Presynaptic dopamine DA2-receptors in rabbit jejunal arteries

Summary Excitatory junction potentials (e.j.ps) evoked by nerve stimulation with 15 pulses at 1 Hz were recorded from muscle cells of rabbit isolated jejunal arteries. LY 171555 1 mol/l, SKF 38393 10 mol/l, dopamine 10 ol/l and clonidine 0.1 mol/l depressed all e j.ps in the train. The percentage inhibition was inversely related to the number of pulses. S- and R-sulpiride, 10 mol/l, domperidone 1 mol/l, SCH 23390 1 mol/l and rauwolscine 1 mol/l did not change, or even depressed the first e j.ps. Of these compounds only S- and R-sulpiride, 10 mol/l and rauwolscine 1 mol/l facilitated the late e.j.ps. The percentage facilitation increased with the number of pulses until a maximum was reached; rauwolscine 1 ol/l had the largest effect. S- and R-sulpiride, 10 mol/l, as well as domperidone 1 ol/l antagonized the action of LY 171555 1 mol/l. S-Sulpiride was more potent than its R-isomer. SCH 23390 1 mol/l and rauwolscine 1 mol/l blunted the effect of SKF 38393 10 mol/l. Rauwolscine 1 mol/l slightly reduced the inhibition by dopamine 10 mol/l; S-sulpiride 10 mol/l was antagonistic only in the presence of rauwolscine 1 mol/l. When rauwolscine 1 mol/l, prazosin 0.1 mol/l, propranolol 1 mol/l and cocaine 10 mol/l was added to the medium, dopamine 10 mol/l continued to produce the same depression of e j.ps, as in the absence of these compounds. Under such conditions S-sulpiride 10 mol/l also counteracted dopamine 10 gmol/l. Rauwolscine 1 mol/l prevented the effect of clonidine 0.1 mol/l. The antagonists were not absolutely selective against only one type of agonist. We suggest that both presynaptic DA₂- and postsynaptic DA₁-receptors are present in rabbit jejunal arteries. The activation of either receptor-type may depress the e j.ps. Dopamine interferes with neuroeffector transmission due to ₂-adrenoceptor agonist properties; its DA₂-effect is unmasked only after ₂-adrenoceptor blockade. There was no evidence for a co-transmitter function of dopamine. Send offprint requests to P. Illes at the above address     

Comparison of measured and FTC-predicted nicotine uptake in smokers

Cigarette smokers have a wide variety of tar and nicotine yields to choose from in the current market, ranging from 0.5 mg tar and less than 0.05 mg nicotine to 27 mg tar and 1.8 mg nicotine by the Federal Trade Commission (FTC) method. To understand better the relationship between FTC nicotine yields and actual nicotine uptake in smokers, we have studied nicotine uptake in 33 smokers of self-selected products representing four tar groupings: 1 mg tar (1 MG), ultra-low tar (ULT), full-flavor low tar (FFLT), and full flavor (FF) cigarettes. These cigarette categories had mean FTC nicotine yields of 0.14, 0.49, 0.67, and 1.13 mg/cigarette, respectively. The subjects smoked their usual brand of cigarette ad libitum and provided a 24-h urine sample for total nicotine uptake analysis over a period during which the number of cigarettes smoked was recorded. Nicotine uptake was determined by monitoring urinary nicotine and its metabolites, including the glucuronide conjugates. Daily nicotine uptake was 9.1±7.3 mg (range 1–21 mg) for 1 MG, 19.2±10.0 mg (range 4–42 mg) for ULT, 21.8±9.4 mg (range 13–38 mg) for FFLT, and 37.1±14.4 mg (range 21–60 mg) for FF smokers. On a per cigarette basis, yields were 0.23±0.11, 0.56±0.23, 0.60±0.18, and 1.19±0.43 mg nicotine, respectively. Although individual variability was fairly large (CVs of 0.39–0.80), means for the different groups showed that lower FTC yield smokers not only absorb less nicotine per 24-h period, but also per cigarette smoked. These data suggest that nicotine uptake is a function of individual smoking behavior within product design limits. We conclude from these data that, while FTC yield cannot precisely predict nicotine uptake for an individual smoker, it is useful in predicting and comparing actual nicotine uptake by smokers who select cigarettes with a particular FTC yield.     

