Hypotensive and bradycardic effects of talipexole (B-HT 920) in anaesthetized rabbits are antagonized by metoclopramide but not by yohimbine

Summary The interactions of talipexole (B-HT 920) and clonidine with selective -adrenoceptor antagonists, yohimbine (a ₂) and prazosin (a ₁), as well as with dopamine receptor antagonists, metoclopramide (D₂), domperidone (D₂) and SCH23 390 (D₁) were investigated in anaesthetized rabbits after i. v. administration.Both talipexole (0.03–0.1 mg/kg) and clonidine (0.01–0.03 mg/kg) dose-dependently induced hypotension and bradycardia. Talipexole had a shorter duration of action.The hypotensive effect of the ₂-adrenoceptor and D₂ agonist talipexole (0.03 mg/kg) was antagonized by pretreatment with metoclopramide (3 mg/kg) or domperidone (0.3–3 mg/kg),but not with yohimbine (3 mg/kg),prazosin (0.1 mg/kg) orSCH 23 390 (1 mg/kg). Its bradycardic effect was antagonized only by metoclopramide (3 mg/kg). The hypotensive and bradycardic effects of clonidine (0.03 mg/kg) were most effectively antagonized by yohimbine (0.3–3 mg/kg).These findings indicate that in anaesthetized rabbits after i. v. administration, talipexole may lower blood pressure by peripheral, and heart rate by central, dopamine D₂ agonism.Parts of the results were presented at the 33rd Spring Meeting of the German Pharmacological and Toxicological Society in Mainz, March 10–12, 1992 (Palluk R, Schilling JC, Stockhaus K, Peil H (1992) Naunyn-Schmiedeberg's Arch Pharmacol 345:R82)Correspondence to R. Palluk at the above address     

Neurobehavioral effects of racemic threo-methylphenidate and its D and L enantiomers in rats

D,L-methylphenidate (Ritalin) is used to treat attention deficit hyperactivity disorder (ADHD) in children. The therapeutic effect is predominantly due to the d enantiomer. Dexmethylphenidate (D-MPH; Focalin) was therefore developed for its better therapeutic index. The present study determined and compared the acute behavioral toxicity of D,L-MPH, D-MPH and L-MPH in rats after oral dosing. Comprehensive functional observational battery (FOB) evaluations and rota-rod tests were performed 30, 60 and 120 min after dosing. Ten rats/sex/dose were administered a single dose of vehicle, 2, 20, 100 mg/kg D,L-MPH and 1, 10, 50 mg/kg D-MPH or 1, 100, 500 mg/kg L-MPH. There was no mortality. Certain FOB evaluations were statistically significant from vehicle control at any of the time points with most occurring at 60 and 120 min in the high D,L-MPH dose. These included increases in rearing, difficulty in removal from box, arousal, click, tail-pinch and decreases in hind-limb splay distance, hind-limb grip strength and handling reactivity. Behavioral responses were also present at the mid-dose D,L-MPH and high dose D- and L-MPH. Responses in female were significantly different from males in D,L- and L-MPH groups suggesting a sex difference in sensitivity. In the rota-rod test, mean latency to remain on the rod was significantly less for males compared to control given high dose D-MPH and D,L-MPH. In females, latency times were significantly less for high doses of all three compounds. In summary, fewer significant FOBs were seen with D- and L-MPH compared to equimolar doses of D,L-MPH. L-MPH was the least potent in producing FOBs. These results were supported by rota-rod studies.     

Pressor effects of acetylcholine injected into the lateral septal area of conscious rats

