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1.
Δ 9-Tetrahydrocannabinol (Δ 9-THC) 1 mg/kg, i.v. produced a slight but significant reduction in the heart rate of conscious mongrel dogs, and these effects were greatly potentiated by pentobarbital and/or urethane anesthesia. However, significant increase in the heart rate was noted following Δ 9-THC administration in the dogs anesthetized with a combination of morphine plus chloralose; further, neither morphine nor chloralose alone could reverse the bradycardic effects of Δ 9-THC. Tachycardia induced by Δ 9-THC in these dogs could be reversed by bilateral vagotomy or by pretreatment of the animals with methylatropine, or propranolol and/or practolol. The data indicated a complex interaction between Δ 9-THC and morphine-chloralose combination and the tachycardia induced by Δ 9-THC under this anesthesia may be due to release of epinephrine by a reflexogenic mechanism involving afferent vagi. Further, while the bradycardic effects of Δ 9-THC were essentially identical under pentobarbital or urethane anesthesia, the hypotensive effects were similar in urethane or chloralose anesthetized dogs. The study emphasizes that anesthetic interaction should be taken into consideration while investigating mechanisms of actions of pharmacological agents. 相似文献
2.
(-)-Δ 9- trans-Tetrahydrocannabinol (Δ 9-THC), when given intravenously (2 mg kg ?1) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (C 1-C 2) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of Δ 9-THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after Δ 9-THC administration. These observations support the hypothesis that Δ 9-THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that Δ 9-THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that Δ 9-THC did not interact with α- or β- adrenoceptors. The possible action of Δ 9-THC on central sympathetic structures was investigated by perfusion of Δ 9-THC into the lateral cerebral ventricle. Δ 9-THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or 14C-Δ 9-THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that Δ 9-THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone. 相似文献
3.
(?)- Δ9- trans-tetrahydrocannabinol ( Δ9-THC) (39 μg–2.5 mg/kg, i.v.) decreased blood pressure, heart rate, cardiac output and right ventricular contractile force in a dose-related manner in intact dogs under pentobarbital anesthesia. The Δ9-THC-induced hypotension appeared to result mainly from a consistent and reproducible attenuation of cardiac output since no marked alteration in total peripheral resistance occured. In these animals the decrease in cardiac output appeared to be related to the bradycardia since there was no change in stroke volume following Δ9-THC. However, when the change in heart rate was prevented by atrial pacing or cardiac denervation, a less but significant reduction in cardiac output was induced by Δ9-THC. Under these experimental conditions Δ9-THC also significantly attenuated stroke volume. In contrast, Δ9-THC did not induce any significant changes in cardiac output, blood pressure, and heart rate of dogs pretreated with a ganglionic blocker. Δ9-THC appeared to be devoid of any measurable direct effect on the myocardium since the compound neither significantly altered right ventricular contractile force of the denervated or ganglionic blocker-pretreated hearts nor interfered with the positive inotropic responses to i.v. calcium and isoproterenol.In the major vessel occlusion preparation administration of Δ9-THC was followed by a reduction in venous tone. Furthermore, measurements of blood and plasma volume excluded an effect of Δ9-THC in these parameters.From these findings it is suggested that the reduction in cardiac output induced by Δ9-THC is the result of the action of this compound on cardiac rate as well as venous return; no evidence could be documented for a direct effect of this compound on the myocardium. 相似文献
4.
Administration of (?)-Δ 9-trans-tetrahydrocannabinol (Δ 9-THC, 2.5 mg/kg i.v.) to pentobarbital-anesthetized dogs in which heart rate was maintained constant by electrical pacing, decreased aortic blood pressure, cardiac output, left ventricular peak pressure and left ventricular end diastolic pressure and dP/dt. However, the contractility index (max. dP/dt)/I.P. was not altered by the compound. Furthermore, it was shown that the decrease in cardiac output due to Δ 9-THC could be restored to original levels by an infusion of saline-dextran in quantities sufficient to elevate the left ventricular end diastolic pressure to pre-Δ 9-THC level.In dogs in which cardiac output was maintained constant by a right heart bypass procedure Δ 9-THC decreased blood pressure and total peripheral resistance and augmented intravascular blood volume. This increase in intravascular blood volume was significantly less (74%) in animals in which the splanchnic (superior, inferior and celiac) arteries were ligated prior to the administration of Δ 9-THC. On the other hand, in spinal dogs Δ 9-THC was devoid of any measurable cardiovascular effects.These observations clearly support the hypothesis that the diminution of cardiac output induced by Δ 9-THC in animals with constant cardiac rate is primarily due to diminished venous return to the heart and not to an impaired ability of the myocardium. 相似文献
5.
