Primary sensory nerves do not only transfer messages to the central nervous system but also transmit messages to the periphery. The peripheral response is one of defense, including neurogenic inflammation such as miosis and a breakdown of the blood aqueous barrier in the eye or vasodilatation and plasma extravasation in the skin. Recent pharmacological, biochemical and immunohistochemical studies have revealed that tachykinins are the most likely transmitters at peripheral as well as central endings of primary sensory nerves. Furthermore, studies with trigeminal nerve-innervated and isolated rabbit iris sphincter muscle have clearly shown that the peripheral neurotransmission is affected by many neuromodulators and irritants. It is not unlikely that the neurotransmission mechanisms at peripheral endings are analogous to those at central endings in the primary sensory nerves.

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In this paper, the effects of three antipsychotic agents using the avian species laboratory model are described. d-Amphetamine (2-5 mg/kg, s.c.) dosedependently antagonized catalepsy induced by haloperidol (0.25 mg/kg, i.p.), YM-09151-2 (0.02-0.04 mg/kg, i.p.) and (-)-sulpiride (20-40 mg/kg, i.p.) in rats. (-)-Sulpiride (10-40 mg/kg, i.p.) dose-dependently antagonized apomorphine (0.125 mg/kg, s.c.)-induced stereotyped behavior in young chicks. Similarly, YM-091 51-2 (0.04 mg/kg, i.p.) antagonized apomorphine (0.125 mg/kg, s.c.)-induced stereotyped behavior in young chicks. (-)-Sulpiride (40 mg/kg, i.p.) significantly antagonized apomorphine (0.25 mg/kg, s.c.)-induced stereotyped behavior in 6 week old chicks. Parachlorophenylalanine (PCPA, 300 mg/kg, i.p.) significantly reduced the intensity of stereotyped behavior induced by apomorphine (0.125 mg/kg, s.c.) in young chicks. However, (-)-sulpiride (40 mg/kg, i.p.) did not significantly influence the effect of PCPA on apomorphine-induced stereotyped behavior. Similarly, catalepsy induced by (-)-sulpiride (40 mg/kg, i.p.), haloperidol (0.25 mg/kg, i.p.) and YM-09151-2 (0.04 mg/kg, i.p.) in male rats was profoundly suppressed by PCPA (300 mg/kg, i.p.). The present results indicate that apomorphine-induced stereotyped pecking in young (4-6 day old) chicks may serve as a suitable laboratory model for testing potential antipsychotic drugs. In addition, the data indicates that endogenous 5-hydroxytryptamine mechanisms may be involved in the genesis of drug-induced catalepsy in rats.

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Hypertens1ve action was observed in conscious rats injected intraventricularly with glandular kallikrein (EC 3.4.21.35) in a dose-dependent manner (4-16 KU), which was associated with the enhancement of brain kinin level. Concurrently administered aprotinin, a kallikrein inhibitor, led to an inhibition of these effects of kallikrein. These results suggest that the central hypertensive action of kallikrein is mediated via the kinin liberated from a kininogen in the brain.

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In the present study, effects of ethanol (EtOH) on C57/BL mouse cortical β-adrenergic receptor coupled adenylate cyclase (AC) were shown to be different from the effects of EtOH on striatal dopaminergic-stimulated AC activity. The addition of EtOH (500 mM) increased the AC activity by 60% in cortical membrane and by less than 10% in striatal membrane preparations in the absence of guanine nucleotide. The dose-response relationship for EtOH stimulation of cortical AC activity in the presence of guanylylimidodiphosphate (Gpp(NH)p) was biphasic, whereas, in the striatum, a linear dose-response relationship for EtOH was found for stimulation of AC in the presence of Gpp(NH)p. Activation of AC by Gpp(NH)p occurred as an apparent pseudo-first order process. EtOH increased the pseudo-first order rate constant for activation of AC by Gpp(NH)p in the cortex, but not in the striatum. Following 10 min preincubation with Gpp(NH)p, catecholamines and Gpp(NH)p were not able to stimulate further the AC activities in either tissue. Nevertheless, EtOH increased AC activity in both cortex and striatum following the preincubation with Gpp(NH)p. These data suggest that one effect of EtOH in striatal tissue is to promote the interaction of an activated guanine nucleotide-binding regulatory protein (G-protein) with the catalytic unit of AC. In cortical tissue, the effects of EtOH may be attributable to direct actions on the catalytic activity of the enzyme, effects on the rate of activation of the G-protein, and an altered interaction of G-protein with the catalytic unit.

