Japanese journal of pharmacology
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We investigated the effects of hypothermia (25 degrees C) on the chronotropic and inotropic effects of zatebradine (a blocker of hyperpolarization-activated inward current, I(f)), E-4031 (a blocker of the rapid type of the delayed rectifier K+ current, I(Kr)) and verapamil, and on the positive cardiac responses to isoproterenol after treatment with zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia shifted the dose-response curves to the right for the negative chronotropic and inotropic effects of verapamil and for the negative chronotropic and positive inotropic effects of zatebradine, but not for the negative chronotropic and positive inotropic effects of E-4031. ⋯ E-4031 did not affect the positive responses to isoproterenol. These results suggest that verapamil and zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in normothermia and that the I(f) and inward Ca2+ current are sensitive to hypothermia in the heart.
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A novel non-peptide bradykinin B2-receptor agonist, FR190997 (8-[2,6-dichloro-3-[N-[(E)4-(N-methylcarbamoyl)cinnamidoacetyl+ ++]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinolin e), induced dose-dependent and longer-lasting swelling than bradykinin in the mouse paw. The swelling, peaking around 30 min, was suppressed dose-dependently by intraperitoneal administration of FR173657, a novel non-peptide B2-receptor antagonist. A known B2-antagonist, Hoe 140, also significantly suppressed this edema. The result indicates that the novel B2-agonist FR190997, being more stable than bradykinin, could induce plasma exudation locally in mice via the B2-receptor as a substitute for bradykinin.
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To elucidate the involvement of nitric oxide in spinal nociceptive processing, the correlation of thermal withdrawal latency with nitric oxide synthase-stained neurons in the rat lumbar dorsal horn was analyzed after adjuvant-induced inflammation. From 4 hr through 5 days after subcutaneous injection of complete Freund's adjuvant into the hind paw, a marked thermal hyperalgesia was observed for heat stimulus applied to the affected region. NADPH-diaphorase- and nitric oxide synthase-positive neurons increased significantly in the superficial layers of the dorsal horn ipsilateral to the inflamed hind paw at day 3 of adjuvant-induced inflammation. ⋯ The intravenous administration of N omega-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg), an inhibitor of nitric oxide synthase, significantly blocked the adjuvant-induced thermal hyperalgesia at day 3 of inflammation, but not at day 1; and it had no effect in non-inflamed rats. This anti-hyperalgesic effect of L-NAME at day 3 of inflammation was reversed by the prior administration of L-arginine (600 mg/kg, i.p.), a substrate of nitric oxide synthase. These data suggest that nitric oxide producing neurons in the spinal dorsal horn are involved in maintaining and facilitating the hyperalgesia associated with chronic nociception.
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We have investigated opioid mechanisms concerning regulation of urine production in the hypothalamic supraoptic nucleus (SON). In this study, the effect of [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), a potent selective mu-opioid agonist, microinjected into the SON of anesthetized hydrated rats, on the urine outflow rate was examined. DAMGO caused a dose-dependent decrease in the urine outflow rate with no significant changes in blood pressure nor heart rate. ⋯ The antidiuresis elicited by DAMGO (0.1 nmol) was partially inhibited by intra-SON pre-injection of naloxone (3 nmol), a relatively mu-selective opioid antagonist, and timolol (100 nmol), a beta-adrenoceptor antagonist, but not by intra-SON pre-injection of phenoxybenzamine (20 nmol), an alpha-adrenoceptor antagonist, nor atropine (300 nmol), a muscarinic antagonist. Intravenous injection of d(CH2)5-D-Tyr(Et)VAVP (16.7 micrograms), a vasopressin receptor antagonist, did not influence the DAMGO-induced antidiuresis. These findings suggest that antidiuresis mediated through mu-opioid receptors in the SON involves beta-adrenoceptors in the nuclei, but does not involve an increase in vasopressin release.
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We studied the effects of perospirone (SM-9018), a novel serotonin-2 (5-HT2) and dopamine-2 (D2) receptor antagonist (SDA), on conditioned fear stress (CFS)-induced freezing behavior in rats and compared its actions with those of other antipsychotics. Exposure of rats to the environment previously paired with foot shock induced marked freezing behavior, which was reduced by the anxiolytic diazepam (0.1-3 mg/kg, p.o.) or antidepressants, desipramine and imipramine (10-100 mg/kg, p.o.). Perospirone at 0.3-3 mg/kg, p.o. significantly attenuated the CFS-induced freezing behavior in a dose-dependent manner, while the effect was reduced at the higher dose of 6 mg/kg. ⋯ However, neither conventional antipsychotic, haloperidol (0.1-3 mg/kg, p.o.), chlorpromazine (3-100 mg/kg, p.o.), thioridazine (3-100 mg/kg, p.o.), mosapramine (3-100 mg/kg, p.o.) nor tiapride (30-1000 mg/kg, p.o.) reduced the CFS-induced freezing behavior. In addition, subacute treatment of rats with perospirone (1-10 mg/kg/day) or imipramine (30 mg/kg/day) for 2 weeks prevented the induction of the freezing behavior by CFS. These findings suggest that SDA-type antipsychotics including perospirone are effective for the treatment of mood disturbances such as anxiety and depressive mood associated with schizophrenia and have a broader efficacy profile as compared with the conventional antipsychotics.