Enhancement of the Antiinflammatory Effect of Ethyl 4-Biphenylyl Acetate in Ointment by β-Cyclodextrin Derivatives: Increased Absorption and Localized Activation of the Prodrug in Rats

Ethyl 4-biphenylyl acetate (EBA) is a prodrug of the antiinflammatory 4-biphenylyl acetic acid (BPAA). The inclusion complexes of EBA with -cyclodextrin (-CyD), heptakis(2,6-di-O-methyl)--cyclodextrin (DM--CyD), and 2-hydroxypropyl--cyclodextrin (HP--CyD) at a molar ratio of 1:2 (EBA:cyclodextrin) were prepared and used to make hydrophilic antiinflammatory ointments. The in vitro release of EBA from the ointments was enhanced by complexation in the order of -CyD < DM--CyD HP--CyD. The improvement correlated with the improved solubility and not with the decreased diffusibility observed to occur upon the complexation of EBA. In vivo the complexation with cyclodextrin derivatives increased both the release of EBA from the vehicle and its conversion in the underlying tissue to BPAA, but the total of EBA and BPAA in the tissue was decreased. In vitro studies confirmed that the effects of cyclodextrin derivatives on the conversion were exerted indirectly. The combination of the enhanced release and of the enhanced prodrug hydrolysis by esterases in the site where the antiinflammatory action is required resulted in increased therapeutic effects. In the model of carrageenan-induced acute edema in rat paw, the complexation improved the therapeutic effects over those of EBA alone in the order of -CyD < DM--CyD < HP--CyD. HP--CyD may be a particularly useful cyclodextrin derivative since it improves the topical availability and does not irritate tissues.     

Which smokers report most relief from craving when using nicotine chewing gum?

Seventy-seven smoker clinic clients who managed at least 2 weeks of smoking abstinence while chewing 2 mg nicotine gum reported the degree to which the gum reduced their craving for cigarettes, their daily gum consumption and the extent of urges to smoke despite the gum. Greatest relief from craving by the gum was reported by smokers with higher pre-abstinence expired-air carbon monoxide (CO) concentrations and higher stimulant and dependent scores on a smoking motivation questionaire but not greater usual daily cigarette consumption. Gum consumption correlated positively with expired-air CO, usual daily cigarette consumption, and stimulant and dependent smoking scores. Despite the gum, urges to smoke and difficulty not smoking were reported and the severity of these was associated with indulgent, stimulant and dependent smoking scores but not CO or usual daily cigarette consumption. The results are discussed in terms of the possible role of pharmacological and non-pharmacological factors in craving.     

Pre-abstinence smoke intake and smoking motivation as predictors of severity of cigarette withdrawal symptoms

Twenty-nine cigarette smokers completed a smoking motivation questionnaire and had expired-air carbon monoxide (CO) and plasma nicotine concentrations measured prior to abstaining from smoking for 24 h. Before and after the abstinence period, the subjects rated mood and physical symptoms known to be affected by cigarette abstinence (e.g. irritability, restlessness). Scores on the dependent smoking subscale of the smoking motivation questionnaire correlated significantly with overall withdrawal severity, craving, and increased irritability. Indulgent smoking scores correlated positively with increased hunger. Pre-abstinence plasma nicotine concentration significantly pedicted craving, hunger, restlessness, inability to concentrate and overall withdrawal severity, while expired-air CO predicted craving and restlessness only. Usual daily cigarette consumption did not significantly predict any withdrawal effects. The data indicate that pre-abstinence measures of smoking motivation and smoke intake may provide a guide to withdrawal severity on smoking cessation and that smokers with a high pre-abstinence nicotine intake experience the greatest discomfort.     

β-methyl-digoxin

Summary The tissue/plasma ratio of -methyl-digoxin for cardiac muscle in cats was about the same 24 h after a single dose of 30 g/kg as after a loading dose of 30 g/kg followed by 3 maintenance doses of 7.5 g/kg at 24 h intervals. The ratio for the brain increased 2-fold during that time.After the i.v. injection of a toxic loading dose of 70 g/kg -methyl-digoxin or digoxin, maintenance doses of as little as 15 g/kg at 48 h intervals sufficed to maintain the minimum plasma glycoside concentrations determined by RIA at about 3 ng/ml. There was no difference in the plasma concentrations or in the severity of intoxication produced by both glycosides.Cats vomited within 3 h after i.v. injection of 100 g/kg -methyl-digoxin, whereas a loading dose of 30 g/kg followed by 3 injections of 7.5 g/kg at 24 h intervals were well tolerated. The concentration of radioactivity in the brain 3 h after 100 g/kg was less than 24 h after the last injection of 7.5 g/kg in the experiments with repeated dosage.Cerebral side-effects such as vomiting, loss of appetite and weight were better correlated with the glycoside concentrations in the plasma than with those in the brain.     