Injections of acetylcholine (ACh) into the lateral septal area (LSA) caused blood pressure increases in unanesthetized freely moving rats. ACh was injected in the dose range of 0.1–54 nmol/500 nl using regular metal needles (200 μm o.d.). In the LSA, injections of carbachol or ACh (2.5 nmol/500 nl) were equipotent ( + 22 ± 2 and + 19 ± 3 mmHg, respectively) suggesting the existence of an ACh-sensitive pressor site in the LSA. Maximum responses to ACh injected either intracerebroventricularly (i.c.v.) or into the LSA were not significantly different ( + 23 ± 1 and +21 ± 2 mmHg, respectively). However, the ED₅₀ for the injection into the LSA (0.24 nmol) was significantly lower than that observed after i.c.v. injection (2.6 nmol), ruling out a possible leakage of ACh from the LSA and into the ventricular space. This idea is supported by data showing that the effect of the intraseptal injection of 30 nmol of ACh was blocked by pretreatment with 3 nmol of atropine either i.c.v. or into the LSA, whereas the effects of i.c.v. ACh were completely blocked by i.c.v. atropine, but only partially (42%) when atropine was injected into the LSA. The idea of the existence of an ACh-sensitive site in the LSA is further supported by the more direct observation that injections of 30 nmol/100 nl of ACh into the LSA using glass needles (50–70μ m o.d.) caused similar pressor responses. Neither the i.v. pretreatment with pentolinium or adrenalectomy affected the response to 30 nmol/500 nl of ACh injected into the LSA, ruling out the involvement of the sympathetic nervous system. The responses to ACh injected either i.c.v. or into the LSA were blocked by i.v. pretreatment with the vasopressin antagonist d(CH2)5Tyr(Me)-vasopressin. In addition, the response to ACh injected into the LSA was also blocked by hypophysectomy, further suggesting a major involvement of circulating vasopressin. The pressor response to intraseptal ACh was significantly reduced by local pretreatment with pirenzepine or 4-DAMP at the equimolar dose of 6.7 nmol, confirming the involvement of M₁-muscarinic receptors in the pressor response to ACh. The existence of a cholinergic muscarinic mechanism in the LSA that mediates pressor responses through the release of vasopressin is proposed.     

Enhancement of the haemodynamic effects of NG-monomethyl-L-arginine by transforming growth factor-beta 1 in conscious, normal, but not endotoxaemic, rats.

1. Male, Long Evans rats (350-450 g) were chronically instrumented for the measurement of regional haemodynamics, and the effects of TGF-beta 1 (25 micrograms kg-1 i.v. bolus) were assessed during infusion of saline (n = 9) or lipopolysaccharide (LPS, 150 micrograms kg-1 h-1; n = 12). In the same animals, responses to NG-monomethyl-L-arginine (L-NMMA 10 mg kg-1 bolus; 10 mg kg-1 h-1 infusion) were determined 18 h after administration of TGF-beta 1. In a separate experiment, the effects of the endothelin antagonist, SB 209670 (10 micrograms kg-1 min-1) on responses to TGF-beta 1 and to L-NMMA subsequently, were determined. 2. In the absence of LPS, TGF-beta 1 had slow-onset bradycardic and pressor effects accompanied by mesenteric and hindquarters, but not renal, vasoconstriction. Eighteen hours after TGF-beta 1, these effects had gone, but the bradycardic, pressor, and mesenteric vasoconstrictor responses to L-NMMA were enhanced. The haemodynamic changes following TGF-beta 1, and the augmentation of the subsequent responses to L-NMMA, were inhibited by SB 209670. These results are consistent with TGF-beta 1 stimulating the synthesis and release of endothelin, and an involvement of the latter in responses to L-NMMA. 3. The pressor effects of TGF-beta 1 were similar in LPS-infused and saline-infused animals, but in the former group the mesenteric vasoconstriction was enhanced and the hindquarters vasoconstriction diminished. Since, in the absence of TGF-beta 1, LPS-infused animals showed a developing hindquarters vasodilatation and mesenteric vasoconstriction, it is feasible that, in the presence of TGF-beta 1 and LPS together, the haemodynamic profile represented an amalgam of the individual effects of the two interventions, rather than a specific effect of TGF-beta 1 on the haemodynamic sequelae of endotoxaemia. 4. In the presence of LPS, haemodynamic responses to L-NMMA were suppressed, and TGF-beta 1 generally did not affect this suppression. A possible explanation of this observation is that LPS increased circulating endothelin levels, and thus resulted in desensitization to the effects of endothelin released following administration of L-NMMA.     

