Desensitization of substance P-induced K+ release in rat parotid

The angiotensin converting enzyme inhibitor enalapril (0.5 mg/kg i.v.) potentiated significantly the inhibitor effect of the thromboxane A₂ antagonist L-640,035 (1 mg/kg i.v.) on electrically induced platelet accumulation in the rabbit in vivo. Enalapril had no effect upon platelet accumulation when given alone. The hypotensive effects of enalapril did not account for the potentiation because a combination of hexamethonium (5 mg/kg i.v.) and hydralazine (1 mg/kg i.v.), which decreased blood pressure similarly to enalapril, did not augment the effect of L-640,035. Determination by radioimmunoassay of plasma levels of immunoreactive 6-keto-PGF₁, suggested that increases in PGI₂ levels after combined administration of enalapril and L-640,035 could explain the observed potentiation.     

Effects of thromboxane synthase inhibitors on renal function

Summary In general the effects of thromboxane A₂(TXA₂) on renal function are opposite those produced by other prostanoids. TXA₂ synthase inhibitors decrease the biosynthesis of TXA₂ and may increase the production of other prostanoids by causing endoperoxide shunting. Therefore, in situations of increased kidney arachidonate mobilization, inhibition of renal TXA₂ synthase might alter renal function by reducing TXA₂ production and/or increasing prostaglandin (PG) biosynthesis. This hypothesis was tested by comparing the changes in renal function induced by suprarenal aortic constriction in anesthetized dogs pretreated with either a TXA₂ synthase inhibitor (UK 38,485; n = 7 or OKY1581; n = 7) or vehicle (0.1 M Na₂CO₃; n = 9). Several renal function parameters were compared in control versus treated animals by analysis of variance. Neither UK38,485 (1 mg/kg, i. v.) nor OKY 1581 (10 mg/kg, i. v.) significantly altered renal artery hypotension-induced changes in mean arterial blood pressure, heart rate, renal blood flow, renal vascular resistance, glomerular filtration, filtration fraction, urine flow rate, sodium excretion rate, fractional sodium excretion, potassium excretion, or fractional potassium excretion. However, both UK 38,485 and OKY 1581 seemed to attenuate the increase in renal renin secretion rate induced by suprarenal aortic constriction. We conclude that acute administration of TXA₂ synthase inhibitors does not modify acute renal artery hypotension-induced changes in either electrolyte excretion or renal hemodynamics. However, acute administration of TXA₂ inhibitors attenuates suprarenal aortic constriction-induced increases in renin release in anesthetized dogs by unknown mechanisms. Send offprint requests to E. K. Jackson     

Involvement of diazepam-insensitive benzodiazepine receptors in the suppression of DOI-induced head-twitch responses in diabetic mice

Rationale We previously reported that the head-twitch responses induced by the 5-HT₂ receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) (DOI-HTRs) were decreased in streptozotocin-induced diabetic mice.Objectives We examined the involvement of γ-aminobutyric acid (GABA)/benzodiazepine system on the suppression of DOI-HTRs in diabetic mice.Results The benzodiazepine receptor antagonist flumazenil (0.1–1 mg/kg, i.v.) dose-dependently and significantly increased DOI-HTRs in diabetic mice to the same levels as in nondiabetic mice. However, flumazenil (0.1–1 mg/kg, i.v.) did not affect DOI-HTRs in nondiabetic mice. The benzodiazepine receptor agonist diazepam (0.1–1 mg/kg, i.p.) had no effect on DOI-HTRs in either nondiabetic or diabetic mice. The GABA_A receptor antagonist bicuculline (0.1–1 mg/kg, i.p.) and the benzodiazepine receptor partial inverse agonist Ro 15-4513 (0.1–1 mg/kg, i.v.) dose-dependently and significantly suppressed DOI-HTRs in nondiabetic mice to the same levels as in diabetic mice. Ro 15-4513-induced reduction of DOI-HTRs in nondiabetic mice was completely antagonized by flumazenil (1 mg/kg, i.v.), but not diazepam (0.3 mg/kg, i.p.).Conclusions We suggest that the abnormal diazepam-insensitive benzodiazepine receptor function partly underlies the suppression of DOI-HTRs in diabetic mice.     

