Comparative studies on distribution and covalent tissue binding of 2,4,2′,4′- and 3,4,3′,4′-tetrachlorobiphenyl isomers in the rat

The ¹⁴C-labeled tetrachlorobiphenyl (TCB) isomers 2,4,2,4-tetrachlorobiphenyl (2,4,2,4-TCB) and 3,4,3,4-tetrachlorobiphenyl (3,4,34-TCB) were administered orally to rats, and distribution and covalent binding were measured in several organs. Marked differences in distribution and covalent binding of the two TCBs were observed. The accumulation and retention of 2,4,2,4-TCB in adipose tissue were much higher than those of 3,4,3,4-TCB, although the level of radioactivity in the blood was consistently higher in 3,4,3,4-TCB treated rats. The radioactivity bound in covalent linkages with cellular macromolecules in several tissues was also measured. The data obtained indicated that covalent binding was higher in 3,4,3,4-TCB treated rats than in those treated with 2,4,2,4-TCB, particularly in liver and blood components. These results suggest that the two TCB isomers have different pharmacokinetic properties in rats, and the association of covalent binding with 3,4,3,4-TCB-induced toxicities might be important. In addition, we found that repeated oral dosing with the two TCB isomers caused an increase in in vitro liver microsomal generation of reactive metabolites of TCBs, indicating that the microsomal enzyme system is likely to play an important role in the in vivo covalent binding of TCB.     

Investigation of the venoconstrictor effect of 8′ hydroxydihydroergotamine,the main metabolite of dihydroergotamine,in man

Summary The time course of the venoconstrictor effect of dihydroergotamine and its main metabolite 8 hydroxy-dihydroergotamine was investigated in a placebo-controlled study in seven healthy male volunteers, after direct local infusion of 0.08 and 0.4 µg into superficial hand veins. Both dihydroergotamine and 8 hydroxy-dihydroergotamine elicited a similar, marked venoconstrictor effect. The time course of the venoconstrictor action was similar for both compounds; about one third of the effect was present at the end of the infusion, which lasted for 10 min, and it took about a further 20 min for the effect to reach its maximum. The effect then remained fairly constant for the rest of the period of observation of 180 min from the start of the infusion. The data indicate that the pharmacological activity of oral dihydroergotamine is due not only to the unchanged drug but also to its main metabolite, 8 hydroxy-dihydroergotamine, which occurs in plasma in concentrations about 5–7 times higher than those of dihydroergotamine itself. The absolute bioavailability of unchanged dihydroergotamine, therefore, does not reflect the markedly higher bioavailability of pharmacologically active drug.     

Hemmung von Adenyl-Cyclase-Präparationen aus der Rattenniere durch Calciumionen und verschiedene Diuretica