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Supersensitivity in chronically sympathectomized smooth muscle has long been studied, but little is known about chronically parasympathectomized smooth muscles. Iris is one of the few smooth muscle organs which can be parasympathetically denervated. We used rats because the denervation supersensitivity in the vas deferens has extensively been studied in this species. The rat was unilaterally ciliary-ganglionectomized. After 1-13 days, strips of the iris sphincter muscle obtained from denervated eye were tested for the sensitivity to acetylcholine (ACh), 5-hydroxytryptamine (5-HT) and K⁺. A significant increase in sensitivity to ACh and 5-HT was recognized as early as 1 day after the operation, and the sensitivity reached a maximum after 5-6 days, when ED50 values of ACh and 5-HT were reduced to approximately 1/28 and 1/4, respectively. The sensitivity to K⁺ was unaffected. When the sensitivity reached the maximum, the maximum responses to ACh, 5-HT and K⁺ were increased by 50%, 140% and 50%, respectively. The shift of the dose-response curve for bethanechol (BeCh) after denervation was comparable to that for ACh. Physostigmine shifted the curve for ACh, but did not shift that for BeCh either before or after denervation. Specific binding of ³H-quinuclidinyl benzylate tended to decrease after denervation, but the change was statistically not significant. These results indicate that the parasympathetic denervation supersensitivity in the rat iris sphincter involves a non-specific component, in addition to one specific to ACh and BeCh. The specific component seems to involve postsynaptic mechanisms.

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The effect of parasympathectomy on the electrical and nonelectrical activation of iris smooth muscle cells was examined 7-10 days after ciliary ganglionectomy in order to explore the mechanisms involved in the nonspecific denervation supersensitivity. Resting membrane potential of rat iris sphincter muscle cells was not altered by cholinergic denervation. Although the degree of depolarization induced by raising [K]_o was little affected by denervation, K-contracture was always potentiated. Acetylcholine (ACh) never modified membrane potential in normal iris muscles even at a high concentration of 50 μM. After denervation, ACh produced a much larger contraction, and at higher concentrations, concomitantly produced a depolarization which was far too small to account for the enhanced contraction. There were 3 and 4.6-fold increases in sensitivity to Ca and Sr, respectively, in the contractile response in high-K, Ca-free solution after denervation. The response to Ca was greatly enhanced also in height, and a large part of the increment of the response to 2 mM Ca was suppressed by 0.1 μM nifedipine. In the depolarized muscle of normal irides, Mn ion had two distinct effects, a calcium blocking effect at lower concentrations (≤1.2 mM) and a contractile effect at higher concentrations (≥1 .8 mM). Denervation caused a marked increase in the contractile effect of Mn (≥=0.6 mM). ACh elicited phasic contraction only once in the absence of external Ca. This response was much enhanced by parasympathectomy. Fluoride ion (F) also produced a distinct contraction many times in the Ca-free solution. F-induced contraction was much larger in denervated muscle than in normal muscle. These results i) indicate that denervation of the rat iris sphincter muscle does not significantly affect the electrical property of the muscle cells, ii) and suggest that denervation may increase Ca-influx of the cell membrane, iii) may increase the amount of releasable Ca from an intracellular store site, and iv) might increase the functional activity of the contractile protein.

