water. On the day following the onset of stroke, idebenone (50 mg/kg), manidipine 2HCl (2 mg/kg) or a combination of idebenone (50 mg/kg) and manidipine 2HCl (2 mg/kg) was administered orally once a day for 3 weeks. In the combination group and manidipine 2HCl-treated group, the neurological deficits after the onset of stroke were ameliorated during the entire experimental period. Especially, the combination significantly decreased the number of days with severe neurological deficits as compared to the control group. The combination and manidipine 2HCl significantly recovered the decrease in body weight and ameliorated the increase of brain weight, which was mainly caused by edema, significantly as compared to the control group. Manidipine 2HCl ameliorated the histological changes in the brain. In the combination group, the histological changes in both the brain and the kidneys were ameliorated. In conclusion, the combination of idebenone and manidipine 2HCl significantly ameliorated the neurological deficits and the histological changes in the brain and the kidney of SHRSP with stroke as compared to each individual treatment. We concluded that manidipine 2HCl enhances the therapeutic effect of idebenone in the treatment of cerebrovascular diseases.

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The affinity of mosapramine, an iminodibenzyl antipsychotic, to dopamine D-receptors in rat brain was investigated by quantitative autoradiography of[³H]-7-OH-DPAT, a selective D₃-ligand. Autoradiograms showed restricted distribution of [³H] 7-OH-DPAT binding sites, with very high levels on the islands of Calleja (ICj), olfactory tubercle (Tu) and nucleus accumbens, while low but distinct labeling was observed in the molecular layer of lobule 10 of the cerebellum and caudate putamen (CPu). Binding of [³H]7-OH-DPAT completely disappeared when 1 μM dopamine was added, and it was reduced by the addition of mosapramine in a concentration-dependent manner. The displacing effect of mosapramine was more potent than that of haloperidol or clozapine in the brain regions examined. Mosapramine showed more potent affinity to receptors in Tu and ICj than those in CPu. On the other hand, haloperidol and clozapine did not show such regional differences. These results suggest that the high affinity of mosapramine to D₃-receptors participates in, at least in part, the development of the clinical effects of mosapramine.

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We assessed the effects of KW-4679 on bronchoconstriction, airway hyperresponsiveness and infiltration of inflammatory cells into the bronchoalveolar lavage (BAL) fluid induced by plateletactivating factor (PAF) in guinea pigs. (1) KW-4679 (1, 10 mg/kg, p.o.) significantly inhibited PAF-induced bronchoconstriction in anesthetized, ventilated guinea pigs. Ketotifen (1, 10 mg/kg, p.o.) also significantly inhibited that reaction. (2) Intravenous administration of PAF (600 ng/kg /hr) to ventilated anesthetized guinea pigs induced bronchial hyperresponsiveness to histamine or substance P. PAF-induced bronchial hyperresponsiveness was significantly attenuated by pretreatment with KW-4679 (3 mg/kg, i.v.). (3) Exposure of guinea pigs to an aerosol of PAF induced an increase in the numbers of total leukocytes, eosinophils, neutrophils and lymphocytes in BAL fluid at 24hr. KW-4679 (10 mg/kg, p.o.) reduced the increase in eosinophils in BAL fluid. Ketotifen (10 mg/kg, p.o.) partially reduced the increase in eosinophils in BAL fluid. (4) KW-4679 did not inhibit PAF-induced rabbit platelet aggregation. These observations indiate that KW-4679 attenuates the PAF-induced pulmonary reactions in guinea pigs and that these actions may be beneficial for the treatment of allergic bronchial asthma.

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