Summary Antidiuretic hormone (ADH) increases the permeability to water of certain epithelial membranes. This effect, found in the urinary bladder of the toad and in the distal tubules and the collecting ducts of kidney, is mediated intracellularly by adenosine 35-monophosphate (Ado-35-P). Calcium ions and the diuretic ethacrynic acid are known to inhibit the ADH-induced increase in water permeability of the toad bladder. In adenyl cyclase preparations from rat renal cortex and medulla, the influence of these substances as well as of other diuretics added in vitro has been studied. Adenyl cyclase activity has been determined, excepted as noted, by measuring Ado-35-P formed from 1 mM ¹⁴C-ATP in the presence of 10 mM Mg⁺⁺, an ATP regenerating system, and 5 mM unlabeled Ado-35-P to reduce the enzymatic degradation of the labeled Ado-35-P.Calcium ions reduced the rate of Ado-35-P formation by particles from renal cortex and medulla when the activity was measured in the presence of either Mg⁺⁺ or Mn⁺⁺. With 10 mM Mg⁺⁺, 1 mM Ca⁺⁺ decreased adenyl cylase activity by about 50%. Activities of cortical adenyl cyclase stimulated by parathyroid hormone, thyrocalcitonin or ADH and of medullary adenyl cyclase stimulated by ADH were also reduced by about 50% in the presence of 1 mM Ca⁺⁺. The inhibition was independent of the ATP concentration, but was influenced by the Mg⁺⁺ content of the incubation medium.Adenyl cyclase activities of cortical and medullary membrane preparations were reduced by about 50% by 0.2 mM ethacrynic acid. The extent of this inhibition was essentially the same whether the enzymatic activity was determined in the absence or presence of stimulating hormones. The inhibitory action of ethacrynic acid was partially prevented by simultaneous addition of dithioerythritol (DTE). A derivative of ethacrynic acid, L 589420-0-2, also inhibited renal adenyl cyclase, but its action was not influenced by the addition of DTE. Adenyl cyclase from both parts of the kidney was inhibited by about 90% by 0.2 mM mersalyl. This action was almost completely prevented by the addition of 1 mM DTE. The pharmacological significance of adenyl cyclase inhibition by these diuretics is still uncertain since the role of Ado-35-P in the regulation of sodium transport is as yet unclear.Other diuretics, hydrochlorothiazide, furosemide, mefruside, amiloride, and the non-diuretic benzothiadiazine, diazoxide, had essentially no effect on cortical and medullary adenyl cyclase preparations when they were added in 0.1–0.5 mM concentration.The methylxanthines, theophylline and caffeine, which are known to inhibit nucleoside 35-monophosphate phosphodiesterase, reduced the rate of Ado-35-P formation. The unstimulated and the hormone-stimulated adenyl cyclases were inhibited to the same extent by theophylline. When adenyl cyclases was stimulated by fluoride, however, we found only a very small inhibition by theophylline. Inhibition of the medullary adenyl cyclase was greater than that of the enzyme prepared from renal cortex. At a concentration of 1 mM these methylxanthines significantly inhibited the medullary enzyme, but the inhibition became asymptotic at about 50% when concentrations up to 20 mM were used. Therefore, it is likely that inhibition by these substances varies in different cell types and tissues.Instead of phosphodiesterase inhibitors, unlabeled Ado-35-P can be used in the assay of adenyl cyclase activity to reduce the degradation of enzymatically formed labeled Ado-35-P. This addition, though, can also influence adenyl cyclase activity. In a medullary enzyme preparation 0.2 mM Ado-35-P reduced the adenyl cyclase activity by 13%, 5 mM Ado-35-P by 35%.

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Abkürzungen Ado-35-P Adenosin-35-monophosphat - Guo-35-P Guanosin-35-monophosphat - ADH antidiuretisches Hormon, Vasopressin - PTH Parathormon - TCT Thyreocalcitonin - DTE Dithioerythrit - EDTA Äthylendiamintetraessigsäure Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.Über einen Teil der Ergebnisse wurde auf der 11. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft berichtet (Jakobs et al., 1970). Einige der vorliegenden Ergebnisse sind der Inauguraldissertation von K. H. J. (Medizinische Fakultät der Universität Heidelberg, 1971) entnommen.     

Involvement of tumor necrosis factor-α in sulfur mustard-induced skin lesion; effect of topical iodine

Sulfur mustard (SM), also termed mustard gas, is a potent vesicant that elicits an inflammatory response upon exposure of the skin. Evaluation of mouse ear 3 h after SM exposure revealed acute inflammatory-cell aggregates in the vascular beds accompanied by strongly TNF--positive neutrophils. Eight hours after SM exposure, this phenomenon became intensified and associated with infiltration into the adjacent dermis. In ear skin topically treated with iodine, however, no inflammatory cells were observed 3 h after SM exposure; 8 h postexposure, blood vessels contained very few TNF--positive inflammatory cells. Since TNF- induction was shown to be associated with reactive oxygen species production, we studied the effect of iodine on activated peritoneal mouse neutrophils. Iodine elicited a concentration-dependent reduction in the oxidative burst of activated neutrophils. Iodine also scavenged hydroxyl radicals generated by glucose oxidase in a concentration-dependent manner. The involvement of TNF- in SM-induced skin toxicity was confirmed by reduction of 49 and 30% in ear edema following administration of 1 and 2 g anti-TNF- antibodies, respectively. These findings were corroborated by quantitative analysis of the histological findings showing 46% reduction in acute inflammation and no signs of subacute inflammation in the treated group, in contrast to the control group treated with SM only. Other epidermal (microblister formation, ulceration, and necrosis) and dermal (neutrophilia, hemorrhage, and necrosis) parameters also showed marked reductions in the antibodies-treated group in comparison to controls. The combination of iodine and antiTNF- antibodies might constitute a new approach for treatment of SM-exposed individuals.U. Wormser is affiliated with David R. Bloom Center for Pharmacy at The Hebrew University.     

