比较Lorcainide和几种抗心律失常药对实验性心律失常的作用

用麻醉大白鼠和豚鼠研究lorcainide抗心律失常作用,并与普鲁卡因胺、异搏定、苯妥英钠和阿托品进行比较。Iv lorcainide 3 mg/kg可对抗肾上腺素、乌头碱、氯化钡和哇巴因心律失常,但不能对抗氯化钙心律失常。Iv阿托品0.1 mg/kg对抗肾上腺素引起的大鼠心律失常作用强于lorcainide。苯妥英钠iv 20 mg/kg对抗乌头碱引起心律失常的作用比qorcainide显著;iv异搏定1.25 mg/kg对抗氯化钡心律失常的作用超过loreainide。Iv lorcainide 3 mg/kg提高哇巴因引起豚鼠心律失常所需剂量显著超过异搏定,普鲁卡因胺与苯妥英钠。     

The Antiarrhythmic Activity of N- Alkyl-1,2-diphenylethanolamines

The activity of N-alkyl-1,2-diphenylethanolamines against CaCl₂-induced cardiac arrhythmia was evaluated in the rat. The potencies of the compounds were compared with that of the established calcium ion-channel blocker, verapamil. The N-methyl, N-ethyl, and N-isobutyl derivatives as well as verapamil at doses of 2–8 µmol kg^–1 protected the animals against the induced arrhythmia. The potency order was verapamil > N methyl > N-ethyl > N-isobutyl derivatives. The N-isopropyl and N-butyl derivatives were inactive. The antiarrhythmic activity of the compounds was not due to local anesthetic activity but may be caused by calcium-channel inhibition.     

Comparison of verapamil and bepridil,two slow channel inhibitors,in protection against calcium-induced arrhythmias

Summary Verapamil and bepridil share the common property of antagonizing the slow inward calcium-mediated current, but bepridil has some additional antiarrhythmic properties. The efficacy of these two compounds against CaCl₂-induced arrhythmias has been compared in rats. CaCl₂ was administered i.v. by continuous infusion until death (25 mg·kg^–1·min^–1 or 40 mg·kg^–1·min^–1) or by bolus injection (160 mg·kg^–1). Bepridil (5, 10 mg·kg^–1) or verapamil (2.5,5 mg·kg^–1) were injected 10 min before CaCl₂. Bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1) prolong the survival time during CaCl₂ infusion. After pretreatment, the injection of 160 mg·kg^–1 CaCl₂ is less toxic: 25% of animals are protected by bepridil (5 mg·kg^–1), 41% by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1).At death the myocardial Ca²⁺ level is not different in controls and pretreated animals, thus, the ratio myocardial Ca²⁺/total injected Ca²⁺ is significantly lowered by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1). The efficacy of the two drugs on this model appears related solely to inhibition of slow inward current despite the additional antiarrhythmic profile of bepridil.     

Synthesis and Antiarrhythmic Activity of 5-Amino-<Emphasis Type="Italic">exo</Emphasis>-3-azatricyclo[5.2.1.0<Superscript>2,6</Superscript>]decan-4-one

Exo-2-amino-exo-3-aminomethylbicyclo[2.2.1]heptane (I) and 5-amino-exo-3-azatricyclo[5.2.1.0^2,6]decan-4-one (II) were synthesized and characterized with respect to antiarrhythmic activity. Compound II exhibited antiarrhythmic activity with ED₅₀ = 0.28 and 0.33 mg/kg on the aconitine and calcium chloride models of arrhythmia, respectively. Compound I did not show antiarrhythmic activity and exhibited acute toxicity corresponding to LD₅₀ = 450 mg/kg. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 6, pp. 9 – 11, June, 2005.     

