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The high affinity binding of [14C]5-HT to nerve ending membranes isolated from rat brain is not affected by neuraminidase treatment. The specificity of ligand receptor interaction was demonstrated by displacement studies with tryptamine derivatives, noradrenaline, and acetylcholine.
Anti-inflammatory activity of griseofulvin has been investigated in comparison with indomethacin and flufenamic acid. In vitro, griseofulvin has been proved the most effective of these agents in suppressing the contractions of smooth muscle preparations induced by a variety of proposed mediators of inflammation, i.e. histamine, 5-hydroxy-tryptamine, bradykinin and prostaglandin E2. In vivo, griseofulvin was unable to modify dextran oedema but suppressed carrageenin oedema, although its activity was poor when compared to that exhibited by indomethacin and flufenamic acid. When tested in rat pleurisy induced by dextran or homologous serum griseofulvin was able to prevent polymorph migration into the pleural space while mononuclears remained virtually unaffected. In contrast indomethacin and flufenamic acid mainly suppressed mononuclear migration while polymorphs resulted only slightly affected. Similar results have been exhibited by the drugs when tested on mononuclear turnover in pleural cavities from normal rats. Results are discussed in the light of the clinically established ability of griseofulvin to prevent cutaneous inflammatory reactions as well as of its effectiveness in the treatment of several polyarthritic syndromes.
Various drugs were tested as inhibitors of diamine oxidase on the basis of chemical relationships to the enzyme substrates. It was found that serotonine tryptamine and phenformin are good competitive inhibitors while cimetidine and pheniprazine are non-competitive inhibitors. Other antihistaminic drugs like promethazine are less powerful inhibitors.
The described technique allows recording of circular smooth muscle activity in isolated airways approx. 1 mm in diameter (bronchioles). It also allows recording of graded contractile and relaxant responses to drugs. Bronchiolar preparations and spirally cut airways (diameters 3-6 mm) were obtained from cat, dog, guinea-pig and man. Histamine is shown to contract cat bronchioles, large airways in cat being unaffected. The contraction is blocked by brompheniramine, but not by atropine. Other contractile agents, cholinoceptor-stimulants, prostaglandin F2alpha'5-hydroxy-tryptamine, and potassium contract the isolated cat airways irrespective of their size. In preparations from dog, guinea-pig and man,histamine was shown to contract both small and large respiratory airways. The effect was blocked by brompheniramine, which did not change the effect of acetylcholine or pilocarpine. Both large and small airways contracted to cholinoceptor stimulation Within species, small and large airways were similarly sensitive to the contractile agents, except for histamine in cat airways. The present findings show a size-and species dependent effect of histamine in respiratory airways. The effect of histamine in isolated cat airways might partly explain the pulmonary effect of histamine in vivo. The importance of including both small and large airways in studies of contractile and relaxant effects is emphasized.
The excitatory and sensitizing properties of 5-HT and different prostaglandins (PGD2, PGE1, PGE2, PGF2 alpha, PGI2 and PGI2-analogue, cicaprost) were characterized on an in vitro preparation of the neonatal rat spinal cord with functionally attached tail. Prolonged (10 min) perfusion of the tail with 5-hydroxy-tryptamine (5-HT, 0.5-10 microM) or any of the tested prostaglandins (0.1-5 microM) did not evoke an excitatory response recorded from a lumbar ventral root, but significantly enhanced responses of peripheral nociceptors to thermal and chemical (bradykinin, capsaicin) stimuli. PGD2 did not induce such an enhancement. Following sensitization of peripheral nociceptors with low concentrations of bradykinin or capsaicin, 5-HT (1-10 microM) evoked a ventral root response. Using specific 5-HT-receptor agonists and antagonists, 5-HT-evoked excitation was determined to be mediated via a 5-HT1-like receptor while 5-HT-induced sensitization involved 5-HT2 receptors.
A reversed-phase HPLC technique in combination with fluorescent detection is described for simultaneous quantification of the precolumn Dansyl derivatives of intracellular amines. The derivatives were stable for at least one week, kept protected from the light at -20 degrees C. The detection limit was between 1 and 5 pmol for all tested polyamines. Serotonin coeluted with tryptamine. The method has a very good reproducibility for both, retention times and chromatographic peak areas. The average recovery of standard amine solutions added to cellular extracts was estimated to be higher than 90%. The described method enables a rapid, reliable and reproducible quantification of biogenic and related polyamines in biological fluids and tissues.