Photochemically induced thrombosis of the rat coronary artery and functional evaluation of thrombus formation by occurrence of ventricular arrhythmias

Summary During i. v. infusion of rose bengal (48 mg/kg/h), the proximal portion of the rat left coronary artery was illuminated from the outside of the myocardium by green light (540 nm) to produce a transluminal thrombus subsequent to endothelial damages. The primary endothelial damages within the illuminated vascular portion, which resulted from the photochemical reaction between the dye and green light, and the subsequent formation of transluminal platelet-rich thrombus, were easily revealed by both light and electron microscopy. The establishment of the thrombus was accompanied in all cases by the occurrence of ventricular arrhythmias due to myocardial ischaemia. The times required to initiate ventricular premature beats (VPBs) and ventricular tachycardia (VT) were 381 ± 96 s and 444 ± 114 s (mean ± SEM, n = 10), respectively. Pretreatment of the rat with acetylsalicylic acid (3 and 10 mg/kg, i. v.) before the initiation of illumination had no effect on the times required to exhibit the first VPBs and VT, the incidences of both types of arrhythmias were not reduced, and the thrombus was finally formed. On the other hand, pretreatment with Y-20811, a novel thromboxane A₂ synthetase inhibitor (0.3, 1 and 3 mg/kg, i. v.), delayed the onset of both VPB and VT in a dose-dependent manner. The incidences of VPBs and VT were significantly reduced at 1 and 3 mg/kg, and the thrombus formation was prevented. The formation of a transluminal thrombus in the left coronary artery by the present technique was highly reproducible and could be functionally evaluated by the occurrence of ventricular arrhythmias. Correspondence to: T. Uematsu at the above address     

On the role of brain 5-HT7 receptor in the mechanism of hypothermia: comparison with hypothermia mediated via 5-HT1A and 5-HT3 receptor

Intracerebroventricular administration of selective agonist of serotonin 5-HT₇ receptor LP44 (4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-pyperasinehexanamide hydrochloride; 10.3, 20.5 or 41.0 nmol) produced considerable hypothermic response in CBA/Lac mice. LP44-induced (20.5 nmol) hypothermia was significantly attenuated by the selective 5-HT₇ receptor antagonist SB 269970 (16.1 fmol, i.c.v.) pretreatment. At the same time, intraperitoneal administration of LP44 in a wide range of doses 1.0, 2.0 or 10.0 mg/kg (2.0, 4.0, 20.0 μmol/kg) did not cause considerable hypothermic response. These findings indicate the implication of central, rather than peripheral 5-HT₇ receptors in the regulation of hypothermia. The comparison of LP44-induced (20.5 nmol) hypothermic reaction in eight inbred mouse strains (DBA/2J, CBA/Lac, C57BL/6, BALB/c, ICR, AKR/J, C3H and Asn) was performed and a significant effect of genotype was found.In the same eight mouse strains, functional activity of 5-HT_1A and 5-HT₃ receptors was studied. The comparison of hypothermic responses produced by 5-HT₇ receptor agonist LP44 (20.5 nmol, i.c.v.) and 5-HT_1A receptor agonist 8-OH-DPAT 1.0 mg/kg, i.p. (3.0 μmol/kg), 5-HT₃ receptor agonist m-CPBG (40.0 nmol, i.c.v.) did not reveal considerable interstrain correlations between 5-HT₇ and 5-HT_1A or 5-HT₃ receptor-induced hypothermia. The selective 5-HT₇ receptor antagonist SB 269970 (16.1 fmol, i.c.v.) failed to attenuate the hypothermic effect of 8-OH-DPAT 1.0 mg/kg, i.p. (3.0 μmol/kg) and m-CPBG (40.0 nmol, i.c.v.) indicating that the brain 5-HT₇ receptor is not involved in the hypothermic effects of 8-OH-DPAT or m-CPBG. The obtained results suggest that the central 5-HT₇ receptor plays an essential role in the mediation of thermoregulation independent of 5-HT_1A and 5-HT₃ receptors.     