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Rats were trained to discriminate (±)-rolipram (0.32 mg/kg, i.p.) from saline in a two-lever food-reinforced drug discrimination procedure (FR 10). (±)-Rolipram served as a drug discriminative stimulus, and its discrimination was readily established with a mean of 42 training sessions to achieve criterion performance (at least 80% correct response in the consecutive generalization tests with both saline and (±)-rolipram). Thereafter, this stimulus was stably maintained. The (-)-isomer of rolipram was generalized at about one-third of the training dose of the (±)-compound, but the (+)-isomer was generalized only at 10 times the dose of the (±)-compound. This finding suggests that the (-)-compound is more extensively involved as a stimulus than either (±)-rolipram or the (+)-isomer. Ro20-1724, caffeine and theophylline, which are phosphodiesterase inhibitors, were generalized to (±)-rolipram. This result strongly suggests that phosphodiesterase inhibition may be an important factor involved in (±)-rolipram discrimination.

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Central effect of thyrotropin releasing hormone (TRH) on gastric acid output and mucosal blood flow (MBF) was examined in urethane anesthetized rats. TRH, microinjected into the dorsal vagal complex [the dorsal motor nucleus of the vagus (NDV), the nucleus tractus solitarius and area postrema] induced dose-dependent (0.5-50 pmole) increases in gastric acid output and MBF. In contrast, 5 pmole TRH microinjected into various hypothalamic regions had no effect on these gastric parameters. Administration of TRH intraventricularly (i.c.v.) also increased these gastric parameters; however, about a 10 times higher dose of TRH was required to obtain the same order of excitatory effects seen with microinjection to the dorsal vagal complex. Application of anti-TRH serum to the dorsal vagal complex inhibited the increases in gastric acid output and MBF induced by TRH (i.c.v.). The effect of TRH applied to the dorsal vagal complex and i.c.v. were not modified by a concomitant administration of atropine. These results suggests that NDV is probably the site of action of TRH in inducing gastric hyperfunctions. The mode of action of TRH seems to be independent of cholinergic muscarinic mechanisms present in the NDV.

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Antiarrhythmic effects of a new beta 1 selective adrenoceptor blocker, betaxolol, were examined in comparison with those of atenolol using two canine ventricular arrhythmia models (adrenaline arrhythmia and digitalis arrhythmia). Both betaxolol and atenolol suppressed adrenaline arrhythmia, and the minimum effective plasma concentration of betaxolol for this arrhythmia model was determined to be less than 10 ng/ml. However, on digitalis arrhythmia, both beta blockers were ineffective, even though the high doses used in these experiments, 3 mg/kg for betaxolol and 5 mg/kg for atenolol, showed significant hypotensive effects. The present results suggest that betaxolol and atenolol may be expected to be clinically effective on arrhythmias related to increased sympathetic tone.

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The effect of agrimoniin, a tannin contained in Agrimonia pilosa LEDEB., on ascites type and solid type rodent tumors was investigated. When agrimoniin was intraperitoneally (i.p.) administered at dosages over 10 mg/kg before or after the MM2 cell i.p. inoculation, this tannin almost completely rejected the tumor growth in the mice. This tannin prolonged the life span of mice bearing MM2 or cured by the intravenous or per oral pre or postmedication. Agrimoniin also inhibited the growth of MH1 34 and Meth-A solid type tumors. Agrimoniin showed strong cytotoxicity on MM2 cells in vitro, but the activity was diminished to about 4% of the initial activity by the addition of fetal calf serum to the culture. On the other hand, i.p. injection of agrimoniin increased the number of peripheral white blood cells and the ratio of monocytes. On the 4th day after the i.p. injection of the tannin, cytotoxic adherent peritoneal exudate cells were also increased. The spleen of the mice was enlarged, and the spleen cells possessed the capacity to take up ³H-thymidine. Agrimoniin showed weak direct migration activity against spleen cells from non-treated mice. These results indicate that agrimoniin is a potent antitumor tannin and suggest that the antitumor effect may be due to this tannin enhancing the immune response of the host animals through the actions on tumor cells and some immunocytes.