大鼠体内硝基精氨酸的手性代谢动力学

目的　应用毛细管电色谱 (CEC)对大鼠体内的硝基精氨酸手性转化和代谢动力学进行研究。方法　采用手性配体交换法检测大鼠血浆中D型硝基精氨酸 (D NNA)和L型硝基精氨酸(L NNA)的浓度,应用非房室模型对所获得的血药浓度-时间数据进行拟合,计算药动学参数。结果　D NNA和L NNA在大鼠体内代谢具有明显的异构体选择性,清除率分别为(0 46±0 02)ml·h-1·kg-1和(0 17±0 03)ml·h-1·kg-1 (P<0 05 );T1 /2分别为 ( 1 44±0 28 )h和(3 48±0 41)h(P<0 05)。D NNA到L NNA的单项手性转化率为(50 03±8 5)%。结论　D NNA和L NNA在大鼠体内的代谢有明显的异构体选择性 (其差异可能主要源于D NNA到L NNA的单向手性转化)。     

Prazosin potentiates the acute hypotensive effects of nitroglycerin but does not attenuate nitrate tolerance in normal conscious rats

Sympathetic activation has been suggested as a mechanism of acute nitrate tolerance, but the available literature is not definitive. We investigated the effects of prazosin, an alpha1-adrenoceptor antagonist, on acute nitroglycerin (NTG) hemodynamics and tolerance development in normal conscious rats. The effect of prazosin bolus injection (300 microg/kg) on NTG hemodynamics was first determined after acute dosing. The extent of maximal mean arterial pressure (MAP) response and the duration of drug-induced hypotension to NTG bolus doses (5, 15, and 30 microg) were measured before and after prazosin. In separate studies, the effects of prazosin on NTG tolerance development were examined. Rats received either 10 microg/min NTG or vehicle infusion for 5 hours after predosing with prazosin (300 microg/kg). Maximal MAP response to the hourly 30-microg NTG i.v. bolus challenge dose (CD) was determined before and after prazosin, and during NTG or vehicle infusion. Our results showed that bolus doses of NTG (at 5, 15, and 30 microg) dose-dependently decreased maximal MAP by 20.8 +/- 5.8, 26.1 +/- 5.0, and 30.6 +/- 5.7 mm Hg, respectively. Prazosin caused an average of 16 mm Hg depression in MAP, and it only slightly potentiated the hypotensive effects of bolus doses of NTG both after acute dosing and during continuous infusion. Prazosin treatment prolonged the duration of NTG-induced MAP response by about 4-fold for all NTG doses examined (P < 0.01 versus corresponding dose before prazosin, ANOVA). In both prazosin-treated and untreated groups, NTG infusion significantly attenuated the MAP response of the NTG CD starting from 1 hour of infusion (P < 0.001 versus 0 hour response, ANOVA), confirming tolerance development. In the presence of NTG tolerance development, prazosin no longer enhanced the apparent duration of NTG action. The hypotensive effect produced by the 30-microg NTG CD lasted for 7 +/- 2 and 10 +/- 2 seconds for prazosin-treated and untreated groups, respectively (P > 0.05, ANOVA). Our results showed that, in both NTG-tolerant and control animals, prazosin only slightly potentiated the maximum hypotensive effects of a challenge NTG dose, but did not significantly alter the pharmacodynamics of NTG-induced hemodynamic tolerance. Thus, in our animal model, sympathetic blockade by prazosin neither prevented nor attenuated in vivo tolerance induced by NTG.     

Co-administration of toluene and xylene antagonized the testicular toxicity but not the hematopoietic toxicity caused by ethylene glycol monoethyl ether in Sprague-Dawley rats.

