α-Adrenoceptor activity of arylalkylimidazoles is improved byα-methylation and impaired byα-hydroxylation

Summary To investigate the effects of hydroxyl and methyl substitution of the alkyl bridge bond on the-adrenoceptor activity of arylalkylimidazole derivatives, the cardiovascular effects of the molecules were studied in anaesthetized and pithed rats. The compounds studied were 4(5)-substituted imidazole derivatives with a methano, ethano or etheno bridge between the imidazole and the 2-, 2,3- or 2,6-methyl substituted phenyl rings. The hypotensive and bradycardic activities of the molecules in the anaesthetized rat were always reduced by-hydroxylation and usually augmented by-methylation of the bridge between the imidazole and phenyl rings. Hydroxylation was associated with a consistent, marked decrease in vasopressor and sympatho-inhibitory activity in the cardiovascular system of the pithed rat, but a methyl moiety as a bulky substituent in the-position of the alkyl bridge did not decrease but even caused an increase in-adrenoceptor activity in this test system. The detrimental effect of-hydroxylation of the compounds at ₁- and ₂-adrenoceptors supports the notion that the interaction of the imidazoles at-adrenoceptor is different from that of the classical, noradrenaline-like phenethylamines. The results also suggest that the alkyl bridge between the phenyl and imidazole rings of the imidazoles may contribute directly to the binding process.     

Antifungal Activity of a New Triterpenoid Glycoside from Pithecellobium racemosum (M.)

Purpose. In a continuation of our search for novel antifungal compounds from higher plants, the standard extract of the bark of Pithecellobium racemosum was found to have good activity against important AIDS-related opportunistic yeasts. Methods. The extract was subjected to bioguided fractionation using silica gel column chromatography which led to purification of triterpene glycosides. The structures of these compounds were determined by a combination of spectroscopic (IR, NMR, HRMS) and chemical methods. Results. Compound 1 is a new glycoside, 3-O[-L-arabinopyranosyl (1 -2)][-L arabinopyranosyl (1 -6)]2-acetoamido-2-deoxy--D-gluco-pyranosyl oleanolic acid and Compound 2 was identified as the known compound 3-O-[-L-arabinopyranosyl (l-2)]-L-arabinopyranosyl (1-6)] 2-acetamido-2-deoxy--D-glucopyranosyl echinocystic acid. Conclusions. Compound 1 is a new glycoside, 3-O-[-L-arabinopyranosyl (1-2)]-L-arabinopyranosyl (l-6)]-2-acetoamido-2-deoxy--D-glucopyranosyl oleanolic acid and exhibits moderate antifungal activity against T. mentogrophytes, C. albicans and S. cerevisiae with MIC values of 6.25, 12.5 and 12.5 g/ml respectively.     

Pharmacological profiles of a novel α1-adrenoceptor agonist,PNO-49 B,at α1-adrenoceptor subtypes