Cardiostimulatory effects of cyclic 3′,5′-adenosine monophosphate and its acylated derivatives

Summary The effects of cyclic 3,5-AMP and of two acylated derivatives, dibutyryl (DBA) and dihexanoyl-3,5-AMP (DHA) were investigated in isolated perfused hearts of guinea pigs, rats and rabbits.In guinea pig hearts, DBA (Ca- and Na-salt) and DHA-Na in high doses (10 moles) produced strong and long lasting increases in the rate and amplitude of contractions, coronary flow, and moderate increases in phosphorylase activity in the majority of experiments. The positive ino- and chronotropic effects occured 3–5 min after injection of the drug, mostly in a fluctuating manner with several maxima. Theophylline augmented the effects of DBA-Na and revealed positive inotropic actions of non substituted 3,5-AMP.In rat hearts, similar, but more pronounced and dose-dependent effects were observed after 1, 5 and 10 moles DBA-Na. Propranolol (50 g) did not block the action of 10 moles DBA-Na. Non substituted 3,5-AMP, 5-AMP and ATP in doses of 10 moles had no significant positive inotropic effects.In rabbit hearts, DBA-Na (50 moles) produced moderate, non fluctuating rises in the amplitude of contraction.The results provide evidence that under certain conditions cyclic 3, 5-AMP itself, like its acylated derivatives DBA and DHA, may produce strong and direct positive inotropic and chronotropic effects in the heart. These findings support the view that cyclic 3,5-AMP is the cellular mediator of the cardiostimulant actions of substances that increase its rate of production in the myocardial cell.The excellent technical help of Mrs. Vera Bauer is gratefully acknowledged by the authors.     

The antinociception induced by \-endorphin administered intrathecally is mediated by the activation of μ and κ-opioid receptors in the rat

The antinociception induced by -endorphin given supraspinally has been previously demonstrated to be mediated by the stimulation of -, but not -, - or -opioid receptors in rats and mice. The present study was designed to determine what types of opioid receptors in the spinal cord are involved in the antinociception induced by intrathecally (i.t.) administered -endorphin. Antinociception was assessed by the tailflick test in male Sprague-Dawley rats. CTOP (0.9–6.6 nmol), a selective -opioid receptor antagonist, or nor-BNI(13.6–95.3 nmol), a selective -opioid receptor antagonist, given i.t. dose-dependently reversed i.t. administered -endorphin-induced inhibition of the tail-flick response. On the other hand, naltrindole (6.6–44.4 nmol), a selective -opioid receptor antagonist, or -endorphin (1–27) (1–6.7 nmol), a selective -opioid receptor antagonist given i.t., did not antagonize the inhibition of the tail-flick response induced by i.t. administered -endorphin. The results are consistent with the previous study in mice [Tseng LF and Collins KA (1992) Eur J Pharmacol 214: 59–65] that the antinociception induced by -endorphin given i.t. is mediated by the stimulation of - and -, but not - and -opioid receptors.Abbreviations i.t. Intrathecal - CTOP D-Phe-Cys-Tyr-D-Try-Orn-Thr-Pen-Thr-NH₂ - nor-BNI Norbinaltorphimine     

Effects of indomethacin on changes in renal blood flow induced by adenosine and its analogues in conscious dogs

Summary The effects of indomethacin on changes in renal blood flow induced by adenosine, NECA (adenosine-5-N-ethyl-carboxamide) and 2,3-dinitro-NECA were investigated in 6 chronically instrumented conscious dogs. Adenosine (187.5, 375 and 750 nmol/kg, i.v.) induced a dose-dependent initial decrease, followed by a reactive increase in renal blood flow. NECA (1.5 nmol/kg, i.v.) also induced an initial decrease, which was, however, followed by a prolonged reactive increase in renal blood fow. 2,3-dinitro-NECA (50 nmol/kg, orally) induced only an increase in renal blood flow. Indomethacin (27.9 mol/kg, i.v.) caused no relevant change of the initial decrease and a significant attenuation of the reactive increase in renal blood flow induced by adenosine. NECA-induced changes in blood flow were affected by indomethacin in the same direction but to a greater extent than were adenosine-induced changes in blood flow. Indomethacin reversed the increase to a decrease in renal blood flow induced by 2,3-dinitro-NECA. Thus, prostaglandins seem to be involved in mediating the response of renal blood flow to adenosine, NECA and 2,3-dinitro-NECA.Part of this study was presented at the fall meeting of the German Pharmacological Society, September 1982 in Vienna, Austria     

A simple method for sampling murine pulmonary and cardiac tissues for analysis of cyclic nucleotide levels