Intrastriatal injections of Δ 9-THC and 1 l-hydroxy-Δ 9-THC induced dose-dependent catalepsy in the rat, the parent compound being more potent than the metabolite. Catalepsy was not induced following intrapallidal injection of either drug. The results suggest that the caudate-putamen could be a “specific site” in the mediation of catalepsy induced by Δ 9-THC.Intrastriatal amphetamine attenuated Δ 9-THC-induced catalepsy whereas intrapallidal amphetamine potentiated the effect indicating a complex interaction with dopaminergic systems in the basal ganglia.Δ 9-THC and the central cholinergic stimulant, RS-86 synergize on administration to either area indicating a possible cholinergic involvement in the phenomenon. 相似文献
6.
The pharmacological potency of R- and S-3′-hydroxy-Δ 9-tetrahydrocannabinol (THC) was compared to that of Δ 9-THC as well as R/S-3′-OH-Δ 9-THC. The S-isomer was found to be considerably more potent than the R-isomer in producing hypoactivity in mice, static-ataxia in dogs, and in generalization testing in rats trained to discriminate Δ 9-THC from vehicle. S-3′-OH-Δ 9-THC was more active than Δ 9-THC in these tests which means that Δ 9-THC may be either activated or inactivated in vivo depending upon which metabolite is formed. The difference in potency of these isomers suggests that the conformation of the side chain is critical for behavioral activity. The R and S isomers were found to be equally active in producing hypothermia in mice which is in contrast to the behavioral effects. 相似文献
7.
A study was designed to investigate the mechanism(s) of the tachycardia produced by histamine and specific H 1- and H 2-receptor agonists in anesthetized dogs. I.v. administration of histamine, 2-methylhistamine, and 4-methylhistamine caused a fall in blood pressure and an increase in heart rate. Prior administration of mepyramine, a histamine H 1-receptor antagonist, significantly antagonized the depressor and positive chronotropic effects of histamine and completely abolished the cardiovascular actions of 2-methylhistamine, whereas responses to 4-methylhistamine were not affected. Subsequent administration of metiamide, a specific H 2-receptor antagonist, completely abolished the remaining cardiovascular effects of histamine and the hypotension and tachycardia observed after 4-methylhistamine were also antagonized.In another series of experiments, bilateral vagotomy significantly attenuated the tachycardia and subsequent removal of cardiac sympathetic nerve supply completely abolished it without affecting the depressor effects of these agents. Pharmacological blockade of muscarinic receptors with atropine in another group of animals also significantly attenuated the positive chronotropic effect which was completely prevented by further treatment with propranolol. The hypotension produced by histamine agonists was not affected by atropine and propranolol. These results demonstrate that in pentobarbital-anesthetized dogs, the tachycardia produced by histamine and specific H 1- and H 2-receptor agonists are due to reciprocal alterations in cardiac autonomic activity as a result of the fall in the arterial pressure. Activation of cardiac histamine receptors does not seem to account for the positive chronotropic effects of these compounds in intact dogs. 相似文献
8.