The involvement of central cholinergic system in the pressor effect of intracerebroventricularly injected U-46619, a thromboxane A2 analog, in conscious normotensive rats

The aim of this study was to determine the involvement of the central cholinergic system in the rise in blood pressure evoked by the thromboxane A2 (TxA2) analog, U-46619, given centrally. Intracerebroventricular (i.c.v.) injections of U-46619 (0.5, 1.0 and 2.0 g) caused dose- and time-related increases in blood pressure and decreased heart rate in awake rats. U-46619 (1 g; i.c.v.) also produced an approximately 65% increase in posterior hypothalamic extracellular acetylcholine and choline levels. Pretreatment with SQ-29548 (8 g; i.c.v.), selective TxA2 receptor antagonist, completely inhibited both the cardiovascular responses and the increase in acetylcholine and choline levels to subsequent injection of U-46619 (1 g; i.c.v.). Atropine (10 g; i.c.v.), nonselective muscarinic receptor antagonist, pretreatment did not affect the cardiovascular responses observed after U-46619 (1 g; i.c.v.). Pretreatment with the nonselective nicotinic receptor antagonist, mecamylamine (50 g; i.c.v.) attenuated the pressor effect of U-46619 (1 g; i.c.v.). Higher doses of mecamylamine (75 and 100 g; i.c.v.) pretreatments did not change the magnitude of the blockade of pressor response to U-46619; however, they abolished the bradycardic effect of U-46619 dose-dependently. Interestingly, pretreatment of rats with methyllycaconitine (10 g; i.c.v.) or -bungarotoxin (10 g; i.c.v.), selective antagonists of 7 subtype of nicotinic acetylcholine receptors (7nAChRs), partially abolished the pressor response to i.c.v. injection of U-46619 (1 g). Similar to the mecamylamine data, the use of higher doses of methyllycaconitine (25 and 50 g; i.c.v.) produced the same magnitude of blockade that was observed after the 10 g methyllycaconitine pretreatment, but it completely abolished the bradycardic effect of U-46619 (1 g; i.c.v.) at the dose of 25 g. The present results show that central administration of U-46619 produces pressor and bradycardic effect and increase in hypothalamic acetylcholine and choline levels by activating central TxA2 receptors. The activation of central nicotinic receptors, predominantly 7nAChRs, partially mediates the cardiovascular responses to i.c.v. injection of U-46619.     

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.     

β-Endorphin-induced release of 5-hydroxytryptamine from human platelets

Platelets of healthy human subjects were incubated with 5-hydroxytryptamine (5-HT) followed by a second incubation with either -endorphin (-end) or the combination of -end and naloxone. -End (300 pg/ml) reduced the levels of 5-HT to 50% of initial values within 15–40 min. After 40–80 min incubation, the levels of 5-HT decreased to approximately zero. Addition of increasing amounts of -end (up to 300 pg/ml) produced increasing releases of 5-HT with increasing doses of -end. The response was dose-related, however variable, across subjects. Addition of either 28.7 or 57.4 pg naloxone to 300 pg -end did not antagonize the effects of -end on 5-HT.     

Viscoelastic Properties of Polyacrylic Acid Gels in Mixed Solvents

The objective of this study is to investigate the viscoelastic properties of Carbopol 934P polymeric systems in a variety of mixtures of pharmaceutical solvents. Carbopol 934P neutralized with a 1:1 equivalent ratio of triethanolamine was dissolved in various binary or ternary solvent mixtures consisting of propylene glycol, glycerol formal, and water. Dynamic moduli G and G, complex viscosities, and , and loss tangent, tan, were examined over a frequency range of 10-3 to 10 Hz using an oscillatory viscoelastic rheometer at 30°C. The results indicated that for 0.5-1.5 wt% neutralized Carbopol in ternary mixtures, G and G increased by 3-4 orders of magnitude and the phase angle decreased from 80 to 25° when the water content in the solvent mixture increased from 10 to 80 wt%. These studies also indicated that the addition of water to nonaqueous Carbopol 934P polymer systems transforms them from low-viscosity solutions to gels with significant elastic behavior involving physical interaction and entanglement of polymer segments with solvents.     