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The modulatory action of prostaglandin D₂ (PGD₂) on the high-K⁺induced release of ³H-norepinephrine (³H-NE) from rat cerebellar slices was investigated in relation to the presynaptic feedback mechanisms for the NE release. PGD₂ (10^-7-10^-5 M) dose-dependently suppressed the release of ³H-NE. The ³H-NE release was also dose-dependently decreased by 10^-10-5×10^-9 M clonidine and increased by 10^-9-10^-6 M yohimbine, and there was an antagonism between clonidine and yohimbine, indicating the presence of an α₂-adrenoceptor-mediated negative feedback mechanism in the rat cerebellum. The inhibitory action of clonidine was not additive to that of PGD₂, while there appeared to be an additiveness between the effects of PGD₂ and yohimbine. The ³H-NE release was increased by I-isoproterenol and decreased by I-propranolol, but only at concentrations higher than 10^-6 M. PGD₂ nearly abolished the actions of these β-adrenergic agents, and the ³H-NE release remained at a level similar to that induced by 10^-5 M PGD₂ alone. Based on these results, it was tentatively suggested that PGD₂ inhibits the ³H-NE release by a mechanism independent of adrenoceptor-mediated feedback mechanisms.

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Rat brain microsomal Mgt₂₊-ATPases with two distinct activities: ethacrynic acid (EA) highly sensitive and EA less sensitive Mg₂₊-ATPase activities were solubilized by the combined treatment with 10 mM 3-(3-chlolamidopropyl)dimethylammonio-1 -propane-sulfate (CHAPS) and 30 mM octyl-β-D-glucoside. The solubilized enzymes had properties similar to those of the membrane-bound enzyme in microsomes with respect to the sensitivity to EA and Cl^-, although the optimal pH and the affinity to ATP were slightly altered after the solubilization. Fast protein liquid chromatography of the solubilized enzymes on an anionexchanger (Mono Q) column with a linear NaCI gradient (0-1.0 M) yielded separate peaks for EA highly sensitive and EA less sensitive Mg²⁺-ATPase activities at 0.1 and 0.35 M NaCl, respectively. Polyacrylamide gradient gel electrophoresis of the samples from the peak-fractions of EA highly sensitive and EA less sensitive Mg²⁺+-ATPase activities yielded prominent bands at 600 and 70 kDa, respectively. These results indicate that EA highly sensitive Mg²⁺+-ATPase is solubilized and separated from EA less sensitive Mg²⁺-ATPase as a large enzyme molecule with anion-sensitive sites.

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The protective effect of 16, 16-dimethyl prostaglandin E₂ (dmPGE₂) against early damage induced by indomethacin in the rat gastric mucosal surface epithelial cells was studied using a scanning electron microscope. Indomethacin (10 or 25 mg/kg, p.o.) induced a widespread exfoliation of the surface epithelial cells and an exposure of the lamina propria both in the corpus and antrum within 1 hr after the administration. Pretreatment with dmPGE₂ (0.3, 3 or 30 μg/kg, p.o.) 30 min before indomethacin (25 mg/kg) dose-dependently inhibited these damages. The effects of dmPGE₂, at least on the surface epithelial cells in the corpus, appear to be related to the prevention of damage formation itself and is unrelated to the enhancement of reconstitution of once damaged mucosa. Enhanced gastric motility by indomethacin was potently inhibited by pretreatment with 3 and 30 μg/kg of dmPGE₂, but not with 0.3 μg/kg. dmPGE₂ pretreatment (30 μg/kg) significantly decreased the absorption of indomethacin (25 mg/kg) when determined 10 min after giving indomethacin, but did not affect it when determined 30 and 60 min later. We conclude that dmPGE₂ protects gastric mucosal surface epithelial cells from indomethacin injury at an early stage, partly by inhibiting gastric motility.