The effect of intracerebral injections of 5,7-dihydroxy-tryptamine (5,7-DHT) on cocaine self-administration behavior was assessed. Rats were tested on a progressive ratio (PR) schedule for cocaine reinforcement. The first response on the lever each day produced an IV infusion of cocaine (0.6 mg/injection) after which the requirements of the schedule escalated with each reinforcement until the behavior extinguished. The final ratio completed was defined as the breaking point. Bilateral injections of 5,7-DHT into either the medial forebrain bundle (MFB) or amygdala (AMY) significantly increased the breaking points on the PR schedule compared to vehicle-injected control animals. We interpret these data to indicate that depletion of forebrain serotonin increases the incentive value of cocaine.
Previously it has been shown that 5-hydroxy-tryptamine (5-HT)1A agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and gepirone increase food intake in free-feeding rats. These experiments were conducted to examine the possible influence of taste and textural factors on the feeding responses induced by these two drugs. Separate groups of non-water-deprived rats were given access to one of a variety of different solutions of saccharin (0.02, 0.04, 0.20 and 2.0% w/v) or water for 2 h each day. Rats were then treated with different doses of 8-OH-DPAT (10, 60 or 100 micrograms/kg) or gepirone (1 or 2.5 mg/kg) in a repeated measures design. Under saline injection an inverted-U shaped concentration-response curve was obtained, with the highest level of intake occurring in rats drinking from the 0.20% saccharin solution. The highest doses of 8-OH-DPAT and gepirone suppressed drinking of saccharin, particularly over the first 30 min of the test period, leading to a flattening of the concentration response curve. At 2 h post-injection 60 micrograms/kg 8-OH-DPAT enhanced the consumption of the 0.04% saccharin solution only. In a second experiment, 8-OH-DPAT or gepirone was administered to rats eating either standard pelleted chow or the same food presented in powdered form. Both drugs stimulated feeding. However, interactions with food type were found. At 60 and 100 micrograms/kg 8-OH-DPAT increased eating of both food types equally, but with 500 micrograms/kg rats are significantly more of the pelleted food.(ABSTRACT TRUNCATED AT 250 WORDS)
Dissociated cell culture preparations were employed to study intracardiac neurones of the atria from human fetal hearts at 9 to 21 weeks' gestation. Intracardiac neurones were not observed in cultures dissociated from the ventricles. Single neurones, as well as groups, could be identified by phase-contrast microscopy in all of the atrial cultures prepared from 14 to 21 weeks' gestation, and protein gene product 9.5-like immunoreactive neurones were detected in cultures from as early as 10 weeks' gestation. The neurones were mononucleate, with a prominent nucleolus or multiple nucleoli, and often had extensive neurites. Neurones tended to be bigger in cultures from later stages in gestation, and these cells appeared to be more mature with a complex pattern of neurite outgrowth. Many neurones from 15 to 20 weeks' gestation expressed somatostatin-like immunoreactivity in culture. A very low proportion of cultured neurones was immunoreactive for neuropeptide Y and its C-terminal flanking peptide. Neuropeptide Y-like immunoreactive neurones also contained 5-hydroxy-tryptamine-like immunoreactivity in culture, but dopamine beta-hydroxylase-like immunoreactive neurones were not detected. This study is the first description of human intracardiac neurones in culture and forms the essential baseline for further direct investigation of these cells.
Serotonin (5-HT), its derivative 5-methoxy-tryptamine (MeOT) and ergot-alkaloid dihydroergosine (DHESN) suppressed the immune reaction of mouse spleen cells against sheep erythrocytes in vitro (PFC assay). Ketanserin and propranolol, antagonists of 5-HT, also caused suppression. However, cells incubated with propranolol 20 min before 5-HT or MeOT produced as many plaques as the non-treated cells. Preincubation with ketanserin resulted in similar interference, but the reversal was not complete. It is concluded that serotonin and related agents probably affect several types of immunocompetent cells participating in successive stages of the PFC reaction. The antagonists probably interfered via 5-HT receptors, adrenergic receptors or both. Immunosuppression observed with serotoninergic agents and their antagonists draws attention to possible side effects of such drugs.