Summary A simple method for the rapid removal and freezing of mouse cardiac and pulmonary tissues is described. Samples thus obtained were judged to be suitable for valid estimation of in vivo levels of cyclic AMP and cyclic GMP based on the following findings: (a) the samples could be obtained and frozen in the very short time period of a few seconds; (b) no indication of adverse effects of the collection procedure was found upon examination of chemical indicators of energy metabolism; (c) the apparent rates of change of cyclic AMP and cyclic GMP levels during the first seconds after tissue isolation could produce small, but acceptable errors; and (d) dose-dependent elevations of pulmonary cAMP levels consistent with known effects in vitro were found after in vivo administration of isoproterenol.Abbreviations cAMP adenosine-3,5-cyclic monophosphate - cGMP guanosine-3,5-cyclic monophosphate     

Plasma levels and β-blocking effect of α-hydroxymetoprolol—Metabolite of metoprolol—in the dog

The plasma levels and the - blocking effect of metoprolol and its active metabolite - hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the - blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of - blockade. Because of differences in the volume of distribution, 2.0 liters/kg for - OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of - OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. - OH-Metoprolol was more slowly eliminated (t_1/27.0 hr, total body clearance 3.5 ml-kg^–1-min^–1) than metoprolol (t_1/22.0 hr, total body clearance 20.0 ml-kg^–1-min^–1). Approximately 5% of an i.v. dose of metoprolol was metabolized to - OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.     

Effect of Coadministered Uridine on Intestinal First-Pass Metabolism of 5′-Deoxy-5-Fluorouridine in Conscious Rats—An Evaluation by Method of Portal-Systemic Concentration Difference

Purpose. The effect of uridine (UR) coadministration on the intestinal metabolism from 5-deoxy-5-fluorouridine (5-DFUR) to 5-fluorouracil (5-FU) was evaluated by a method of concentration difference between portal and systemic bloods in conscious rats (PS method). Methods. 5-DFUR (100 mg/kg) alone (Group A), or 5-DFUR + UR (100 mg/kg each) (Group B) was orally administered to conscious rats. The portal and arterial bloods were simultaneously withdrawn from two canulas at appropriate time intervals, and blood concentrations of 5-DFUR, 5-FU, UR and uracil (U) were assayed by HPLC. The concentration-time profiles of these drugs and its metabolites were analyzed by local moment analysis. Results. UR coadministration made the local absorption ratio (F_a) of 5-DFUR decrease significantly from 60.1 ± 10.5% to 38.0 ± 18.6% of dose. Though the local absorption ratios (F_a ^m) of the metabolite (5-FU) were the same between Group A and Group B (8.3 ± 1.9 and 8.7 ± 4.0% of 5-DFUR, respectively), AUC of arterial 5-FU in Group B was 5 times greater than that in Group A. UR was not detected in the portal blood, and F_a ^m of U was estimated to be 41.9 ± 26.8% of UR in Group B. Conclusions. It is predicted that a large portion of 5-FU generated from 5-DFUR is further degraded in the intestine in Group A, and U generated from UR blocks 5-FU degradation in the intestine and the systemic circulation in Group B.     

Evaluation of cardiotoxicity of a new anthracycline derivative: 4′ -deoxy-4′ -iodo-doxorubicin

Summary The present study in rats was performed to evaluate the cardiotoxic activity of 4 -deoxy-4 -iodo-doxorubicin (4-deoxy-4-I-DXR), a new anthracycline derivative with interesting antineoplastic properties and possible lower cardiotoxicity than doxorubicin (DXR). DXR produced ECG alterations consisting of a progressive and irreversible prolongation of SaT and QaT. In contrast, in 4-deoxy-4-I-DXR-treated rats the increase in SaT and QaT duration was significantly lower than that observed in DXR-treated rats and slightly increased over controls.DXR produced significant histologic changes in myocardium consisting of myocyte vacuolization and myofibrillar loss. No significant modifications were observed in mitochondria. In contrast, no significant cardiac lesions were observed in 4-deoxy-4-I-DXR-treated rats. These results suggest that this new anthracycline derivative has a significantly lower degree of cardiotoxic activity than DXR.     

Inhibition by papaverine and eupaverin of 3′,5′-cyclic AMP phosphodiesterase from rabbit skeletal muscle

Summary Papaverine and eupaverin are potent inhibitors of 3,5-cyclic AMP phosphodiesterase from rabbit white skeletal muscle. These drugs inhibit more the activity associated with the particulate fractions than that associated with the soluble fraction.     