The central sympatho-inhibitory effect of 5,6-dihydroxy-2-dimethylaminotetralin (M7) is mediated by α2-adrenoceptors

M7 (5,6-dihydroxy-2-dimethylaminotetralin) produces in anesthetized rats a hypotensive response previously attributed to peripheral dopaminergic mechanisms. We re-examined the effects of this drug on arterial blood pressure, heart rate and sympathetic nerve activity in anesthetized rats and dogs. M7 (1–100 μg/kg i.v.) produced in the rats transient dose-dependent pressor effects, with bradycardia and sympatho-inhibition, followed by long-lasting dose-dependent hypotension, bradycardia and sympatho-inhibition. The sympatho-inhibitory and hypotensive effects were comparable in baroreceptor-denervated rats and were reversed by idazoxan (0.1 mg/kg i.v.). The sympatho-inhibitory response induced by M7 (1–100 μg/kg) was prevented by treatment with the specific α₂-adrenoceptor antagonist, 2-methoxy-idazoxan (0.03 mg/kg i.v.). This central effect of M7 was not altered by treatment with the α₁-adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.) and was reduced by treatment with the α₂-adrenoceptor antagonists, yohimbine (1 mg/kg i.v.) or idazoxan (0.3 mg/kg i.v.), and the dopaminergic antagonists, haloperidol (0.5 mg/kg i.v.) or sulpiride (3 mg/kg i.v.). Bilateral microinjections of M7 (0.3–3 nmol) into the rostroventral medulla in the rat produced dose-dependent hypotension, bradycardia and sympathetic nerve inhibition which were reversed and prevented by bilateral microinjection of 2-methoxy-idazoxan (1 nmol) into the same sites. Microinjections of 2-methoxy-idazoxan into the rostroventral medulla also inhibited the central effects of M7 at 0.03 mg/kg i.v. In anesthetized dogs, M7 administered into the cisterna magna (1–10 μg/kg) reduced arterial blood pressure, heart rate and sympathetic nerve activity; these effects were reversed by administration of 2-methoxy-idazoxan (0.03 mg/kg i.v.). In conclusion, M7, a rigid catecholamine, produces a potent central sympatho-inhibitory and hypotensive effect by activation of α₂-adrenoceptors.     

Involvement of central histaminergic and cholinergic systems in the morphine-induced increase in blood-brain barrier permeability to sodium fluorescein in mice

Summary Morphine (5 mg/kg, s.c.) caused a submaximal increase in the brain level of sodium fluorescein administered i.v. Histamine H₁-antagonists, diphenhydramine and mepyramine, given either i.p. or i.c.v., had no significant influence on the effect of morphine. H₂-Antagonists, cimetidine and ranitidine, administered i.c.v., but not i.p., significantly inhibited the morphine effect. -Fluoromethylhistidine, a specific histidine decarboxylase inhibitor (given i.p. and i.e.v.) and antimuscarinic drugs, atropine and biperiden, but not methylatropine (given i.p.) also significantly reduced the morphine effect. Physostigmine (i.p.) significantly enhanced the effects of 0.5 and 1 mg/kg of morphine. Similar effects of histaminergic and cholinergic drugs were also observed on the buprenorphine- and DAGO-induced increase in blood-brain barrier (BBB) permeability to sodium fluorescein. None of the treatments with 6-hydroxydopamine, -methylayrosine, 5,7-dihydroxytryptamine or p-chlorophenylamine had any significant effect on the morphine-induced increase in BBB permeability. These findings suggest that the activation of brain H₂-receptors by neuronal histamine and muscarinic receptors by acetylcholine is involved in the increase in BBB permeability to sodium fluorescein caused by opioid receptor agonists. Send offprint requests to K. Saeki at the above address     