The antiemetic effects of granisetron, a selective 5-hydroxy-tryptamine type 3 receptor antagonist, on postoperative nausea and vomiting were studied and compared with placebo and metoclopramide in 60 patients undergoing general anaesthesia for major gynaecological surgery. The patients received a single i.v. dose of either granisetron (3 mg, n = 20) metoclopramide (10 mg, n = 20), or placebo (saline, n = 20) immediately after recovery from anaesthesia. The effects were assessed during the first three and the next 21 hr after recovery from anaesthesia by means of a nausea and vomiting score; 0 = no emetic symptoms, 1 = nausea, 2 = vomiting. The mean scores during 0-3 hr were 0.8, 0.1 and 0.1 after administration of placebo, metoclopramide and granisetron, respectively; the corresponding scores during 3-24 hr were 0.6, 0.5 and 0.1. The scores of the metoclopramide and the granisetron groups were different from the placebo group in the first three hours (P < 0.05). Although there were no differences in the scores during 0-3 hr between the metoclopramide and the granisetron groups, there were differences during 3-24 hr (P < 0.05). It is concluded that granisetron is superior to metoclopramide in the long-term prevention of postoperative nausea and vomiting after anaesthesia.
Aqueous solutions of tryptamine, tyramine and ethanolamine are extracted and derivatizated to azomethine chelates using a solution of DOOB in diethyl ether. The extraction takes about 2 h. Diisopropyl ether and toluol have also been tested as extractants. The separation of the azomethine chelates is realized by a gradient program on a Si 60 column using a mixture of n-heptane/tert-butyl methyl ether. UV detection is carried out at 280 nm. The concentration of these three amines has been determined in a Chianti wine sample.
OBJECTIVE: The goal of this study was to determine the frequencies of important allelic variants of two drug targets, dipeptidyl carboxypeptidase ( DCP1) and cholesteryl ester transfer protein ( CETP), and two other drug receptors, beta-2 adrenergic receptor ( ADRB2) and 5-hydroxy tryptamine 2A receptor ( HTR2A), in the Egyptian population and compare them with the frequencies in other ethnic populations. METHODS: A sensitive real-time polymerase chain reaction assay was developed and successfully applied for genotyping of the consensus (wild-type) alleles plus five variants of four genes: DCP1 [the insertion allele ( I) versus the deletion allele ( D)], CETP*TaqI ( B1 versus B2), ADRB2*R16G, ADRB2*Q27E, and HTR2A*102T>C. This study was carried out in 242 unrelated Egyptian subjects and is the first to describe these allelic variants in the Egyptian population. RESULTS: The frequencies of the tested alleles were found as: DCP1 ( I: D, 0.32:0.68), CETPTaqI ( B1: B2, 0.65:0.35), ADRB2*R16G ( Arg16: Gly16, 0.57:0.43), ADRB2*Q27E ( Gln27: Glu27, 0.76:0.24), and HTR2A*102T>C ( T102: C102, 0.53:0.47). The common Arabian ancestors of the Egyptians, Spanish, Saudi, and Emirate had created a common pattern of distribution of some allelic variants ( DCP1 and CETP). However, in the genotyping of ADRB2, the frequency of the polymorphism at codon 16 was found to be similar to the Chinese population, whereas that at codon 27 was similar to African-Americans with significant differences than other Caucasian populations. The frequency of the HTR2A*102T>C variant appeared to be similar to many Caucasian populations and African-Americans. CONCLUSIONS: We have explored the frequencies of important allelic variants DCP1, CETP, ADRB2, and HTR2A among the Egyptian population focusing on the ethnic diversity in the distribution of the tested mutant alleles. Our results may help in better understanding the observed ethnic variation in angiotensin-converting enzyme inhibition and atherosclerosis therapy. It also may contribute to better characterization of interethnic differences in isoprenaline and clozapine response, which will have implications for the cost effective and rational prescribing of these drugs.
We have measured fluid secretion rate in Rhodnius prolixus upper Malpighian tubules (UMT) stimulated to secrete with 5-OH-tryptamine. We used double perfusions in order to have access separately to the basolateral and to the apical cell membranes. Thirteen pharmacological agents were applied: ouabain, Bafilomycin A(1), furosemide, bumetanide, DIOA, Probenecid, SITS, acetazolamide, amiloride, DPC, BaCl(2), pCMBS and DTT. These agents are known to block different ion transport functions, namely ATPases, co- and/or counter-transporters and ion and water channels. The basic assumption is that water movement changes reflect changes in ion transport mechanisms, which we localize as follows: (i) At the basolateral cell membrane, fundamental are a Na(+)-K(+)-2Cl(-) cotransporter and a Cl(-)-HCO(3) (-) exchanger; of intermediate importance are the Na(+)-K(+)-ATPase, Cl(-) channels and Rp-MIP water channels; K(+) channels play a lesser role: (ii) At the apical cell membrane, most important are a K(+)-Cl(-) cotransport that is being located for the first time, a V-H(+)-ATPase; and a Na(+)-H(+) exchanger; a urate-anion exchanger and K(+) channels are less important, while Cl(-) channels are not important at all. A tentative model for the function of the UMT cell is presented.