Effects of an antiarrhythmic drug A-2545 on canine ventricular arrhythmia models; comparison with mexiletine and flecainide

We investigated effects of a new Na⁺ channel blocking antiarrhythmic drug, A-2545, N-3 (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)-propyl-phthalimide-hydrochloride, on various canine ventricular automaticity arrhythmias induced by two-stage coronary ligation, digitalis and adrenaline, and compared them with those of mexiletine. A-2545 showed antiarrhythmic effects, significantly decreasing the arrhythmic ratio of 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced automaticity arrhythmias. The antiarrhythmic plasma concentrations (IC₅₀) of A-2545, 2 mg kg^–1 10 min^–1, i.v., for 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced arrhythmias were 1.8, 1.3, 5.8 and 3.7 μg ml^–1, respectively, and that calculated for oral A-2545 (25 mg kg^–1) in 24-h coronary ligation-induced arrhythmia was 1.8 μg ml^–1. A-2545 is specifically potent in suppressing coronary ligation-induced arrhythmias, i.e., decreasing the arrhythmic ratio nearly to zero by oral administration, and among the intravenously given experiments A-2545 was effective at lower concentrations than other arrhythmia models; A-2545, 2 mg kg^–1 10 min^–1, was equipotent to 5 mg kg^–1 10 min^–1 mexiletine in suppressing 24-h coronary ligation-induced arrhythmia, indicating that A-2545 is more potent than mexiletine. In order to determine whether A-2545 has arrhythmogenic effects, we used programmed electrical stimulation (PES)-induced reentry arrhythmias in dogs with old myocardial infarction and compared effects of A-2545 and flecainide. A-2545, 2 and 5 mg kg^–1 10 min^–1, significantly suppressed the PES-induced arrhythmias in all six dogs without aggravating them. These arrhythmias were not markedly suppressed by flecainide either with 1 or 3 mg kg^–1 10 min^–1; moreover even in one out of six dogs aggravation of arrhythmia was noted after 1 mg kg^–1 10 min^–1. In conclusion, A-2545 suppressed various canine ventricular arrhythmias, and the antiarrhythmic effect of A-2545 was more potent than that of mexiletine, and A-2545 did not show arrhythmogenic effects compared to flecainide. Received: 16 February 1998 / Accepted: 7 October 1998     

Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite,norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5–64.8%, and the peak plasma concentration (C_max) of verapamil by 34.1–65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T_max) and the terminal half-life (t_1/2) of verapamil in the presence of lovastatin. The AUC and C_max of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.     

Patent Evaluation: Tetrahydroprotoberberine quaternary compounds as antiarrythmic agents

Summary

Novelty: Tetrahydroprotoberberine quaternary compounds are claimed which suppress arrhythmia and ventricular fibrillations. The compounds protect against myocardial ischaemia and can be conveniently administered orally.

Biology: A number of assays were performed to determine protection against arrhythmia, ventricular fibrillation and myocardial ischaemic injury. One of the compounds had an ED₅₀ of 0.22 (iv) against arrhythmias and 0.016 mg/kg against ventricular fibrillation. After po administration ED₅₀ values were 16.5 and 20 mg/kg, respectively.

Chemistry: The synthesis of five compounds is described. They are prepared in two steps starting from protoberberine and involve reduction with potassium borohydride followed by alkyfation with an alkyl halide.     

山莨菪碱的抗心律失常作用

山莨菪碱(anisodamine,简称Ani)有阻断M受体和α受体等作用。近年来,有人报道Ani有钙拮抗作用,这可能与茛菪碱类药物用于治疗心律失常有关。本文采用七种实验动物模型,观察了Ani的抗心律失常作用。     

Antiarrythymic evaluation of verapamil,nifedipine, perhexiline and SKF 525-A in four canine models of cardiac arrhythmias