MJ 9465-2 elicited pronounced dose-dependent pressor, and positive inotropic and chronotropic responses upon rapid i.v. injection into pentobarbital-anesthetized, atropine-treated dogs. These responses were modified or abolished following pharmacologic blockade (chlorisondamine, dibozane, protriptyline, or reserpine) or surgical intervention (spinal cord transection [C 1] or bilateral vagotomy). This imidazoline demonstrated little, if any, α-, β-, or intrinsic cardiovascular actions at the doses studied. MJ 9465-2 appears not to stimulate sympathetic ganglia or the adrenal medulla. The cardiovascular responses evoked by i.v. administration of MJ 9465-2 are comprised of at least 2 components. Component I is a reflex which is dependent upon: (a) an afferent pathway contained within the vagus nerve, (b) efferent sympathetic pathways arising from within the CNS above the level of C 1 and (c) intact sympathetic ganglia. Component II relies upon: (a) the release of norepinephrine from sympathetic nerve terminals and/or chromaffin tissue via an indirect mechanism and (b) the release of vasopressor material, possibly antidiuretic hormone. 相似文献
9.
Both intravenous Δ 9-tetrahydrocannabinol (Δ 9-THC) and intraseptal muscimol reduce the turnover rate of acetylcholine (TR ACh) in the hippocampus by 50 and 58%, respectively, without affecting the hippocampal content of ACh. The ACh content and the TR ACh, in other areas of rat brain examined are unchanged. Bicuculline fails to alter the hippocampal TR ACh when administered intraseptally but prevents the decreased hippocampal TR ACh induced by Δ 9-THC or muscimol. The effect is specific to the septal-hippocampal cholinergic pathway since lesioning the fimbria (2 hr) abolishes the effect. Moreover, neither naltrexone nor destruction of septal dopaminergic nerve terminals with 6-hydroxy-dopamine injected into area A 10 prevents the decreased TR ACh after Δ 9-THC. This suggests that neither endophinergic nor dopaminergic neurons are involved in the reduction of the TR ACh in the hippocampas following administration of Δ 9-THC or muscimol. When the metabolism of γ-aminobutyric acid (TR GABA) is measured, Δ 9-THC produces a 2-fold increase in the TR GABA which is specific for the septum. These results suggest that Δ 9-THC inhibits TR ACh in the cholinergic septal-hippocampal pathway by increasing the release of GABA from septal GABAergic interneurons. 相似文献
10.
Δ 8-Tetrahydrocannabinol (Δ 8-THC) as isomer of the well-known Δ 9-THC has a similar mode of action, and the potency was estimated to be two thirds compared with Δ 9-THC. Content of Δ 8-THC in plant material is low, but formulations containing Δ 8-THC in high concentrations are gaining popularity. Δ 8-THC is to be regarded as prohibited substance according to the Prohibited List of the World Anti-Doping Agency (WADA). Contradictory results between initial testing procedure and confirmatory quantitation for 11-Nor-9-carboxy-Δ 9-tetrahydrocannabinol (Δ 9-THC-COOH) of a doping control sample gave rise for follow-up testing procedures. After alkaline hydrolysis and liquid–liquid extraction, the sample was analyzed by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) using isocratic elution instead of gradient elution, which is used for standard procedure. Isocratic elution resulted in two peaks instead of one using gradient elution. Both peaks showed same fragmentation. Using certified reference materials, one peak could be assigned to Δ 9-THC-COOH and the other one with higher intensity to the less common 11-Nor-9-carboxy-Δ 8-Tetrahydrocannabinol (Δ 8-THC-COOH) in a concentration of approximately 1200 ng/ml. As complementary method, gas chromatography tandem mass spectrometry (GC-MS/MS) can also be used for identification. Here Δ 8- and Δ 9-THC-COOH can be distinguished by chromatography and by fragmentation. Additional investigations of doping control samples containing Δ 9-THC-COOH revealed the simultaneous presence of Δ 8-THC-COOH in low concentrations (0.22–8.91 ng/ml) presumably due to plant origin. Percentage of Δ 8-THC-COOH varies from 0.05 to 2.83%. In vitro experiments using human liver microsomes showed that Δ 8-THC is metabolized in the same way as Δ 9-THC. 相似文献
11.