The effects of a newly synthesized compound, PNO-49B, (R)-(-)-3-(2-amino-l-hydroxyethyl)-4-fluo-romethanesulfonanilide hydrochloride, on ₁-adrenocepfor subtypes were examined in various tissues in which the following distribution of ₁-adrenoceptor subtypes has been suggested: dog carotid artery (_1B), dog mesenteric artery (_1N), rabbit thoracic aorta (_1B + _1L), rat liver (₁B), rat vas deferens (_1A + _1L), rat cerebral cortex (_1A + _1B) and rat thoracic aorta (controversial subtype).PNO-49 B (0.1–100 M) produced concentration-dependent contractions in dog mesenteric artery, rabbit thoracic aorta, rat thoracic aorta and rat vas deferens; and the maximal amplitudes of contraction were almost the same as or slighly less than those of noradrenaline. By contrast, the maximal response to PNO-49 B in dog carotid artery was markedly smaller than the response to noradrenaline. In rabbit thoracic aorta, the contractile response to PNO-49 B was not affected by inactivation of the _1B subtype with chloroethylclonidine (CEC), although the response to noradrenaline was attenuated by that treatment. The dissociation constants (K_A) of PNO-49 B were not different among the rat thoracic aorta, dog carotid and mesenteric arteries and rabbit thoracic aorta (CEC-pretreated). The contractile responses to PNO-49 B were inhibited competitively by prazosin, HV723 (-ethyl-3,4,5-trimethoxy--(3-((2-(2-methoxy-phenoxy)-ethyl)))-amino(propyl)benzeneacetonitrile fumarate) and by WB4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane). The estimated pA₂ values were high for prazosin and WB4101 in rat thoracic aorta and for HV 723 in dog mesenteric artery, whereas the pA₂ values for these three antagonists in rabbit thoracic aorta were low and were not altered by pretreatment with CEC. The binding of [³H]-prazosin to membranes prepared from rat vas deferens and liver was inhibited by PNO-49 B in a concentration-dependent manner. The resulting pK₁ value for the liver was approximately 1.5 log units lower (one thirtieth in affinity) than the values for the epididymal and prostatic portions of the vas deferens. PNO-49B also inhibited biphasically [³H]prazosin binding to prazosin-high affinity sites of rat cerebral cortex membranes, and the low but high affinity sites for PNO-49B was abolished by CEC-pretreatment. PNO-49B had no effect on the prejunctional ₂-adrenoceptors in rat vas deferens (prostatic portion) nor on the -adrenoceptors in rat atria. The contractile response to PNO-49 B in rat thoracic aorta was not inhibited by cimetidine, pyrilamine or ketanserin.These results indicate that PNO-49B is an ₁-adrenoceptor agonist with a lower affinity and/or efficacy at the _1B subtype as compared with other ₁-subtypes.     

Motor disturbance induced by tremorine and oxotremorine

Summary The action of tremorine and oxotremorine on spinal motor activity was studied in the rat. Both tremorogenio agents increased a reflex activity and spontaneous activity. The increase in spontaneous activity consisted of rhythmic bursts of discharges. The increase in a reflex activity was accompanied by rigidity, which manifested itself by the appearance of tonic muscle activity.Tremorine and oxotremorine-induced tremor was depressed by the antitremor agents metixene and Kr 339, the antiparkinson drugs atropine and biperiden, and the adrenergic receptor blocking agents propranolol and pronethalol. The adrenergic. receptor blocking agents azapetine, dihydroergotamine, haloperidol, phenoxybenzamine and phentolamine failed to inhibit tremor activity. Chlorpromazine, however, as well as procaine, verapamil and DOPA, diminished the intensity of tremor activity without blocking the generation of tremor bursts.Drugs which depressed tremor activity also antagonized the effect of oxotremorine on and motor activity, whereas the drugs, which only diminished tremor intensity, depressed the increased reflex discharge without reducing spontaneous activity. Rigidity disappeared when reflex discharge was normalized.It is concluded that experimental parkinsonlike rigidity may be interpreted in terms of a disturbed balance between monoaminergic and cholinergic mechanisms in the brain.The authors are grateful to KnolI-Ludwigshafen for the support of the investigation.     

Effects of Δ8-THC,and Δ9-THC on the acquisition of a discriminative positional habit in rats

Using a reversal learning paradigm the dissociative effects of two tetrahydrocannabinols (THC) on the acquisition and reversal of a discriminative positional habit in rats were studied. A T-shaped water maze was used. From these experiments it is concluded that learning under the influence of ⁸-THC (10 and 20 mg/kg), and ⁹-THC (5 mg/kg) is state-dependent (StD) in the rat.Numbering system according to IUPAC rules.Parts of the results were presented at the Symposium on the chemistry and biological activity of cannabis, Stockholm, October 26–28, 1971 and at the Symposium on medical plants of Brazil, Sao Paulo, April 17–20, 1972.     

Influence of respiratory acidosis or alkalosis on pressor responses mediated byα 1- andα 2-adrenoceptors in pithed normotensive rats