Verapamil, nifedipine, perhexiline and SKF 525-A (2-diethylaminoethyl-2,2-diphenylvalerate · HCl) were evaluated for cardiac antiarrhythmic activity by assessing their effectiveness in increasing left ventricular fibrillation threshold (FT) and antagonizing ouabain-induced arrhythmias (OA), 24 h inifarction arrhythmias (CLA) and aconitine-induced atrial arrhythmias. Calcium antagonistic doses (ID₅₀) of each agent were approximated by intravenous titration of the amount of drug required to reduce the left ventricular contractile force by 50% in dogs pretreated with hexamethonium (10 mg/kg) to block autonomic reflexes. ID₅₀ doses of calcium antagonists were found not to be universally effective in any single arrhythmia model while causing significant changes in heart rate, blood pressure and frequently producing death or convulsion. It is suggested that local anesthetic or ‘class 1’ action probably accounts for the antiarrhythmic effectiveness of SKF 525-A (7–20 mg/kg i.v.) in all four arrhythmia models and for perhexiline-induced incresed FT and antagonism of CLA (15–20 mg/kg). Anti-arrhythmic effectiveness of verapamil against OA may be due to calcium antagonism action.     

Efficacy and Safety of FospropofolFD Compared to Propofol When Given During the Induction of General Anaesthesia: A Phase II,Multi‐centre,Randomized, Parallel‐Group,Active‐Controlled,Double‐Blind,Double‐Dummy Study

The present phase II study aimed to compare the efficacy and safety of fospropofol disodium for injection (Fospropofol_FD) and propofol when given during the induction of general anaesthesia in patients scheduled for elective surgery. Fospropofol_FD is a water‐soluble prodrug of propofol. Approved by the Ethical Committee, 240 participants aged 18–65 years were equally randomly allocated to receive an intravenous bolus of Fospropofol_FD 20 mg/kg or propofol 2 mg/kg without any anaesthetic pre‐treatment. The primary efficacy end‐point was the sedation success rate within 5 min. after administering investigational drugs (the sedation success is defined as obtaining Modified Observer's Assessment of Alertness/Sedation scale score of 1). All the participants completed the induction and intubation within 25 min. after administration. The sedation success rates within 5 min. after administration of Fospropofol_FD 20 mg/kg and propofol 2 mg/kg were 94.50% versus 100% in the intention‐to‐treat population and 95.10% versus 100% in the per‐protocol population, respectively. The non‐inferiority test obtained a p‐value less than 0.025, and the lower limits of the one‐sided 97.5% confidence interval were more than ?0.09. This meant that Fospropofol_FD 20 mg/kg was considered non‐inferior to propofol 2 mg/kg for the primary efficacy end‐point. Compared with propofol 2 mg/kg, Fospropofol_FD 20 mg/kg had a slower sedation efficacy. No serious adverse events were observed in the two groups. The sedation success rate within 5 min. after administration of Fospropofol_FD 20 mg/kg was non‐inferior to propofol 2 mg/kg, and Fospropofol_FD 20 mg/kg can be used for the induction of general anaesthesia safely.     

Clinical pharmacokinetics of verapamil in patients with atrial fibrillation

Summary The pharmacokinetic parameters and oral bioavailability of the antiarrhythmic drug verapamil were determined in six patients with atrial fibrillation. Plasma samples were taken following i.v. injection of verapamil 10 mg (Isoptin^® 2 ml), and oral verapamil 80 mg (Isoptin^® 2 tablets of 40 mg). Verapamil and its N-demethylated metabolite, norverapamil, were analyzed to 1 ng/ml plasma by gas chromatography-mass spectrometry using deuterated standards. Following intravenous injection, the disposition of verapamil followed a biexponential pattern with a fast distribution phase and a slower elimination phase (t_1/2=5.79 h), corresponding to a plasma clearance of 0.26 1/kg/h. After oral administration, only an elimination phase was evident, with the same elimination rate (t_1/2=5.53 h). The oral bioavailability was 10.5%±7.5%. The norverapamil formed after i.v. and oral administration of verapamil had plasma half-lives of 5.86 h and 6.77 h, respectively. The elimination of verapamil in patients with atrial fibrillation was decreased compared to that in healthy young volunteers and the oral bioavailability was lower. Very good correlation between the percentage reduction in heart rate and the log plasma concentration of verapamil was found in every patient during the elimination phase, irrespective of the route of administration. There was also a high correlation when the plasma concentration — effect data from all the patients were pooled (r=0.59,n=71;p<0.0005).     