The effects of various doses of l-trans-Δ 9-tetrahydrocannabinol (Δ 9-THC) on naloxone-induced withdrawal were studied in mice rendered dependent on morphine by the pellet implantation procedure. When administered i.p., 30 min prior to naloxone, Δ 9-THC, inhibited the naloxone-induced withdrawal jumping response. Two other signs of morphine withdrawal (defecation and rearing behavior) were also suppressed by Δ 9-THC. It is suggested that Δ 9-THC or some of its derivatives may have potential use in narcotic detoxification. 相似文献
12.
Δ 9-Tetrahydrocannabinol (Δ 9-THC) and a water soluble ester derivative (compound I) caused a concentration-related decrease in the uptake of 14C-dopamine into crude synaptosomal preparations derived from mouse striata. Both were less potent than amphetamine in this preparation. In the presence of 10 ?7m amphetamine the IC 50 of Δ 9-THC was unaffected. The IC 50 is the concentration of drug in the medium which will inhibit the uptake of 14C-dopamine into the synaptosomes by 50%. However in the presence of 3.0 × 10 ?6m Δ 9-THC, the dose response curve to amphetamine was shifted to the right and the IC 50 of amphetamine was increased. Δ 9-Tetrahydrocannabinol and compound I increased the release of 14C-dopamine from preparations pre-incubated with 14C-dopamine. The effect was small but significant. The effects of amphetamine and Δ 9THC combined were additive on this system. The mode of action of Δ 9-THC with regard to the dopaminergic system of the striatum is discussed. 相似文献
13.
1. One isotopic and three non-isotopic methods were used to determine the effect of an acute intravenous dose of Δ 9-tetrahydrocannabinol (Δ 9-THC, 2 mg/kg) on the rat brain turnover rate of serotonin. 2. In control animals the turnover rate of serotonin was about 2 nmol/g per h. This rate was not altered by Δ 9-THC when it was calculated from the rise of 5-hydroxyindoleacetic acid following probenecid or from the rise of serotonin following pargyline. 3. Δ 9-THC did not alter the serotonin turnover rate when it was calculated from the conversion of 3H-tryptophan to 3H-serotonin. 4. The serotonin turnover rate was significantly increased by Δ 9-THC when the rate was calculated from the decline of 5-hydroxyindoleacetic acid following pargyline. 5. These results suggest that Δ 9-THC does not alter the turnover of rat brain serotonin. The previously reported Δ 9-THC-induced changes in body temperature and increased brain levels of 5-hydroxyindoleacetic acid may be mediated by some other mechanism such as interference by Δ 9-THC of the vesicular binding of serotonin. 相似文献
14.
Marijuana abuse during adolescence may alter its abuse liability during adulthood by modifying the interoceptive (discriminative) stimuli produced, especially in females due to an interaction with ovarian hormones. To examine this possibility, either gonadally intact or ovariectomized (OVX) female rats received 40 intraperitoneal injections of saline or 5.6 mg/kg of Δ 9-THC daily during adolescence, yielding 4 experimental groups (intact/saline, intact/Δ 9-THC, OVX/saline, and OVX/Δ 9-THC). These groups were then trained to discriminate Δ 9-THC (0.32-3.2 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food presentation. After a training dose was established for the subjects in each group, varying doses of Δ 9-THC were substituted for the training dose to obtain dose-effect (generalization) curves for drug-lever responding and response rate. The results showed that: 1) the OVX/saline group had a substantially higher mean response rate under control conditions than the other three groups, 2) both OVX groups had higher percentages of THC-lever responding than the intact groups at doses of Δ 9-THC lower than the training dose, and 3) the OVX/Δ 9-THC group was significantly less sensitive to the rate-decreasing effects of Δ 9-THC compared to other groups. Furthermore, at sacrifice, western blot analyses indicated that chronic Δ 9-THC in OVX and intact females decreased cannabinoid type-1 receptor (CB1R) levels in the striatum, and decreased phosphorylation of cyclic adenosine monophosphate response element binding protein (p-CREB) in the hippocampus. In contrast to the hippocampus, chronic Δ 9-THC selectively increased p-CREB in the OVX/saline group in the striatum. Extracellular signal-regulated kinase (ERK) was not significantly affected by either hormone status or chronic Δ 9-THC. In summary, these data in female rats suggest that cannabinoid abuse by adolescent human females could alter their subsequent responsiveness to cannabinoids as adults and have serious consequences for brain development. 相似文献
15.