Differential modulation by muscimol and baclofen on antinociception induced by morphine, β-endorphin,d-Pen2,5-enkephalin and U50,488H administered intracerebroventricularly in the mouse

The present study was designed to investigate the modulatory effects of stimulation of GABA_A and GABA_B receptors at supraspinal sites on antinociception induced by supraspinally administered -, -, -, and -opioid receptor agonists. The effects of the GABA_A and GABA_B receptor agonists, muscimol and baclofen respectively, on the antinociception induced by morphine (a -receptor agonist), -endorphin (an -receptor agonist), D-Pen^2,5-enkephalin (DPDPE, a -receptor agonist) and U50,488H ({trans-3,4-di-chloroN-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeocetamide}; a -receptor agonist) injected intracerebroventricularly (i.c.v.) were studied. The anti-nociception was assayed using the tail-flick and hot-plate tests. Muscimol at doses of 25–200 ng, administered i.c.v. alone did not affect the latencies of tail-flick and hot-plate thresholds, but attenuated dose-dependently the inhibition of the tail-flick and hot-plate responses induced by i.c.v. administered morphine (2 g), -endorphin (1 g), DPDPE (10 g), and U50,488H (60 g). Baclofen (1.25–10 ng) administered i.c.v. alone did not affect the latencies of the tail-flick and hot-plate responses, but attenuated dose-dependently the inhibition of the tail-flick and hot-plate responses induced by -endorphin and U50,488H, without affecting morphine-or DPDPE-induced responses. Our results indicate that activation of GABA_A receptors at the supraspinal sites by i.c.v. injection of muscimol antagonizes antinociception induced by supraspinally administered -, -, -, and -opioid receptor agonists. On the other hand, activation of GABA_B receptors at supraspinal sites by i.c.v. baclofen antagonizes antinociception induced by i.c.v. administered - and -opioid agonists, but not - or -opioid agonists.     

Tobacco “chippers” —individual differences in tobacco dependence

This study explores the behavior of tobacco chippers — very light smokers who regularly use tobacco without developing dependence. Eighteen chippers (CHs) who averaged a maximum of five cigarettes per day, but who smoked at least 4 days per week, were compared to 29 dependent smokers (DSs). Laboratory data showed that CHs inhale cigarette smoke and are exposed to nicotine. In both experimental and retrospective self-report data, CHs showed no signs of tobacco withdrawal when abstinent. CHs also differed from DSs in their pattern of smoking: their smoking was less linked with mood states. However, the hypothesis that they were social smokers was contradicted. CHs also differed on psychosocial variables relevant to a stress-coping model of smoking: they reported less stress, better coping, and more social support, but these differences were small. Although the two groups were demographically similar, smoking behavior differences between CHs and DSs were long-standing: the two groups differed in their responses to initial smoking and in their family histories of smoking and cessation. CHs' smoking behavior challenges classical theories of dependence; further research is needed on the factors that may protect CHs from addiction.     

Evans blue blocks P2X-purinoceptors in rat vas deferens

Summary In rat vas deferens, Evans blue 100 M increased contractions elicited by high K⁺ and by noradrenaline but markedly reduced contractions elicited by the P_2X-purinoceptor-selective agonist ,-methylene ATP (3 M). The concentration-response curve of ,-methylene ATP was shifted to the right by Evans blue 30 M and the maximal contraction was increased. In tissues incubated with nifedipine 10 M, Evans blue 100 M tended to increase the residual contraction elicited by noradrenaline and abolished the residual response to ,-methylene ATP (3 M). The concentration-response curve of ,-methylene ATP was progressively shifted to the right by increasing concentrations of Evans blue in the presence of nifedipine; maximal contractions were increased by Evans blue 10 and 30 but not 100 M. From the shifts to the right caused by Evans blue 30 M, apparent pK_B values of 5.9 (no nifedipine) and 6.0 (nifedipine present) were calculated. It is concluded that Evans blue blocks P_2X-purinoceptors in rat vas deferens and in addition causes a non-receptor-specific enhancement of contractions.Correspondence to: R. Bültmann at the above address     

Effects of intrathecal or intracerebroventricular pretreatment with pertussis toxin on antinociception induced by β-endorphin or morphine administered intracerebroventricularly in mice