Gastroprokinetic properties of the benzimidazolone derivative BIMU 1, an agonist at 5-hydroxytryptamine4 and antagonist at 5-hydroxytryptamine3 receptors

We have investigated the in vivo motor stimulating and gastroprokinetic properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3dihydro-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-2-oxo 1H-benzimidazole-1-carboxamide hydrochloride) and its binding profile at 5-hydroxytryptamine₃ and 5-hydroxytryptamine₄ receptors, in an attempt to assess the serotonergic mechanism underlying its prokinetic action.BIMU 1 dose-dependently (0.01–0.3 mg/kg iv.) increased the motility of a denervated pouch of canine stomach. This excitatory action was sensitive to muscarinic blockade. A similar stimulatory effect was exerted by the benzamidic prokinetic agent cisapride (0.03–0.3 mg/kg i.v.) but not by the 5-HT₃ receptor antagonist ondansetron (up to 1 mg/kg i.v ). The significance for propulsive efficacy of the motor stimulating activity of BIMU 1 was evaluated in a model of gastric emptying of liquids in the conscious dog. The emptying rate of a non-caloric liquid meal instilled through a gastric fistula was accelerated by both BIMU 1 (0.01–1 mg/kg i.v. and 0.1–3 mg/kg p.o.) and cisapride (0.03–1 mg/kgiv.and0.3–10 mg/kgp.o.).Ondansetron (1 mg/kg i.v.) did not show any effect. The activity of the 5-HT₄ receptor antagonist DAU 6285 was evaluated in the gastric emptying model per se and in interaction experiments on the accelerating action of BIMU 1 (0.3 mg/kg L v.). At 1 mg/kg iv., DAU 6285 was ineffective on its own and failed to antagonize BIMU 1-induced prokinetic action;at the dose of 3 mg/kg i.v., it depressed the gastric emptying rate per se by 15% and totally abolished the accelerating effect of BIMU 1.In the binding assay, BIMU 1 exhibited an appreciable affinity for 5-HT3 receptors in NG 108-15 cells (K_D: 0.8 nmol/l) and for 5-HT₄ receptors in pig striatum (K_D: 26.5 nmol/l). Compared to BIMU 1, cisapride bound with a similar affinity to 5-HT₄ (K_D: 35.2 mnol/l) and a much lower affinity to 5-HT₃ receptors (K_D: 155 nmol/l). By contrast, ondansetron was highly selective for 5-HT₃ sites (K_D: 4.7 nmol/l), being ineffective in the assay for 5-HT₄ receptors (K_D > 10000).Our results show that BIMU 1, like cisapride and unlike ondansetron, is an effective stimulant of gastric motility and propulsion. The action of BIMU 1 appears to depend on 5-HT₄ receptor stimulation and to involve the activation of cholinergic nerve pathways. Correspondence to: C. A. Rizzi at the above address     

Studies on L-640,035: a novel antagonist of contractile prostanoids in the lung

1 The effects of L-640,035 (3-hydroxymethyl-dibenzo [b,f] thiepin-5,5-dioxide) have been studied on pulmonary smooth muscle contraction in vitro and in vivo.

2 When studied in vitro on guinea-pig tracheal chains, L-640,035 produced significant shifts in the dose-response curves to a prostaglandin (PG) endoperoxide analogue (U-44069) (pA₂ 7.0), PGF_2α (pA₂ 5.9) and PGD₂ (pA₂ 6.5). L-640,035 produced no significant shift in the dose-response curves to leukotriene D₄ or histamine and produced a small but statistically significant shift in the dose-response curve to 5-hydroxytryptamine (5-HT) (pA₂ 5.2). With the exception of PGF_2α, Schild analysis did not in general indicate competitive inhibition. The main metabolite of L-640,035, L-636,499, also produced significant parallel shifts in the dose-response curves to U-44069 (pA₂ 6.0) and PGF_2α (pA₂ 6.0), but with some reduction in the maximal contraction.