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Two kinds of inspiratory gases, 100% O₂ and 81% O₂+19% CO₂, were used for the artificial respiration. Elevating the inspiratory CO₂ tension enhanced the decrease in coronary vascular resistance caused by isosorbide dinitrate (100 μg/kg), without any change in heart rate and systemic arterial pressure. Such a change in coronary vascular resistance was prevented by indomethacin. The results suggested an interaction between isosorbide dinitrate and CO₂, which was mediated by prostaglandins.

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In the cytochrome P-450-reconstituted system, CCl₄ stimulated NADPH-dependent lipid peroxidation of the system containing the P-450 form to a much greater extent than that of the system containing the P-448 form. When the P-450-reconstituted system was preincubated in the presence of both NADPH and CCl₄, 7-ethoxycoumarin O-deethylase, aminopyrine N-demethylase and aniline hydroxylase activities were decreased by 40-60%, whereas, with P-448 form reconstituted system, no suppression was observed in these enzyme activities or in 7-ethoxyresorufin O-deethylase activity. These observations suggest that the P-450 form, but not the P-448 form, is active in metabolizing CCl₄ to a reactive species that subsequently impairs the hemoprotein.

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Ecto-5'-nucleotidase (ecto-5'-NU) of platelets was enhanced by concanavalin A (Con A). This effect of Con A was antagonized by α-methyl-D-mannose, a specific antagonist of Con A binding to glycoprotein. Coformycin, an adenosine deaminase inhibitor, did not change the effect of Con A on the ecto-5'-NU. Uptake of adenosine by platelets was not affected by Con A. It was suggested that the ecto-5'-NU of platelet might be a direct and primary site of action of Con A.

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Calcium antagonistic activity of MCI-176, a new calcium antagonist, was compared with those of diltiazem and nifedipine in isolated depolarized porcine coronary arteries. MCI-176, diltiazem and nifedipine competitively inhibited calcium contraction of the large coronary arteries, and their pA₂ values were 7.49, 6.89 and 9.55, respectively. Similar competitive inhibition by MCI-176, diltiazem and nifedipine of calcium contraction was also observed in the small coronary arteries, and their pA₂ values were 7.38, 6.83 and 9.91, respectively. Although calcium antagonistic activity of nifedipine was several hundreds times more potent than MCI-176 and diltiazem, the action of nifedipine, unlike MCI-176 and diltiazem, favored the small coronary arteries rather than the large coronary arteries.

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Cholinesterase (ChE) activity was examined in 15 veins from dogs by pharmacological and histochemical procedures. Potentiation of acetylcholine (ACh)-induced contractile response by neostigmine was observed in helical and longitudinal strips of portal, mesenteric veins and middle segment of the inferior vena cava, but not in the other 12 veins. Histochemical studies with an electronmicroscope (the method of Karnovsky-Roots) revealed that ChE activity was identified as high density granules around the smooth muscle cells only in the former three veins. The visible ChE activity was abolished by pretreatment with neostigmine.

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Effects of condensed tannins isolated from Rhei Rhizoma on the activities of angiotensin converting enzyme (ACE) and various proteases were examined in vitro. Among the various condensed tannins tested, procyanidin B-5 3, 3' di-O-gallate and procyanidin C-1 3, 3', 3''-tri-O-gallate strongly inhibited the activity of ACE. The concentration of procyanidin B-5 3, 3'-di-O-gallate required for 50% inhibition of ACE was 1.3×10^-6 M. The inhibition of ACE by condensed tannins was reversible and non-competitive, according to dialysis and to Dixon plots. However, over one hundred times the concentration was required to inhibit activities of other proteases such as trypsin, chymotrypsin, leucine aminopeptidase, carboxypeptidase A and urinary kallikrein. These results suggest that the inhibitory effects of condensed tannins on the activities of ACE are specific.

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