We have previously demonstrated that -endorphin and morphine, when administered supraspinally, produce antinociception by activating different descending pain inhibitory systems in both rats and mice. However, the signal transduction mechanisms involved in the descending pain-inhibitory systems that are activated by -endorphin and morphine administered intracerebroventricularly (i.c.v.) have not been characterized. Therefore, in the present study, the effects of intrathecal (i.t.) and i.c.v. pretreatments with pertussis toxin (PTX) on antinociception induced by -endorphin or by morphine administered i.c.v. were studied in ICR mice. Antinociception was assessed by the tail-flick assay and by the hotplate assay. Intrathecal pretreatment with PTX (0.5 g) for 6 days effectively reduced the inhibition of the tail-flick response induced by -endorphin (1 g) or by morphine (1 g) administered i.c.v. However, i.t. pretreatment with PTX was not effective in reducing the inhibition of the hot-plate response induced by -endorphin or by morphine administered i.c.v. Intracerebroventricular pretreatment with PTX (0.5 g) for 6 days effectively reduced the inhibition of the tail-flick and hot-plate responses induced by morphine (1 g), but not that induced by -endorphin (1 g), administered i.cv. Our results suggest that there are PTX-sensitive G proteins coupled to the spinal descending pain inhibitory systems that are activated by -endorphin and morphine administered i.c.v. At a supraspinal level, i.cv. morphine- but not -endorphin-induced antinociception is mediated by PTX-sensitive G proteins. Correspondence to: Hong W. Suh at the above address     

Metabolism and presynaptic inhibitory activity of 2′,3′ and 5′-adenine nucleotides in rat vas deferens

Summary In the isolated rat vas deferens stimulated at 0.2 Hz, [¹⁴C]labelled 5-AMP, 5-ADP and 5-ATP (10 M) inhibited twitch responses, were broken down to [¹⁴C]adenosine in the medium and incorporated into [¹⁴C]adenine ribonucleotides in the tissue. Pretreatment of tissues with 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine (NBTGR), a potent inhibitor of adenosine transport, potentiated the presynaptic inhibitory action of these 5 nucleotides and reduced their incorporation in [¹⁴C]adenine nucleotides, but did not alter the appearance of [¹⁴C]adenosine in the medium.A series of 2, 3 and 5-substituted adenine nucleotides (10 M) inhibited the twitch responses of the vas deferens stimulated at 0.2 Hz. This effect was potentiated by NBTGR. Addition of exogenous adenosine deaminase very significantly reduced the inhibitory actions of adenosine, 5-AMP, 5-ADP and 5-ATP and also reduced those of 2, 5-ADP, NAD⁺ and dePCoA. The inhibitory actions of the other 2, 3 and 5 adenine nucleotides studied were not altered by exogenous adenosine deaminase.These results indicated that the presynaptic inhibitory actions of 5-AMP, 5-ADP and 5-ATP in rat vas deferens predominantly result from their prior hydrolysis to adenosine whereas the 2, 3 and 5-substituted adenine nucleotides appear to act mainly directly to inhibit transmitter release.Abbreviations. The following abbreviations are used 5-ADP 5-adenosine diphosphate - 2,5-ADP 2,5-adenosine diphosphate - 3,5-ADP 3,5-adenosine diphosphate - 2,3 or 5-AMP 2,3 or 5-adenosine monophosphate - 5-ATP 5-adenosine triphosphate - CoA coenzyme A - 2,3-cAMP 2,3-cyclic adenosine monophosphate - cNADP⁺ -nicotinamide dinucleotide 2,3-cyclic monophosphate - dePCoA dephosphocoenzyme A - NAD⁺ -nicotinamide adenine dinucleotide - NADP⁺ -nicotinamide adenine dinucleotide phosphate - NBTGR 6-(2-hydroxy-5-nitrobenzyl)-thioguanosine - oxid CoA oxidized-coenzyme A     

Effective serum concentration and action in pharmacokinetics

Summary A formula has been derived for the calculation of effective serum concentration based on the assumption of both exponential absorption and exponential elimination of an administered drug. In order to permit quantitative comparisons of different drugs and/or different dosage schedules, a new term is proposed called action or COTT (for concentration times time).This paper is dedicated to Prof. Heinz Oeser, M. D., on his 60th birthday.     