For preclinical toxicologic evaluation, Δ9-tetrahydrocannabinol ( Δ9-THC), Δ8-THC, and Cannabis extract were administered po to rats, dogs and monkeys as solutions in either absolute ethanol, sesame oil, or sesame oil with 2.5–9.0% ethanol. All three compounds were significantly more potent in female than in male Wistar-Lewis and Fischer rats. However, within the dosage range of 225–3600 mg/kg, Δ9-THC and Δ8-THC produced the same lethality, while both isomers were approximately twice as potent as the Cannabis extract. Death due to all three compounds consistently occurred between 36 and 72 hr after treatment regardless of the dose level or sex of the rats. Mortality in rats apparently resulted from severe hypothermia and other central effects. Toxicity was characterized by severe hypothermia, bradypnea, rapid weight loss, inactivity, wide stance, ataxia, muscle tremors, and prostration. Rats treated with equimolar amounts of tetrahydrocannabinol from the three compounds exhibited equivalent diversities and severities of clinical signs. In dogs and monkeys, single oral doses of Δ9-THC and Δ8-THC between 3000 and 9000/mg/kg were nonlethal. Predominant toxic signs in dogs included drowsiness, ataxia, prostration, anesthesia, tremors, mild hypothermia, salivation, emesis, and anorexia. Toxic signs in monkeys included hyperreactivity to stimuli, lethargy, drowsiness, characteristic huddled posture, slow movements, abnormal eating procedures and sedation. Histopathologic alterations did not occur in either dogs or monkeys. 相似文献
16.
1. Rat isolated hearts perfused with Δ 1-THC (0·5 μ/ml) showed a reduction in the rate of beating which was not altered by pretreatment with propranolol (2 μg/ml), atropine (4 μg/ml) or hexamethonium (4 μ/ml). 2. Propranolol (2 μg/ml) also caused a decrease in the rate of beating, which was not affected by pretreatment with Δ 1-THC (0·5 μg/ml). 3. In pithed rats, propranolol (2 mg/kg, i.v.) caused a decrease in the pulse rate, which was not altered by prior administration of Δ 1-THC (1 mg/kg, i.v.). 4. In both preparations, the responses to isoprenaline were markedly reduced or abolished by propranolol, but they were unaffected by Δ 1-THC. 5. It is concluded that the hypotensive and cardiac slowing actions of Δ 1-THC are not mediated by activation of parasympathetic nerves or by β-adrenoceptor blockade. 相似文献
17.
1 In intact dogs anaesthetized with pentobarbitone, clonidine (10 μg/kg, i.v.) produced a sustained decrease in heart rate. This effect was significantly smaller in vagotomized dogs in which the sympathetic drive to the heart was either left intact or experimentally created by continuous electrical stimulation of the decentralized cardioaccelerator nerve. In the latter preparation, the negative chronotropic action of clonidine was reversed by an intravenous injection of phentolamine, whereas in the former experimental situation it was antagonized only by an intravenous plus an intravertebral artery injection of phentolamine. 2 In dogs with denervated hearts the tachycardia produced by electrical stimulation of the cardioaccelerator nerve was accompanied by a rise in noradrenaline overflowing into the coronary sinus plasma. Clonidine inhibited both these effects and phentolamine restored them to pre-clonidine levels. 3 Clonidine decreased heart rate in dogs with an intact parasympathetically innervated heart and decentralized stellate ganglia. When the low basal heart rate of this preparation was elevated by electrical stimulation of the cardioaccelerator nerve, clonidine had a negative chronotropic effect, the degree of which was similar to that observed in intact dogs. 4 Clonidine neither modified baseline heart rates of dogs with denervated hearts nor the levels of heart rate which in this preparation were reduced by a sustained electrical stimulation of the right vagus or increased by intravenous infusions of either isoprenaline or noradrenaline. 5 These findings indicate that in the intact dog, bradycardia induced by clonidine resulted both from a reduction of sympathetic drive and from a concomitant increase in parasympathetic tone. The latter action did not occur at the level of cardiac neuroeffector structures since it was observed only in the presence of centrally connected vagal pathways. The inhibition of cardiac sympathetic tone was of both peripheral and central origin. Clonidine, in fact, diminished the quantity of noradrenaline overflowing into the coronary sinus plasma in cardiac denervated dogs with a tachycardia elicited by electrical stimulation of the decentralized cardioaccelerator nerve. This peripheral effect was probably due to an activation of α-adrenoceptors located on sympathetic nerve terminals since it was antagonized by phentolamine. However, in vagotomized dogs (intact sympathetic pathways) intravenous phentolamine failed to antagonize the heart rate effects of clonidine which were abolished by a subsequent injection of phentolamine into the vertebral artery. Thus, the clonidine-induced inhibition of both the peripheral and central sympathetic drive to the heart would appear to be mediated via α-adrenoceptors. 相似文献
18.