Summary The effect of respiratory acidosis and alkalosis on the vasoconstriction to ₁- and ₂-adrenoceptor stimulation was studied in pithed normotensive rats. The selective ₁-adrenoceptor agonists (-)amidephrine, cirazoline, (±)erythro methoxamine (-)phenylephrine, Sgd 101/75 and St 587 were used, as well as the selective ₂-adrenoceptor agonists B-HT 920, B-HT 933, DP-6,7-ADTN, M-7 and UK 14,304. The non-selective-adrenoceptor agonists xylazine, noradrenaline and adrenaline were included as well. The latter two were also studied under selective doses of the antagonists rauwolscine and prazosin, thus yielding the respective ₁- and ₂-adrenoceptor components of the vasoconstriction to these agonists. The effect of acid-base balance disturbances on presynaptically released noradrenaline elicited by electrical stimulation of preganglionic nerves was studied as well. Dose response curves for the agonists were generated under various conditions of ventilation, yielding either alkalotic, normal or acidotic values of arterial blood pH. Pressor responses to all agonists were maximally affected by changes in acid-base status at the low doses of the agonists. Acidosis was found to inhibit increases in diastolic pressure mediated by the ₁- as well as the ₂-adrenoceptor agonists studied, although not to the same extent. Alkalosis exerted either an obvious potentiation or did not significantly influence ₁-adrenoceptor mediated pressor responses. On the basis of acid-base sensitivity the following groups of agonists were distinguised: (1) Cirazoline, phenylephrine, methoxyamine, electrically released noradrenaline from presynaptic sites, of which pressor responses are obviously potentiated and attenuated by alkalosis and acidosis, respectively. (2) Sgd 101/75, St 587, noradrenaline- ₁, amidephrine and adrenaline- ₁, eliciting pressor responses which are strongly acid-sensitive and base-insensitive. (3) B-HT 920, B-HT 933, DP-6, 7-ADTN (lower doses), of which vasoconstriction is markedly inhibited by both acidosis and alkalosis. (4) Noradrenaline- ₂, UK 14,304, M-7 (lower doses), adrenaline- ₂ and high doses of the agonists of the former group. Pressor responses of these agonists were found to be not or slightly base-sensitive, but profoundly acid-sensitive. Xylazine does not fit into this classification. The present data are not in accordance with purported subdivisions of-adrenoceptor agonists by others. It is therefore concluded that the differential effect of acid-base status on-adrenoceptor mediated vasoconstriction in pithed rats is an exponent of the differential way of interaction of the agonists with the adrenoceptors involved.Preliminary data were communicated at the Joint Meeting of the French and German Pharmacological and Toxicological Societies, Feiburg i. Br., September 19–22, 1983 (De Jonge et al. 1983)     

The effect of α-amanitin on passive and active avoidance acquisition in mice

-Amanitin, a specific and potent inhibitor of form II DNA-dependent RNA polymerase, produced greater than 98% inhibition of the enzyme in mouse brain within 2 h of intracerebroventricular (icv.) injection. Mice were given one trial passive avoidance training and retested on the task 4 h later. Mice treated with -amanitin 2 h before training or immediately after training demonstrated a retention deficit when compared to non-injected or saline injected controls.Active avoidance was trained for 1 h using a Sidman schedule with a drumturning response. Performance during the last 15 min of training was compared to performance in the first 15 min of a retesting session, 4 h after training. -Amanitin, 2 h prior to training reduced the number of responses, per cent escapes and per cent avoidances in the retesting session. Post-training injection of -amanitin significantly reduced the number of responses and per cent avoidances.Rotarod and spontaneous motor activity were not affected by -amanitin. Whole body temperature was slightly and transiently reduced in icv. administration of -amanitin.     

Role of Peripheral Adrenergic Responsiveness in the Development of DOCA/NaCl Hypertension in Rats

Alterations in - and -adrenergic responsiveness were investigated prior to and during the development of hypertension in rats treated with desoxycorticosterone acetate and NaCl (DOCA/ NaCl). The DOCA/NaCl rats became noticeably hypertensive (> 150 mm Hg) six weeks after the initiation of treatment. Prior to the development of hypertension, a reduced in vivo and in vitro - and an enhanced -adrenergic responsiveness of the DOCA/NaCl group resulted. At 2 and 12 weeks of the study, the dipsogenic response to isoproterenol was significantly attenuated in the DOCA/NaCl rats, whereas no difference in the dipsogenic response to 24 hour water deprivation was observed between control and DOCA/NaCl rats. Isoproterenol-induced relaxation of aortic smooth muscle from the DOCA/NaCl treated rats was significantly reduced at 4 weeks and further attenuated at 12 weeks of the study. However, aortic smooth muscle sensitivity to norepinephrine stimulation was significantly increased at 4 and 12 weeks of the study. These results suggest that alterations in both in vivo and in vitro - and -adrenergic responsiveness occur prior to establishment of hypertension of the DOCA/NaCl rats and that these alterations may have a role in the early stages of the development of this form of hypertension.     