Comparative Hemodynamic Effects of Levosimendan Alone and in Conjunction with 4-Aminopyridine or Calcium Chloride in a Rodent Model of Severe Verapamil Poisoning

Levosimendan (Levo) increases sensitivity of troponin-C to calcium, thus increasing myocardial contractility. It is also a vascular K+-ATP channel agonist producing peripheral vasodilation. Previous research with levosimendan revealed an increase in cardiac output (CO) but not blood pressure (BP) in experimental verapamil poisoning. Levosimendan’s K+-channel agonist properties may augment verapamil’s vasodilatory effects. 4-Aminopyridine (4-AP) is a K+-channel antagonist. It has successfully reversed hypotension in experimental verapamil poisoning. We hypothesized that coadministration of these agents may improve BP and CO in verapamil poisoning. Anesthetized, ventilated, and canulated male Wistar rats were poisoned with verapamil. Animals received one of six treatments, which are as follows: (1) n-saline infusion (control), (2) Levo 6.25 μg/kg loading dose and 36 μg/kg/h infusion, (3) 4-AP 2 mg/kg loading dose and infusion (4-AP), (4) Levo+4-AP, (5) CaCl₂ loading dose and infusion, and (6) Levo+CaCl₂. Hemodynamic parameters were recorded for 60 min. Outcome measures were changes in CO, BP, and heart rate (HR) compared to control. All groups had similar pretoxicity and peak toxicity CO (50% of pretoxicity value), BP (50% or pretoxicity value), and HR. Control group CO, BP, and HR progressively dropped during the verapamil infusion. Levosimendan produced a statistically significant improvement in CO (75% of pretoxicity level) but not BP in comparison to control. 4-AP produced a significant improvement in CO (110% of pretoxicity) and BP (78% of pretoxicity). Levo+4-AP and Levo+CaCl₂ groups improved CO (100% of pretoxicity) and BP (77% and 50% of pretoxicity, respectively), but there was no additive increase in CO or BP in animals compared to 4-AP or CaCl₂ alone. Levosimendan moderately improved CO but not BP in verapamil poisoning. The hypotensive effects of levosimendan were not overcome by coadministration of either 4-AP or CaCl₂. Levosimendan may not be an appropriate agent to use in the treatment of verapamil poisoning.     

Effect of Curcumin and its Analogue on Lipids in Carbon Tetrachloride–Induced Hepatotoxicity: A Comparative Study

Abstract

Curcumin and its analogue (bis.demethoxy curcumin analogue [BDMC-A]) were studied for their possible lipid-lowering properties in carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Carbon tetrachloride (3 ml kg^?1 wk^?1) administration to albino Wistar rats increased the levels of hepatic marker enzymes such as aspartate transaminase (AST), alkaline phosphatase (ALP), and γ.-glutamyl transferase (GGT) in the plasma. The levels of lipids cholesterol, triglycerides, and free fatty acids were also increased in plasma and tissues (liver, kidney, heart, and brain). Phospholipid levels increased in plasma, heart, and brain but decreased in liver and kidney. Curcumin (80 mg/kg) and BDMC-A (80 mg/kg) administration to CCl₄-treated rats for a period of 3 months significantly decreased the lipid levels. The effect exerted by BDMC-A was more prominent than that of curcumin. Studies on the histopathology of the liver are also in line with the biochemical parameters studied. These observations show the lipid-lowering efficacy of curcumin and its analogue in CCl₄-induced hepatotoxicity.     