(—)- trans-Δ 9-Tetrahydrocannabinol (Δ 9-THC) was isolated from marihuana plant extract, by adsorptive column and glc. The adsorptive column chromatography method consisted of chromatographing marihuana extract on a column packed with a mixture of silica gel (gas chromatography grade (100/120 mesh), silver nitrate and calcium sulphate (CaSO 4·H 2O) (3:1:0·5) with benzene as the eluting solvent. The glc method consisted of chromatographing the extract on a 3 ft silanized glass column (3/8 inch o.d.) packed with 1·5 ft of 2% QF-1 and 1·5 ft of 2% OV-17 on chromosorb W, AW 30–60 mesh, prep grade. A purity of 99% for the isolated Δ 9-THC was confirmed by infrared spectroscopy, nuclear magnetic resonance, mass spectroscopy. The effects of storage conditions on Δ 9-THC stability, monitored by glc, indicated the best method for preserving Δ 9-THC was at 0°, protected from light, stored under nitrogen. 相似文献
19.
The effects on body temperature produced by graded doses of Δ 9-tetrahydrocannabinol (Δ 9-THC) and phenylbutazone were compared in both normal and pyretic rats. Dose related hypothermic responses were produced by the oral administration of Δ 9-THC in normal animals. Moreover, Δ 9-THC significantly reduced elevated temperatures in yeast-induced pyretic rats to near normal levels at doses which exhibited little hypothermic activity in normal rats. The oral antipyretic potency of Δ 9-THC was approximately 2 times that of phenylbutazone. The comparative oral antinociceptive activity of Δ 9-THC and selected narcotic and non-narcotic analgesics was determined by the increase in response latency to pressure applied to normal and yeast-inflamed paws. Δ 9-THC administered orally was essentially inactive at dose levels below those producing pronounced central nervous system depression. The oral anti-inflammatory efficacy of Δ 9-THC was compared to phenylbutazone and acetylsalicylic acid. Δ 9-THC was ineffective in inhibiting carrageenin-induced edema of the rat paw following acute or chronic administration. 相似文献
20.
Based on previous observations that cannabidiol (CBD) blocks some effects of Δ9-tetrahydrocannabinol ( Δ9-THC) in laboratory animals, the present work was carried out to study possible interaction between CBD and Δ9-THC in human beings. In a double blind procedure, 40 healthy male volunteers were assigned to 1 of 8 experimental groups, receiving per oral route, placebe, 30 mg Δ9-THC, 15 30 or 60 mg of CBD, and mixtures of 30 mg of Δ9-THC plus either 15, 30 or 60 mg of CBD respectively. Pulse rate, time production tasks and psychological logical reactions were measured at several time intervals after drug ingestion. 30 mg Δ9-THC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects. 15–60 mg of CBD alone provoked no effects. On the other hand, CBD was efficient in blocking most of the effects of Δ9-THC when both drugs were given together. CBD also decreased the anxiety component of Δ9-THC effects, in such a way that the subjects reported more pleasurable effects. 相似文献
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