3 When L-640,035 was administered intravenously to guinea-pigs, significant inhibition of increases in pulmonary resistance or insufflation pressure induced by U-44069 (ED₅₀ 0.16 mg kg^-1), leukotriene D₄ (ED₅₀ 0.25 mg kg^-1) and 5-HT (ED₅₀ 3.4 mg kg^-1) but not histamine (ED₅₀ > 10 mg kg^-1) was observed.

4 When L-640,035 was administered intravenously to dogs a significant inhibition of increases in pulmonary resistance induced by U-44069 (ED₅₀ 0.85 mg kg^-1) but not histamine (ED₅₀ > 30 mg kg^-1) was observed.

5 When L-640,035 was administered by the intraduodenal route to dogs at doses of 3 and 10 mg kg^-1 significant inhibition of increases in pulmonary resistance induced by sodium arachidonate (3 mg kg^-1 i.v.) was observed with a duration of action of > 255 min.

6 It is concluded that L-640,035 is a novel, relatively selective, and orally active antagonist of the actions of contractile prostanoids on pulmonary smooth muscle.

     

Spinal facilitation in cholinergic-sympathetic efferents by desipramine

Summary Electrodermal potentials (EDPs) evoked by electrical stimulation of the cholinergic-sympathetic system at different levels were recorded in the forepaws of anaesthetized cats and used as a measure of sudomotor activity. After pretreatment with yohimbine (0.25 mg/kg i.v.) to block ₂-adrenoceptors, unilateral electrical stimulation of the hypothalamus (square wave pulses 1 ms duration, 16 Hz, 2 s train length at intervals of 1 min) induced EDPs in both forepaws. Injection of the inhibitor of neuronal catecholamine reuptake, desipramine (1 mg/kg i.v.), facilitated the EDPs in both forepaws, even though access of the drug to the sweat glands was prevented by application of a tourniquet to one paw. The facilitation was abolished by injection of the specific ₁-adrenoceptor antagonist, prazosin (0.5 mg/kg i.v.). An equal enhancement of this effect by desipramine (1 mg/kg i.v.) and its abolition by prazosin (0.5 mg/kg i.v.) was obtained in cats with the brain stem transected at the level of the medulla oblongata and electrical stimulation of the spinal cord at C1. EDPs evoked in the right forepaw by preganglionic electrical stimulation of the right stellate ganglion were inhibited by desipramine (1 mg/kg i.v.).From these and previous results it is concluded that inhibition of neuronal reuptake of catecholamines results in facilitation of activity in sudomotor efferents. This effect is mediated by spinal ₁-adrenoceptors and provides an explanation of the occasional occurrence of excessive sweating in psychiatric patients treated with tricyclic antidepressants.     

Modulation of noradrenaline and neuropeptide Y (NPY) release in the pig kidney in vivo: involvement of alpha2, NPY and angiotensin II receptors