Lysergic acid diethylamide antagonizes shaking induced in rats by five chemically different compounds

Thyrotropin-releasing hormone (TRH), sodium valproate, AG-3-5 (1-[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one), RX336-M (7,8-dihydro-5, 6-dimethylcyclohex-5-eno-1,2,8,14 codeinone), and Sgd 8473 (-[(4-chlorobenzylideneamino)-oxy]-isobutyric acid) each induced repetitive shaking of the body of rats after intraperitoneal injection. This action of the five diverse chemicals appears to be subserved by a common pharmacological component, because pretreatment with d-lysergic acid diethylamide (0.03–1.0 mg kg^-1, s.c.) attenuated the shaking behavior in a dose-related manner, and cross tolerance was found between RX 336-M and TRH, sodium valproate, and AG-3-5.     

Hemmung der Insulininkretion durch α-Receptoren stimulierende Substanzen

Summary Experiments are described in which the influence of an -adrenergic blocking agent, phentolamine, and of two hypotensive drugs, diazoxide and 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (DCAI) on blood glucose, plasma insulin and glucose-stimulated insulin secretion has been measured in male Wistar rats.Blood glucose concentration has been found to be decreased and plasma insulin concentration has been found to be increased after one or two injections of 50 mg phentolamine/kg b.w., intraperitoneally. These results are in accordance with the observation that -adrenergic stimulation inhibits and -adrenergic stimulation promotes insulin secretion (Porte, 1967 a, 1967 b). If the -adrenergic stimulatory effect of endogenous catecholamines is blocked by phentolamine, the remaining -adrenergic stimulatory effect of endogenous epinephrine leads to an increase in insulin secretion.Treating rats with diazoxide (200 mg/kg b.w., i.v.) or DCAI (200 g/kg b.w., s.c.), respectively, has been found to lead to a decrease in plasma insulin concentration as well as to an almost complete inhibition of the ability of the pancreas to secrete insulin in response to an elevation of blood glucose concentration. As these effects have been found to be abolished by pretreatment with phentolamine, the inhibition of insulin secretion caused by diazoxide and DCAI may be regarded as being mediated by -adrenergic stimulation.Recent studies of Turtle and Kipnis (1967) have shown that -adrenergic stimulation lowers islet 3,5-AMP concentration and prevents the increase in islet 3,5-AMP concentration which is caused by -adrenergic stimulation. In view of these results indicating an antagonistic influence of - and -adrenergic stimulation on 3,5-AMP formation in islet tissue, the inhibitory action of diazoxide and DCAI on insulin secretion may be explained by a decrease in adenyl cyclase activity in this tissue.

Wir danken der Deutschen Forschungsgemeinschaft für die Unterstützung unserer Untersuchungen.     

Human pharmacokinetics of esorubicin (4′ -deoxydoxorubicin)

Summary The pharmacokinetics of esorubicin, a new anthracycline antibiotic, was investigated in conjunction with a phase I clinical trial. The drug was administered to 12 patients as an intravenous bolus at a dose of 20 to 40mg/m². All patients had normal renal and hepatic functions and no third space fluid accumulation. Plasma and urine samples were assayed by HPLC. The peak plasma concentration of esorubicin was 0.74 ± 0.57 M (mean ± SE). Esorubicin disappeared from plasma according to a tri-exponential pattern with a terminal half-life of 20.4 ± 7.3 hr. The area under the plasma concentration versus time curve was 0.64 ± 0.31 Mxhr. Total body plasma clearance was 45.5 ± 26.8 liter/min/m² and the apparent volume of the central compartment, 41.0 ± 24.8 L. A single metabolite, 4-deoxydoxorubicinol, was detected in plasma. This metabolite was observed in 5 patients only and its mean peak concentration was 0.029 ± 0.017 M. The area under the plasma versus concentration time curve for 4-deoxydoxorubicinol was 0.02 ± 0.014 Mxhr. The urinary excretion of total fluorescence within 5 days of therapy was 7.3 ± 1.3% of the administered dose. Esorubicin represented more than 80% of the excreted anthracyclines. As in plasma, 4 -deoxydoxorubicinol was the only metabolite detectable in urine. No correlation between the various pharmacokinetic parameters and drug-induced toxicity was observed in this small group of patients.This work was presented in part at the 4th NCI EORTC Symposium on New Drugs in Cancer Therapy (Brussels, Belgium, December 14–17, 1983) and at the 20th Annual Meeting of the American Society of Clinical Oncology (Toronto, Canada, May 6–8, 1984).     