Environmental Impacts of Diesel Fuel on Bacteria and Phytoplankton in a Tropical Estuary Assessed Using <Emphasis Type="BoldItalic">In Situ</Emphasis> Mesocosms.

Dissolved or dispersed petroleum hydrocarbon concentrations (DDPH) were monitored in Ponggol estuary, Singapore, fortnightly from July 1999 to June 2000. DDPH concentrations ranged from 4.4 to 248.9gl^–1 and 0.4 to 1099.7gl^–1 for surface and subsurface waters, respectively and with mean concentrations of 41.01gl^–1 in the water column. Absorbed or adsorbed petroleum hydrocarbon (AAPH) concentrations measured in sediments ranged from 20.6 to 541.0 mg kg^–1, with mean concentrations of 148.23 mgkg^–1. In situ mesocosm studies of bacteria and phytoplankton were based on field monitoring ofenvironmentally measured concentrations of petroleum hydrocarbons, using diesel fuel as the source of contaminant. The mesocosm comprised of 25 L clear polycarbonate carboys incubated in situ for 6 days. Water and sediments from a clean site with undetectable levels of petroleum hydrocarbons were used in controls. The treatment mesocosms comprised of mean and highest concentrations of DDPH and AAPH. The study revealed signs of acute toxicity to autotrophs viz., phytoplankton and autotrophic bacteria in treatments simulating concentrations of diesel fuel found in the sediments. A stimulatory effect was seen at lower concentrations. Bacterial heterotrophs responded positively to all concentrations of diesel fuel because of the abundance of a carbon source, reduced grazing pressure and reduced competition for nutrients from phytoplankton.     

Behavioural and anticonvulsant effects of Ca2+ channel toxins in DBA/2 mice

This study investigated the behavioural and anticonvulsant effects of voltage-sensitive calcium channel blockers in DBA/2 mice.-Conotoxin MVIIC (0.1, 0.3 g ICV/mouse) and-agatoxin IVA (0.1, 0.3, 1 g ICV), which act predominantly at P- and/or Q-type calcium channels, prevented clonic and tonic sound-induced seizures in this animal model of reflex epilepsy (ED₅₀ values with 95% confidence limits for protection against clonic sound-induced seizures were 0.09 (0.04–0.36) g ICV and 0.09 (0.05–0.15) g ICV, respectively and against tonic seizures 0.07 (0.03–0.16) g ICV and 0.08 (0.04–0.13) g ICV, respectively). The N-type calcium channel antagonists-conotoxin GVIA and-conotoxin MVIIA were also tested in this model.-Conotoxin GVIA was anticonvulsant in DBA/2 mice, but only at high doses (3 g ICV prevented tonic seizures in 60% of the animals; 10 g ICV prevented clonic seizures in 60% and tonic seizures in 90% of the animals), whereas-conotoxin MVIIA did not inhibit sound-induced seizures in doses up to 10 g ICV. Both-conotoxin GVIA and-conotoxin MVIIA induced an intense shaking syndrome in doses as low as 0.1 g ICV, whereas-conotoxin MVIIC and-agatoxin IVA did not produce shaking at any of the doses examined. Finally,-conotoxin GI (0.01–1 g ICV) and-conotoxin SI (0.3–30 g ICV), which both act at acetylcholine nicotinic receptors, were not anticonvulsant and did not induce shaking in DBA/2 mice. These results confirm that blockers of N- and P-/Q-type calcium channels produce different behavioural responses in animals. The anticonvulsant effects of-conotoxin MVIIC and-agatoxin IVA in DBA/2 mice are consistent with reports that P- and/or Q-type calcium channel blockers inhibit the release of excitatory amino acids and are worthy of further exploration.     