EEG,heart rate and mood change (“high”) after Cannabis

Fourteen experienced marijuana users smoked marijuana, hashish, ⁹-THC, and placebo. EEG, ECG and ratings of subjective feelings of high and pleasantness were recorded. EEGs were processed by period analysis.In EEG, marijuana and ⁹-THC increased the amount of alpha activity, and the three Cannabis preparations decreased the amount of beta activity. The average frequency of alpha activity was decreased by 0.15–0.20 c/sec after marijuana, hashish and ⁹-THC. The peak EEG effect occurred during the first 10 min after smoking; most of the changes disappeared after 40 min. Heart rate was increased by all the three drugs, and the effect persisted for the entire observation period (50 min).Feelings of high were elicited by each Cannabis preparation. This was not true of the pleasantness of the experience: only marijuana and hashish were perceived as more pleasant than placebo. Intensity of high increased with the amount of alpha activity, and decreased with the average alpha frequency. Pleasantness was unrelated to the EEG.The high showed a linear increase with heart rate, whereas pleasantness of the experience was an inverted U-function of heart rate.Aided, in part, by MH 13358, 18172 and by a contract with the New York State Narcotic Addiction Control Commission.     

Is there a need for more precise definitions of bioavailability?

Summary After evaluation of the present definitions in a set of particular cases, it was agreed that there was no need for more precise definitions and that the current ones were adequate in the majority of cases. However, it was felt that the present definitions might be improved, in particular in view of the existence of non-systemically acting drugs and future targeted drugs. Thus, the FDA definition might be modified as follows: Bioavailability means the rate and extent to which the active drug ingredient or therapeutic moiety from a drug product becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action.     

Evidence for prejunctionally located β2-adrenoceptors in the cat spleen

Summary The number of -adrenoceptors in myocardium and spleen from 6-hydroxydopamine (6-OH-DA) treated cats was determined by radioligand binding with [¹²⁵I]-iodohydroxybenzylpindolol (IHYP). The effectiveness of 6-OH-DA pretreatment was assessed by analyses of the tissue content of catecholamines and the contractile response of isolated splenic strips to electrical stimulation. Since no effect on the splenic strip was produced by the -agonist isoprenaline, whereas noradrenaline caused contraction, it is concluded that the smooth muscle of the splenic capsule is controlled by postjunctional -adrenoceptors.The number of specific IHYP binding sites were reduced by 70% in whole spleen tissue and totally abolished in the splenic capsule by pretreatment with 6-OH-DA. Subclass analysis revealed that the reduction in total splenic -adrenoceptor number was due to a loss of ₂-adrenoceptors. However, the 6-OH-DA induced chemical sympathectomy did not produce any alteration either in -adrenoceptor density or the relative distribution of the -adrenoceptor subtype in the myocardium. It is suggested that a loss of prejunctional -adrenoceptors, due to chemical sympathectomy, might be compensated for by an increased number of postjunctional -adrenoceptors in the myocardium due to the development of denervation supersensitivity in this tissue.In conclusion, the findings provide direct biochemical evidence for existence of prejunctional ₂-adrenoceptors on the sympathetic nerve terminals of the cat spleen.     

The effect of some antidepressants on prejunctional muscarinic receptors on the sympathetic nerves of the isolated rabbit ear artery

Summary The antimuscarinic activity of amitriptyline, desipramine, iprindole, mianserin and viloxazine on prejunctional sympathetic nerve endings were compared in the isolated rabbit ear artery. In the presence of cocaine (10 M) and yohimbine (1 M), amitriptyline (0.5–1 M), desipramine (1–3 M) and iprindole (5–10 M), desipramine (1–3 M) and iprindole (5–10 M) produced parallel rightward shifts of the concentration-response curve for the inhibitory effect of carbachol (CCh) on responses to electrical stimulation of the preparation at 3 Hz. Mianserin (3 M) produced some inhibition but altered the slope of the concentration-responses curve to CCh while viloxazine (10 M) produced no inhibition.The depression of tritium efflux by CCh from arteries preincubated in ³H-noradrenaline was inhibited significantly (P<0.05) by amitriptyline (0.1 M) and desipramine (1 M) and not by iprindole (17 M), mianserin (3 M) or viloxazine (10 M). Amitriptyline was 10-fold more active than desipramine and at least 30-fold more active than the other antidepressants as a muscarine receptor blocking drug in this preparation.Thus, mianserin, viloxazine and iprindole exhibit much weaker antimuscarinic activity relative to amitriptyline on prejunctional muscarine receptors on sympathetic nerve endings compared with that observed by others for excitatory muscarine receptors in sympathetic ganglia. The findings support an earlier suggestion that these receptors differ.