Biodegradation of alpha-hexachlorocyclohexane

Summary Alpha-hexachlorocyclohexane (-HCH) is dechlorinated by enzymes contained in rat liver cytosol and microsomes. An evidence was obtained that in the cytosol there are two -HCH dechlorinating enzymes at least: one operates only in the presence of reduced glutathione (GSH) and catalyzes dechlorinations associated with the formation of another hydrophilic product. This product is probably a conjugate of the -HCH-residue with GSH. The other cytoplasmic -HCH-dechlorinase requires no additions. The microsomes, too, contain two -HCH dechlorinases at least: one is stimulated by GSH, the other by NADPH.Part V.: Naunyn-Schmiedeberg's Arch. Pharmacol. 288, 65–78 (1975)     

Postjunctional α-adrenoceptors

Summary The postsynaptic -adrenoceptors in rat aorta and in pithed rat were investigated according to their sensitivity to nine -adrenergic agonists and to the selective antagonists yohimbine (₂) and prazosin (₁) and the non-selective one, phentolamine. In addition, in radioligand binding studies, the affinity and selectivity of the drugs were determined on rat cerebral cortex using [³H] yohimbine and [³H] prazosin.On rat aorta, prazosin is 1,000 times more potent than yohimbine against each -adrenoceptor agonist, whether ₁- or ₂-selective. Rat aorta probably contains only ₁-adrenoceptors.Pressor effects in pithed rats are mediated by post-junctional ₁- and ₂-adrenoceptors. The dose-response curve for -methylnorepinephrine in the presence of prazosin, using Hofstee's plots, revealed ₁- and ₂-adrenoceptors, respective proportions being 80.5 and 19.5%     

The effect of gamma-butyrolactone on locomotor activity in the rat

The effect of -butyrolactone (GBL) on locomotor activity in the rat was studied. Low doses of GBL (100 and 200 mg/kg) had a biphasic effect on activity. Initially, the activity of the rats was reduced, and this reduction was then followed by a period of hyperactivity. The effect of -flupenthixol (50 g/kg -FPT), atropine (10 mg/kg), benztropine (25 mg/kg), protriptyline (15 mg/kg), and clomipramine (25 mg/kg) was investigated on this biphasic effect. -FPT reduced the hyperactivity while benztropine potentiated it; atropine, clomipramine, and protriptyline had little effect. It is concluded that the increase in activity could be due to a release of dopamine.     

α1B- but not α1A-adrenoceptors mediate inositol phosphate generation

Summary We used novel highly subtype-selective antagonists to study whether _1A- and/or _1B-adrenoceptors mediate the stimulation of inositol phosphate generation by noradrenaline in rat cerebral cortex. Phentolamine (10 M) and prazosin (100 nM) completely abolished the stimulated inositol phosphate generation. The _1A-selective antagonists 5-methyl-urapidil (100 nM) and (+)– and (–)-niguldipine (10 nM) caused only weak inhibition or none at all although these concentrations occupied _1A-adrenoceptors almost completely. In contrast, pretreatment with the irreversible _1B-selective chloroethylclonidine reduced the noradrenaline-stimulated inositol phosphate generation by 76 ± 8%. These data demonstrate that _1B-adrenoceptors couple to inositol phosphate generation; the signal transduction system of _1A-adrenoceptors remains unclear. Send offprint requests to G. Gross at the above address     

Enhancement by α-fluoromethylhistidine of the thiopental sleep-prolonging action of Δ9-tetrahydrocannabinol

The effect of -fluoromethylhistidine (-FMH), a specific inhibitor of histidine decarboxylase, on the potentiation of thiopental-induced sleep by ⁹-tetrahydrocannabinol (THC), which inhibits the histamine turnover in the brain, was examined in mice and rats. The sleeping time after injection of thiopental sodium (40 mg/kg, IV) was prolonged by THC (10 mg/kg, IP, 1 h before) to approximately twice the control value. -FMH (50 mg/kg, IP) administered alone had no significant influence on the thiopental sleeping time. However, -FMH given 1 or 3 h before THC treatment markedly enhanced the THC potentiation of thiopental-induced sleep. Such an enhancement by -FMH was not observed when -FMH was administered 15 h before THC treatment. The brain histamine level decreased by 60% during the first 4 h after -FMH injection and remained low until 15 h after the treatment. The thiopental sleep-potentiating action of morphine, chlorpromazine and diazepam was not affected by pretreatment with -FMH. The transient enhancing effect of -FMH on the THC potentiation of thiopental-induced sleep suggests that the histaminergic system is one of the activating transmitter systems in the brain.