Development and Application of an Isolated Perfused Rat Liver Model to Study the Stimulation and Inhibition of Tumor Necrosis Factor-α Production ex Vivo

Purpose. To develop an isolated perfused rat liver (IPRL) model with low baseline levels of tumor necrosis factor (TNF)- in the outlet perfusate to study the effects of immunostimulants and immunosuppressants on the release of TNF- from this organ. Methods. Isolated rat livers were perfused with a buffer containing no albumin or three different bovine serum albumin (BSA) preparations. Using the no-albumin perfusate, the inhibitory effects of methylprednisolone (MP) on lipopolysaccharide (LPS)-stimulated release of TNF- were studied in livers isolated 1 or 5 h after the intravenous administration (5 mg/kg) of MP. The concentrations of TNF- in the outlet perfusates were measured using enzyme-linked immunosorbent assay. Results. In the absence of albumin, the perfusate levels of TNF- were close to zero. However, when the perfusate contained BSA, the TNF- levels in the perfusate reached as high as 1200 pg/ml at steady state. An injection of LPS into IPRLs perfused with a no-albumin perfusate resulted in mean (± SD) TNF- steady-state concentrations of 825 ± 125 pg/ml. The pretreatment of rats with MP before liver harvest attenuated the LPS-induced TNF- release in the livers. However, the attenuation was substantial (>60%) and was statistically significant only 5 h after pretreatment with MP. Conclusions. Perfusates containing BSA may result in nonphysiologically high levels of TNF-. An IPRL with a no-albumin perfusate is more suitable for studies of the stimulation and inhibition of TNF- production by this organ.     

Quantitative Structure–Activity Relationship Analysis of Combretastatins: A Class of Novel Antimitotic Agents

Combretastatins and their synthetic analogues, having structural features resembling that of colchicine, also have similar modes of action. In this report we have correlated the cytotoxicity of combretastatins against the murine leukemic cell line L1210 with physicochemical parameters such as the summation of the Hansch-Fujita constant, which was used as an index of lipophilicity of the substituent groups on ring A (_a) and ring B (_b), the vector summation of the group dipole moments of ring A (µ_a) and ring B (µ_b), the nature of the linker chain between ring A and ring B (B_t-L), indicator parameters (NOH)_a and (NOH)_b, which represent the number of hydroxyl groups on ring A and ring B, respectively, and the summation of values of the substituents on the linker (_L). Cytotoxicity correlated well with (_b), (NOH)_a, (B_t-L), and (µ_b), and the dependency on (_b) was found to be parabolic.     

ATP and endogenous agonists inhibit evoked [3H]-noradrenaline release in rat iris via A1 and P2y-like purinoceptors

Summary Effects of ATP, adenosine and purinoceptor antagonists on field stimulation-evoked (3 Hz, 2 min) [³H]-noradrenaline overflow were investigated in the rat isolated iris.ATP and adenosine inhibited the evoked overflow of [³H]-noradrenaline. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX) shifted the concentration-response curve of ATP to the right in a concentration-dependent manner, but with a potency (–log K_B = 7.88) much lower than expected for an A1 adenosine receptor. In the continuous presence of DPCPX, the ATP-induced prejunctional inhibition was unaffected by suramin (100 mol/l) and DIDS (4,4-diisothiocyanatostilbene-2,2-disulfonic acid, 50 mol/l) but was antagonized by the P_2Y-receptor antagonist cibacron blue ( = reactive blue 2;30 and 100 mol/l, –log K_B = 4.7)and ,-methylene-ATP (10 mol/l). Whereas the evoked [³H]-noradrenaline overflow was unaffected by suramin and DIDS, cibacron blue and ,-methylene-ATP caused a small and transient increase. Cibacron blue at 30 mol/l failed to antagonize the inhibition of evoked [³H]-noradrenaline overflow that adenosine produced in the absence of DPCPX. Basal [³H]-noradrenaline overflow was enhanced by cibacron blue, not changed by ,-methylene-ATP and DIDS, and decreased by suramin.The results show that exogenous ATP inhibits sympathetic neurotransmission in the rat iris via A₁ and P_2Y-like purinoceptors. The latter have a low apparent affinity for cibacron blue and probably are blocked by ,-methylene-ATP. Under the present conditions, endogenous purines exert a tonic inhibition not only via A₁- but also via these P_2Y-receptors. Correspondence to: H. Fuder at the above address     

Solasodine glycosides of Solanum unguiculatum (A.) Rich

Besides solasonine, three new glycosides, namely, 3-O--L-rhamnopyranosyl-(13)-solasodine, 3-O--L-rhamnopyranosyl-(12)--L-rhamnopyranosyl-(14)--D-galactopyranosyl solasodine, and 3-O--L-rhamnopyranosyl-(12)--D-galactopyranosyl solasodine, were isolated fromSolanum unguiculatum (A.) Rich. Their structures were determined on the basis of chemical and spectral methods.     