Summary The modulation of the release of noradrenaline (NA) and neuropeptide Y-like immunoreactivity (NPY-LI) was investigated in the pig kidney in vivo. Under control conditions a reproducible co-release of NA and NPY-LI was obtained upon stimulation of the renal nerves with 5 Hz for 1 min. Infusion of peptide YY (PYY, 1 g/kg/min i.v.), which binds to NPY receptors, caused renal vasoconstriction and reduced the stimulation-evoked overflow of NA and NPY-LI by 24 ± 4 and 33 ± 11%, respectively (P < 0.01). The PYY effect was reversible and was absent 1 h after the infusion. The alpha₂-adrenoceptor antagonist yohimbine (0.2 mg/kg i. v.) enhanced the overflow of NA and NPY-LI 2- to 3-fold. The angiotensin converting enzyme inhibitor captopril (5 mg/kg i. v.) did not significantly affect the overflow of NA or NPY-LI evoked by the nerve stimulation. Angiotensin II (0.5 g/kg/min i. v.), on the other hand, induced a reversible enhancement of the overflow of both NA and NPY-LI by 71 and 77%, respectively (P<0.01). Infusion of endothelin (0.2 g/kg/min i.v.), which reduced renal blood flow by a magnitude similar to that evoked by angiotensin II, did not significantly alter the nerve stimulation-evoked overflow of NA or NPY-LI. None of the administered drugs did significantly affect the percentage reduction in renal blood flow evoked by nerve stimulation.It is concluded that the release of NA and NPY-LI from sympathetic nerves in the pig kidney is inhibited in parallel via activation of NPY receptors by PYY and via alpha₂-adrenoceptors by endogenous NA. Furthermore, angiotensin II receptor stimulation facilitates the release whereas endothelin has no major effect on transmitter secretion.Send offprint requests to J. Pernow at the above address     

Analgesic Effects of Bee Venom Derived Phospholipase A2 in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A₂ (bvPLA₂) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA₂ (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA₂, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA₂-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA₂ treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system.     

Effects of the 5-HT1 receptor agonists DP-5-CT,CGS 12066B,and RU 24969 on plasma adrenaline and glucose levels in the rat

Summary Recent results have indicated that the 5-HT_1A receptor subtype mediates the adrenaline-releasing and hyperglycemic effects of 8-hydroxy-2-(di-n-propylamino)tetralin in the rat. The aim of this study was to analyse, by means of the peripherally acting 5-HT_1A receptor agonist, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT), whether these 5-HT_1A receptors are peripherally or centrally localised. In view of the appreciable affinity of DP-5-CT for the 5-HT_1D receptor subtype, the effects of the mixed 5-HT_1B/5-HT_1D receptor agonist 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo(1,2-a)quinoxaline (CGS 1206613), and the mixed 5-HT_1A5-HT_1B/5-HT_1D receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)1H-indole (RU 24969) were also investigated.Administration of DP-5-CT (0.3 and 1 mg/kg i. v.) increased plasma glucose levels dose-dependently, whereas only the 1 mg/kg dose of DP-5-CT elicited a rise in plasma adrenaline levels. In contrast, CGS 1206613(1.5 and 4.5 mg/kg 1. v.) did not affect either plasma adrenaline or plasma glucose levels. Administration of RU 24969 (0.5–4.5 mg/kg i. v.) increased dose-dependently both plasma adrenaline and glucose levels. The data suggest that central 5-HT_1A receptors, but neither 5-HT_1B nor 5-HT_1D receptors, regulate plasma adrenaline and glucose levels. Send offprint requests to F. Chaouloff at the above address     

5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram

In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT_1A receptor antagonists, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropionamide dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT_1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.).We have also studied the effects of (S)-UH-301 (0.03–0.50 mg/kg i.v.) on the firing rate of single DRN5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. × 14 days). Administration of (S)UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 m1/kg/day i.p. × 14 days), control rats. Our results thus suggest that 5-HT_1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission. Since the antidepressant effect of SSRIs is critically linked to the availability of 5-HT, these findings support the notion that 5-HT_1A receptor antagonists may not only shorten the latency of onset of SSRIs in the treatment of depression, but also increase their efficacy.     