Evaluation Of 5-hydroxy-2,3-diaryl (substituted)-cyclopent-2-en-1-ones as <Emphasis Type="Italic">cis</Emphasis>-restricted analogues of combretastatin A-4 as novel anti angiogenic and anticancer agents

Two potent cis-restricted CA-4 analogues 11 and 42 belonging to 2,3-diaryl-5-hydroxycyclopent-2-en-1-one class were evaluated for anticancer and anti angiogenic activity. The compound 42 displayed potent cytotoxic activity (IC₅₀ < 1 μM) against a panel of human cancer cell lines viz PTC, MDA.MB.453, PA1, SKOV3, DU145 and Miapaca2, whereas compound 11 displayed cytotoxicity activity (IC₅₀ < 1 μM) only in Miapaca2. Both the compounds inhibit growth factor stimulated endothelial cell proliferation, migration and capillary tube formation. In all the above parameter compound 42 was superior to 11. Based on the above results compound 42 was assessed for inhibition of vasculature in vivo and showed significant inhibition at 25 mg/kg dose. Further it was evaluated for in vivo anti tumor activity in athymic mice bearing DU145 and SKVO3 tumor xenograft and showed regression in tumor volume (T/C) of 23.8% (CA-4), 50.1% (compound 42) and 23.5% (CA-4), 56% (compound 42) respectively at a dose of 20 mg/kg (i.v.) daily for 14 days.     

Effects of Rb1 from the Panax notoginseng saponins on arrhythmia and Ca2+ movement in rat heart cells

We determined the antiarrhythmic effect of Rb₁ (from Panax notoginseng) on different arrhythmia models and its effect on cytoplasmic Ca²⁺ concentrations ([Ca²⁺]i) in rat heart cells with fura-2 fluorescence. At doses of 30 and 50 mg/Kg, Rb₁ produced an antirrhythmic effect on BaCl₂-induced ventricular tachyarrhythmia in rats, atrial fibrillation induced by CaCl₂-ACh, and ventricular fibrillation induced by chloroform in mice. The rest [Ca²⁺]i was 108 ± 10.7 nM in the freshly isolated rat heart cells. Sixty mM KCl caused an increase in [Ca²⁺]i to 379.4 ± 77 nM. Rb₁ from 0.1 to 0.8 mM significantly reduced this increase in a concentration-dependent manner. mM Rb₁ (0.4 mM) also completely inhibited the increase in [Ca²⁺]i induced by 1 μM isoprenaline. The radioligand binding study in rat heart cells showed that Rb₁ did not change the B_max and K_d values of [³H]-dihydroalprenolol binding. These data suggest Rb₁ can inhibit Ca²⁺ entry through voltage-dependent and receptor-linked Ca²⁺ channels, and that this is related to its antiarrhythmic effect. Drug Dev. Res. 39:179–183. © 1997 Wiley-Liss, Inc.     

Assessment of CYP3A‐mediated drug–drug interaction potential for victim drugs using an in vivo rat model

The present study aims to determine if an in vivo rat model of drug–drug interaction (DDI) could be useful to discriminate a sensitive (buspirone) from a ‘non‐sensitive’ (verapamil) CYP3A substrate, using ketoconazole and ritonavir as perpetrator drugs. Prior to in vivo studies, ketoconazole and ritonavir were shown to inhibit midazolam hydroxylation with IC₅₀ values of 350 ± 60 nm and 11 ± 3 nm , respectively, in rat liver microsomes (RLM). Buspirone and verapamil were also shown to be substrates of recombinant rat CYP3A1/3A2. In the rat model, the mean plasma AUC_0‐inf of buspirone (10 mg/kg, p.o.) was increased by 7.4‐fold and 12.8‐fold after co‐administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. The mean plasma AUC_0‐inf of verapamil (10 mg/kg, p.o.) was increased by 3.0‐fold and 4.8‐fold after co‐administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. Thus, the rat DDI model correctly identified buspirone as a sensitive CYP3A substrate (>5‐fold AUC change) in contrast to verapamil. In addition, for both victim drugs, the extent of DDI when co‐administered was greater with ritonavir compared with ketoconazole, in line with their in vitro CYP3A inhibition potency in RLM. In conclusion, our study extended the rat DDI model applicability to two additional victim/perpetrator pairs. In addition, we suggest that use of this model would increase our confidence in estimation of the DDI potential for victim drugs in early discovery. Copyright © 2013 John Wiley & Sons, Ltd.     