Effects of deuterium substitution on the chronotropic responses to some sympathomimetic amines in the isolated rat atria

Summary In spontaneously beating rat atria the potencies for the chronotropic effects of the following deuterated phenylethylamine derivatives were higher than the potencies of the corresponding non-substituted (protio-) amines: ,,d₂--phenylethylamine; ,,,-d₄-p-tyramine; ,,,-d₄-m-tyramine; ,,-d₃-p-octopamine. In contrast, ,,-d₃-noradrenaline and ,,-d₃-m-octopamine were equipotent with the corresponding protio-amines. Experiments performed in atria depleted of endogenous noradrenaline by pretreatment with reserpine and in atria exposed to the monoamine oxidase (MAO) inhibitor pargyline indicated: a. p-octopamine had both direct and indirect effects, but the chronotropic responses to p-octopamine in tissues with normal MAO activity depended mostly on the direct action of the amine; deuterium substitution enhanced the indirect component of action of p-octopamine; b. m-octopamine possessed considerable indirect effects while d₃-m-octopamine behaved as an amine of direct action. The substitution of deuterium for hydrogens in the -carbon of the alkyl-side chain of phenylethylamines decreases the rate of deamination by MAO. Therefore, the results obtained with all the amines, except for m-octopamine and ,,p-d₃-m-octopamine, could be interpreted in terms of the direct, indirect or mixed action of those compounds and/or of the influence that MAO activity has on the chronotropic responses to these amines. The results obtained with protio-and deuterio-m-octopamine suggested that deuterium substitution, either at the - or the -carbon, can alter some other mechanisms in addition to the enzymatic deamination.Career Investigator on leave of absence from the Consejo de Investigaciones Cientificas y Técnicas, ININFA, Junín 956, 5°P, RA-1113 Buenos Aires, Argentina Send offprint requests to S. M. Celuch     

Effects of alpha-methyl tyrosine and adrenergic blocking agents on the facilitating action of amphetamine and nicotine on learning in rats

dl-amphetamine sulphate (2 mg/kg) and nicotine (0.2 mg/kg) showed a facilitatory action on the acquisition of a conditioned response in a shuttle-box by rats and this was reversed by pretreatment with -MT (30 mg/kg).Pretreatment with dibenamine (10 mg/kg) impaired the action either of amphetamine or nicotine. Nethalide (5–10 mg/kg) exerted a partial protection on the depressant effect produced by the interaction between dibenamine and nicotine.Animals treated with -MT (30 mg/kg) and kept in the cold (4–6° C for 3 h) also showed a depressed learning capacity. dl-Dopa (200 mg/kg) provided a partial protection on the depressive effects caused by the interaction of -MT with amphetamine, nicotine or cold. It is suggested that the facilitatory learning action of amphetamine and nicotine involves a common adrenergic mechanism. The depressant effects of amphetamine, nicotine or cold after -MT treatment are attributed to depletion of functional pools of catecholamines.This work was supported by grant N 2911/67 from the Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina (O. A. Orsingher).     

Genetic and hormonal regulation of steroid hydroxylases and drug metabolizing enzymes in rat liver

Two microsomal steroid hydroxylase activities (cholesterol-7-hydroxylase and progesterone-16-hydroxylase) were measured in the livers of Sprague-Dawley and Wistar rats and compared to three other monooxygenase activities (aryl hydrocarbon hydroxylase, p-nitro-anisole-O-demethylase and aminopyrine-N-demethylase). Cholesterol-7-hydroxylase behaves in a very unique manner. It is the only one of the studied enzymes to be more active in the female than in the male, it is very poorly induced by phenobarbital and methylcholanthrene, but responds quickly to the administration of glucocorticoids. In fact, the cholesterol-7-hydroxylase activity presents a very pronounced circadian rhythm which is under the control of the hypothalamo-adrenal axis. Marked differences are also found in the response of the various enzymatic activities to the administration of inducers as well as in their relative activities in untreated male and female animals.Read at the Symposium Relevance of Chronobiology for Toxicology and Pharmacology held at the 16th Spring Meeting of the Deutsche Pharmakologische Gesellschaft, Section: Toxicology, March 6, 1975, Mainz     