Increased dopamine receptor sensitivity in the rat following acute administration of sufentanil,U50,488H and d-Ala2-d-Leu5-enkephalin

Summary The effects of acutely administered opioid receptor agonists sufentanil, U50,488H and [d-Ala², d-Leu⁵]-enkephalin (DADL) were observed upon dopamine D₁ and D₂ binding site density in the striatum of the rat. In addition, the functional implications of opioid-induced changes in dopamine receptor sensitivity were studied using the behavioural profile elicited by apomorphine in the rat. The -agonist sufentanil (1 or 20 Erg/kg, i. p.), the -agonist U50,488H (10 mg/kg, i. p.) and DADL (1 g/animal, i. c. v.) all significantly elevated D₂ but not D₁ binding site density in rat striatum. Pretreatment with sufentanil (1 g/kg, i. p.) induced an elevation in apomorphine-induced sterotyped behaviour, but attenuated locomotor activity. Following administration of U50,488H (10 mg/kg, i. p.), both the degree of stereotypy and the intensity of the locomotor activity were enhanced. Contralateral rotation was observed in animals pretreated with DADL (1 g/animal, i. c. v.) following challenge with apomorphine. It is concluded that the opioid agonists studied induce a significant elevation in functional D₂ sites to the exclusion of D₁ sites. However, the precise mechanism by which this effect is elicited remains to be established. Send offprint requests to R. D. E. Sewell at the above address     

Inhibition of platelet aggregation by polyaspartoyl L-arginine and its mechanism

AIM: To observe the oral anti-platelet efficacy and the potential action mechanism of polyaspartoyl L-arginine (PDR), a new L-arginine rich compound. METHODS: Platelet aggregation was conducted by Born's method; bleeding time was determined using tail's bleeding time in mice; platelet adhesion was carried out with glass bottle method; nitric oxide (NO) was tested with Griess's method; and cAMP, thromboxane B(2) (TXB(2)) and 6-keto-PGF(1 alpha ) were assessed with commercial kits. RESULTS: The inhibition by PDR (15-60 mg/kg i.g. or 10 mg/kg i.v.) of platelet aggregation induced by adenosine diphosphate (ADP), collagen or thrombin at 1 h after oral administration or at 20 min after i.v. injection for rats (P<0.01), and its (15 mg/kg, i.g.) inhibition of ADP-induced platelet aggregation for rabbits during 6 h after administration were observed. PDR (15-60 mg/kg) prolonged the bleeding time of mice (P<0.05) and (30 mg/kg) increased NO concentration in plasma. On the other hand PDR did not change the contents of cAMP in platelet and TXB2 or 6-keto-PGF(1 alpha) in plasma. CONCLUSION: PDR is a novel, oral effective platelet aggregation inhibitor and its action mechanism possibly related to increasing NO generation.     

Centrally administered histamine evokes the adrenal secretion of noradrenaline and adrenaline by brain cyclooxygenase-1- and thromboxane A2-mediated mechanisms in rats

Plasma adrenaline is originated from adrenal medulla, while plasma noradrenaline reflects the release from sympathetic nerves in addition to the secretion from adrenal medulla. The present study was designed to characterize the source of plasma catecholamines induced by centrally administered histamine, with regard to the brain prostanoids. Intracerebroventricularly (i.c.v.) administered histamine (1, 5 and 10 microg/animal) elevated plasma noradrenaline and adrenaline (noradrenaline相似文献   

Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve endothelial vasodilator function in L-NAME-induced hypertensive rats