Melatonin (N-acetyl-5-methoxi-tryptamine), a well-known animal hormone synthetised by the pineal gland, plays a key role in the circadian rhythm of vertebrates. An exhaustive bibliographical revision of studies on melatonin in plants published since 1990 points to very few studies (around 20), of which only 8 have a clear plant physiological focus. The data presented in this study demonstrate that melatonin plays a physiological role in plant tissues. Melatonin is seen to be a molecule that promotes vegetative growth in etiolated Lupinus albus L. hypocotyls, in a similar way to IAA. The measurements of melatonin and IAA in lupin hypocotyls by high-performance liquid chromatography with electrochemical detection, and their identification by tandem mass spectrometry, point to a different distribution of these molecules in etiolated hypocotyls.
A proteomic approach is undertaken aiming at the identification of novel proteins involved in the alkaloid biosynthesis of Catharanthus roseus. The C. roseus cell suspension culture A11 accumulates the terpenoid indole alkaloids strictosidine, ajmalicine and vindolinine. Cells were grown for 21 days, and alkaloid accumulation was monitored during this period. After a rapid increase between day 3 and day 6, the alkaloid content reached a maximum on day 16. Systematic analysis of the proteome was performed by two-dimensional polyacrylamide gel electrophoresis. After day 3, the proteome started to change with an increasing number of protein spots. On day 13, the proteome changed back to roughly the same as at the start of the growth cycle. 88 protein spots were selected for identification by mass spectrometry (MALDI-MS/MS). Of these, 58 were identified, including two isoforms of strictosidine synthase (EC 4.3.3.2), which catalyzes the formation of strictosidine in the alkaloid biosynthesis; tryptophan synthase (EC 4.1.1.28), which is needed for the supply of the alkaloid precursor tryptamine; 12-oxophytodienoate reductase, which is indirectly involved in the alkaloid biosynthesis as it catalyzes the last step in the biosynthesis of the regulator jasmonic acid. Unique sequences were found, which may also relate to unidentified biosynthetic proteins.
The characteristics and kinetic properties of an arylalkylamine N-acetyltransferase were studied in partially purified preparations of the human filarial parasite Onchocerca volvulus. The enzyme, which had a relative molecular mass (M(r)) of 37-38 kDa, catalyzed the acetylation of arylalkylamines but did not accept arylamines or polyamines as substrates. The optimal pH for enzyme activity was found to be 8.5 in TRIS-HCI. The apparent Michaelis constant (K(m)) and maximum velocity (Vmax) determined from Lineweaver-Burk plots for tryptamine were 1.8 microM and 29 nmol min-1 mg protein-1, respectively. Except for the catecholamines, the other arylalkylamines such as 5-hydroxytryptamine (5-HT), tyramine, and octopamine similarly exhibited high affinities and reaction rates. Whereas the enzyme is inhibited by metals and p-chloro-mercuribenzoate, it is inactivated neither by amethopterin nor by cystamine and is thereby distinguished from the mammalian arylamine N-acetyltransferase. Like other N-acetyltransferases whose function is the regulation of intracellular amine levels, the enzyme may have a role in the inactivation of excess biogenic amine in this parasite.
beta-Carbolines structurally related to the selective dopaminergic neurotoxin 1-methyl-4- phenylpyridinium (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease. The chloral-derived mammalian alkaloid derivative 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is formed endogenously by a Pictet-Spengler condensation from the biogenic amine tryptamine (Ta) and the hypnotic aldehyde chloral (Clo). Here we examine the dopaminergic toxicity of TaClo and related compounds by testing their differential cytotoxicities in dopaminergic SH-SY5Y and non-dopaminergic murine Neuro2A neuroblastoma cell lines as well as in heterologous expression systems of the dopamine transporter (DAT) using both HEK-293 and Neuro2A cells. All TaClo derivatives showed significant cytotoxicity in all cell lines after 72 hours with the following rank order of toxic potency: 1-Tribromomethyl-1,2,3,4-tetrahydro-beta-carboline (TaBro) > TaClo > MPP(+) > 1,2,3,4-tetrahydro-beta-carboline (THbetaC) > 2[N]-methyl-TaClo > 2[N]-methyl-THbetaC. In contrast to MPP(+), there was no selectivity towards dopaminergic cells or cells ectopically expressing the DAT in vitro. Our results suggest that TaClo and related analogs are strong cytotoxins without selectivity towards dopaminergic cells.