The relaxant action of osthole isolated from Angelica pubescens in guinea-pig trachea

The effect of osthole, isolated from Angelica pubescens, on the contraction of guinea-pig trachea was studied. Osthole (25–100 mol/l), theophylline (10–1000 mol/l) and higher concentrations of nifedipine (0.1–100 mol/l) suppressed the contraction response curves of tracheal smooth muscle caused by carbachol, prostaglandin F₂ (PGF₂), U46619 (thromboxane A₂ analogue) and leukotriene C₄ (LTC₄) in a concentration-dependent manner. The contraction caused by high K⁺ (120 mmol/1) and cumulative concentrations of CaCl₂ (0.03–3 mmol/1) was also inhibited concentration-dependently by osthole (25–100 mol/l), theophyl line(10–1000 mol/l) and lower concentrations of nifedipine (0.01–0.1 mol/l). The relaxant actions of osthole were not affected by propranolol (1 mol/l), glibenclamide (10 mol/l) or removal of tracheal epithelium. Osthole (100 mol/l) was still effective in causing tracheal relaxation in the presence of nifedipine (1 mol/l). In Ca²⁺-free- and EGTA (0.2 mmol/1)-containing medium, the relaxing effect of osthole was more potent than in normal Krebs solution. Osthole (25 and 50 mol/l) caused 2.9 and 6.5, or 3.0 and 5.6 fold, respectively, increase in potency of forskolin or sodium nitroprusside in causing tracheal relaxation but did not affect that by cromakalim. Osthole (50 mol/l) enhanced the increase in tissue cAMP and cGMP levels induced by forskolin and sodium nitroprusside, respectively, and in higher concentrations (100 and 250 mol/l), itself increased markedly tissue cAMP and cGMP contents. Osthole (10–250 mol/l) inhibited the activity of cAMP and cGMP phosphodiesterases in a concentration-dependent manner. It is concluded that osthole exerts a nonspecific relaxant effect on the trachealis by inhibiting the cAMP and cGMP phosphodiesterases. Correspondence to: C. M. Teng at the above address     

Role of catecholamines in the anorectic effects of amphetamine in rats

Inhibition of catecholamine synthesis with -methyl-p-tyrosine antagonized amphetamine-induced anorexia. This effect of -methyl-p-tyrosine was reversed by l-Dopa administration. Comparison of the anorectic potencies of the stereoisomers of amphetamine yielded a d-amphetamine to l-amphetamine ratio of 2.751. It is concluded that amphetamine produces anorexia through an action on catecholamines, with dopamine playing a major role.This work was supported in part by National Institute of Mental Health Grants MH01562 and MH08501 to Byron A. Campbell.     

Withdrawal-like behaviour induced by inhibitors of biogenic amine reuptake in rats treated chronically with Δ 9-tetrahydrocannabinol

The effects of the biogenic amine reuptake inhibitors fluoxetine, clomipramine and imipramine on the behaviour of rats after chronic treatment with ⁹ tetrahydrocannabinol ( ⁹-THC) for 5 and 10 days were examined. Rats with permanently in-dwelling IV cannulae were injected twice daily with doses of ⁹-THC (2–6 mg/kg). ⁹-THC treatment reduced the rate of body weight gain and induced the typical biphasic modifications of behaviour. Tolerance developed to both of these effects. On days 6 and 11 of the experiment, rats were injected IP with 15 mg/kg imipramine HCl, clomipramine HCl or fluoxetine HCl, and behaviour, consisting of writhes, backward kicks, jumps and wet shakes, was observed for the next 30 min. Each of the amine reuptake inhibitors induced changes in behaviour, the severity of which appeared to correlate with their ability to inhibit the reuptake of 5-hydroxytryptamine (5-HT). It is suggested that tryptaminergic mechanisms are involved in the production of a withdrawal-like behaviour after chronic ⁹-THC treatment.