Male Sprague-Dawley rats given N^ω-nitro-l-arginine methyl ester (l-NAME) in drinking water for 8 weeks showed: (1) a clear-cut increase in systolic blood pressure; (2) a consistent decrease of endothelial-cell nitric oxide synthase (eNOS) gene expression in aortic tissue; (3) a marked reduction of plasma nitrite/nitrate concentrations; (4) a reduction of the relaxant activity of acetylcholine (ACh, from 10⁻¹⁰ to 10⁻⁴ M) on norepinephrine-precontracted aortic rings (reduction by 48 ± 5%); (5) a marked decrease (−58%) of the basal release of 6-keto-prostaglandin F1α (6-keto-PGF1α) from aortic rings. In l-NAME-treated rats, administration in the last 4 weeks of either the angiotensin-converting enzyme (ACE) inhibitor enalapril (10 mg/kg/day in tap water) or the angiotensin AT₁-receptor antagonist losartan (10 mg/kg/day in tap water) decreased systolic blood pressure levels, completely restored eNOS mRNA levels in aortic tissue and plasma nitrite/nitrate levels, and allowed a consistent recovery of both the relaxant activity of acetylcholine and the generation of 6-keto-PGF1α. Coadministration of icatibant, a bradykinin B₂-receptor antagonist (200 μg/kg/day), with enalapril blunted the stimulatory effect of the ACE inhibitor on eNOS mRNA expression, circulating levels of nitrite/nitrate, the relaxant activity of ACh and the release of 6-keto-PGF1α in l-NAME-treated rats. The generation of 6-keto-PGF1α from aortic rings was also decreased in rats coadministered icatibant with losartan. These findings indicate that (1) the ACE inhibitor enalapril and the angiotensin AT₁-receptor blocker losartan are equally effective to reverse NAME-induced endothelial dysfunction; (2) the beneficial effect of enalapril on the endothelial vasodilator function in l-NAME-treated rats is mediated by bradykinin B₂-receptor activation; and (3) the enhanced endothelial generation of prostacyclin induced by losartan in l-NAME rats is also mediated by bradykinin B₂-receptor activation.     

Acute lead poisoning of the pigeon induced by single,intraperitoneal administration of lead acetate

A single dose of lead acetate (either 30 mg/kg or 150 mg/kg) was intraperitoneally (i.p.) adminstered to adult feral pigeons, Columba livia var and the effects of calcium disodium ethylenediamine tetraacetate (CaNa₂EDTA), (0, 150, 300, 600 mg/kg), administered i.p. twice a week in the ensuing period were observed. Lead acetate caused dose related mortality and decreases in weight, hematocrit and -aminolevulinic acid dehydratase activity (ALA-D). Acute toxicity of lead acetate in the pigeon, when given intraperitoneally, appeared approximately equivalent to that in the rat and mouse in terms of LD₅₀. Blood lead (blood Pb) levels observed during the lethal stage were five to ten times less than those reported for chronic oral lead poisoning in the pigeon. Biological implications of elevated levels of blood Pb observed in the feral pigeon in the urban Tokyo area are discussed. CaNa₂EDTA induced dose related recovery in ALA-D in 30 mg/kg group, and reduction of blood Pb levels in the group dosed with 150 mg/kg of lead acetate.     

The cardiovascular effects of intraventricularly administered histamine in the anaesthetised rat

Summary In urethane-anaesthetised rats intraventricular (i.c.v.) injections of histamine (0.1–10.0 g) elicited dose-related rises in both the resting blood pressure and heart rate. These cardiovascular effects of histamine were antagonised in a dose-dependent manner by i.c.v. pretreatments with the histamine H₁-receptor antagonists mepyramine (10, 50 and 100 g) and diphenylpyraline (100 and 200 g). Pretreatment with the histamine H₂-receptor antagonist metiamide (100 and 200 g i.c.v.) failed to modify either of the responses. A dose-related antagonism of the hypertensive response to histamine i.c.v. was elicited by phentolamine (100 and 200 g i.c.v.) but the positive chronotropic effect was not modified by this pretreatment. The cardiovascular responses to histamine i.c.v. were abolished by mecamylamine (5.0 mg/kg i.v.) and greatly reduced by 6-hydroxydopamine (3×250 g i.c.v.), but only the tachycardia was significantly modified by atropine (100 g i.c.v.) and propranolol (1 mg/kg i.v.). Propranolol (100 g i.c.v.), bilateral vagotomy, or acute bilateral adrenal demedullation failed to modify the cardiovascular responses to histamine i.c.v. The results suggest that histamine is able to modify the resting blood pressure and heart rate by independent central modes of action, which involve central adrenergic and cholinergic mechanisms.Preliminary findings of this study were presented at the Autumn meeting of the British Pharmacological Society (Finch and Hicks, 1975).