Antinociceptive and anti-inflammatory activities of the Jatropha isabellei dichloromethane fraction and isolation and quantitative determination of jatrophone by UFLC-DAD

Context: Jatropha isabellei Müll. Arg. (Euphorbiaceae) has been used in the traditional medicine to treat arthritis.

Objective: To evaluate the anti-inflammatory and antinociceptive activities of the dichloromethane fraction (DF_Ji) from underground parts of J. isabellei, and to develop an analytical method to quantify the diterpene jatrophone.

Materials and methods: Anti-inflammatory and antinociceptive activities of the DF_ji were determined by an acute arthritis model through assessment of the paw elevation time (PET) and articular diameter (AD) of Wistar rats treated orally (50, 100 or 200?mg/kg in a single-dose), and intravenously (0.1, 1, 10, 25 or 50?mg/kg in a bolus administration). The isolation of jatrophone from the DF_ji was carried out and confirmed by spectroscopic techniques. A UFLC-DAD method was developed and validated.

Results: When orally administered, the highest dose (200?mg/kg) of DF_Ji was able to significantly reduce the PET to 24.8?±?1.4?s (p?p?_Ji at dose of 200 and 10?mg/kg significantly prevented the formation of edema, reducing the AD in 25.3% and 32.5% (p?Discussion and conclusion: The DF_Ji displayed antinociceptive and antiedematogenic activities, representing a promising plant product for the arthritis treatment.     

Enhanced bioavailability of verapamil after oral administration with hesperidin in rats

The aim of this study was to investigate the effects of hesperidin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of hesperidin (3 or 10 mg/kg). Compared to the control group, the presence of hesperidin significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 71.1–96.8% and the peak concentration (C_max) of verapamil by 98.3–105.2%. Hesperidin significantly (p<0.01) decreased the total plasma clearance (CL/F) of verapamil by 41.6–49.2% in rats. However there was no significant change in the time to reach the peak plasma concentration (T_max), the elimination rate constant (K_el) and the terminal half-life (T_1/2) of verapamil in the presence of hesperidin. The AUC and C_max of norverapamil were significantly (p<0.05) higher in rats coadministrated with hesperidin than those of the control. Consequently hesperidin significantly enhanced bioavailability of verapamil in rats. These results might be due to the decreased efflux and metabolism of verapamil in the intestine. Drug interactions should be concerned in the clinical setting when verapamil is used concomitantly with hesperidin or hesperidin-containing dietary.     

Differential regulation of rat peripheral 5-HT<Subscript>2A</Subscript> and 5-HT<Subscript>2B</Subscript> receptor systems: influence of drug treatment

Most studies of 5-HT₂ receptor regulation have been carried out on the central nervous system (CNS) (which expresses 5-HT_2A and 5-HT_2C receptors); very few in vitro studies have addressed the peripheral receptors 5-HT_2A and 5-HT_2B. The aim of this investigation was to compare the possible short- and long-term processes regulating these peripheral receptors in the rat.The in vitro contractile response elicited by serotonin (5-HT, 10 µM) in the rat gastric fundus (5-HT_2B receptor system) was rapid and followed by a partial fade to a steady state, in contrast with the rat thoracic aorta response (5-HT_2A receptor system), which was more stable, slower and sustained. To characterize drug-receptor interactions, cumulative concentration/response curves (CCRCs) for 5-HT were constructed ex vivo for rat tissues treated with drugs acting at these receptors. Rats were examined 4 or 24 h after a single, i.p. administration of (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI, 1 or 2.5 mg/kg], clozapine, cyproheptadine or rauwolscine (10 mg/kg), 48 h after a single i.p. administration of (±)DOI (2.5 mg/kg), clozapine or cyproheptadine (10 mg/kg) or 24 h after the last of with 15 daily i.p. administrations of (±)DOI (1 or 2.5 mg/kg), clozapine, cyproheptadine or rauwolscine (10 mg/kg). In the aorta, E_max (the maximum response elicited by 5-HT) was unchanged 4 h after a single dose of any of the drugs tested. However, 24 h after a single dose, E_max was lower in animals treated with (±)DOI (2.5 mg/kg), clozapine or cyproheptadine than in controls, whilst 48 h after a single dose of (±)DOI (2.5 mg/kg), clozapine or cyproheptadine there was no difference in E_max between experimental and control animals. After chronic treatment with (±)DOI (2.5 mg/kg), clozapine and cyproheptadine, E_max was lower than in controls. In the gastric fundus, E_max 4 h after a single dose of each drug was lower than in controls, and the response recovered by 24 or 48 h. Following chronic treatment, E_max was significantly lower than in controls for each drug used.These findings suggest first, that regulation of peripheral 5-HT₂ receptors (5-HT_2A and 5-HT_2B) is a functionally significant phenomenon in vivo, and occurs after administration of both agonists and antagonists. Second, the kinetics of peripheral 5-HT₂ receptor regulation were similar in both in vivo and ex vivo experiments. The 5-HT_2B receptors in rat gastric fundus are more sensitive to drug-induced regulation than the 5-HT_2A rat aortic receptors. Finally, long-term regulation of both receptors stabilizes short-term desensitization for longer.     

Buspirone-induced antinociception is mediated by <Emphasis Type="SmallCaps">l</Emphasis>-type calcium channels and calcium/caffeine-sensitive pools in mice

Rationale. Previous studies have shown that buspirone, a partial 5-HT_1A receptor agonist, produces antinociceptive effects in rats and mice; Ca²⁺ plays a critical role as a second messenger in mediating nociceptive transmission. 5-HT_1A receptors have been proven to be coupled functionally with various types of Ca²⁺ channels in neurons, including N-, P/Q-, T-, or L-type. It was of interest to investigate the involvement of extracellular/intracellular Ca²⁺ in buspirone-induced antinociception. Objectives. To determine whether central serotonergic pathways participate in the antinociceptive processes of buspirone, and investigate the involvement of Ca²⁺ mechanisms, particularly L-voltage-gated Ca²⁺ channels and Ca²⁺/caffeine-sensitive pools, in buspirone-induced antinociception. Methods. Antinociception was assessed using the hot-plate test (55°C, hind-paw licking latency) in mice treated with either buspirone (1.25–20 mg/kg i.p.) alone or the combination of buspirone and fluoxetine (2.5–10 mg/kg i.p.), 5-HTP (25 mg/kg i.p.), nimodipine (2.5–10 mg/kg i.p.), nifedipine (2.5–10 mg/kg i.p.), CaCl₂ (25–200 nmol per mouse i.c.v.), EGTA (5–30 nmol per mouse i.c.v.), or ryanodine (0.25–2 nmol per mouse i.c.v.). Results. Buspirone dose dependently increased the licking latency in the hot-plate test in mice. This effect of buspirone was enhanced by fluoxetine, 5-HTP, nimodipine, and nifedipine. Interestingly, central administration of Ca²⁺ reversed the antinociceptive effects of buspirone. In contrast to these, ryanodine or EGTA administered centrally potentiated buspirone-induced antinociception. Conclusions. Decreasing neuronal Ca²⁺ levels potentiated buspirone-induced antinociception; conversely, increasing intracellular Ca²⁺ abolished the antinociceptive effects of buspirone. These results suggest that Ca²⁺ influx from extracellular fluid and release of Ca²⁺ from Ca²⁺/caffeine-sensitive microsomal pools may be involved in buspirone-induced antinociception. Electronic Publication