Occupational painters are exposed to ethylene glycol monoethyl ether (EGEE), a widely used emulsifying solvent known to cause testicular degeneration and bone marrow depression, together with toluene (TOL) and xylene (XYL) as a mixture. In the previous study (Chung et al., Tox. Lett. 104:143, 1999), testicular atrophy caused by EGEE (200 mg/kg) was shown to be antagonized by co-administration of TOL (250 mg/kg) and XYL (500 mg/kg). This study was conducted to provide histological support for the previously observed antagonistic protective effect of TOL + XYL on EGEE inducible testicular toxicity and to determine whether a similar antagonistic effect can be demonstrated against the EGEE derived hematopoietic toxicity. Compared to the extent of seminiferous tubule degeneration caused by EGEE (150 mg/kg, six times per week for 4 weeks), testes of rats given co-administration of TOL (250 mg/kg) + XYL (500 mg/kg) showed dramatically reduced tubular degeneration. Hyperplasia of Leydig cells in the interstitium was observed in both EGEE and EGEE + TOL + XYL-treated rats. Although a minimal dose of EGEE causing testicular atrophy was used, WBC and platelet counts were decreased significantly. In the TOL + XYL-treated control group, the WBC and platelet counts were not decreased. However, the bone marrow depression caused by EGEE was not reversed by the combined administration of TOL + XYL. In all experimental groups (EGEE alone, TOL + XYL, EGEE + TOL + XYL), plasma levels of creatinine and alkaline phosphatase were significantly decreased. In addition to the marked testicular atrophy, EGEE also decreased the weights of adrenal glands and epididymis. In conclusion, while the testicular degeneration caused by EGEE was antagonized by TOL + XYL, the EGEE derived hematopoietic suppression was not reversed.     

Pressor sensitivity to exogenous vasopressin in conscious, adult rats treated neonatally with capsaicin.

Pressor responses to exogenous arginine vasopressin were assessed in adult rats that had been treated neonatally with capsaicin or its vehicle. Measurements were made under control conditions, after inhibition of baroreflexes (with pentolinium), and after inhibition of baroreflexes (with pentolinium) and the production of angiotensin II (with captopril). Resting arterial blood pressures and pressor sensitivities to exogenous arginine vasopressin were similar in capsaicin-treated and vehicle-injected rats. Sixty minutes after the administration of pentolinium, systolic and diastolic blood pressures were reduced in both groups of rats and the pressor responses to arginine vasopressin were similarly and significantly enhanced. In both groups of rats 60 min after administration of pentolinium and captopril, systolic and diastolic blood pressures were lower than in the presence of pentolinium alone, but pressor responses were not different from those seen in control conditions. The possibility that the present results are explicable in terms of baroreflexes, the renin-angiotensin system and endogenous vasopressin interacting to influence the pressor sensitivity to exogenous vasopressin is discussed. From the present findings, it seems that our previous observation of impaired, vasopressin-mediated blood pressure recovery following acute hypotension in capsaicin-treated rats cannot be attributed to a reduced pressor sensitivity to the hormone.     

毛细管电色谱手性配体交换法检测生物样品中的硝基精氨酸异构体研究

目的：建立毛细管电色谱（CEC）分离检测生物样品中硝基精氨酸异构体的方法。方法：采用CEC手性配体交换模式检测血浆样品中D-硝基精氨酸（D—NNA）和L-硝基精氨酸（L—NNA），流动相为50mmol／L醋酸缓冲液[pH5．0，含2mmol／Laspartame，1mmol／L Cu^2＋和5％（v／v）甲醇]；流速为0．02mL／min；操作压为1000psi；检测波长为UV280nm。结果：L—NNA和D—NNA在0．025～0．75mmol／L的浓度范围内峰面积／浓度的相关系数均可达0．99以上，日内变异系数均小于3．0％，日间变异系数分别为3．1％和3．4％。结论：本研究方法具有快速、高分辨、检测样品量和流动相用量少等优点。     

Strain-dependent effects of anandamide on memory consolidation in mice are antagonized by naltrexone

Post-training administration of anandamide (1.5, 3, 6 mg/kg) dose-dependently impaired retention of an inhibitory avoidance response in DBA/2 mice, while improving it in C57BL/6 mice. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. They were observed when drug was given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. These effects of anandamide parallel those of opioid agonists, as previously reported. Moreover, the opioid antagonist naltrexone improved retention in DBA/2 mice, while impairing it in C57BL/6 mice. Pre-treatment with the opioid antagonist at a non-effective dose (0.1 mg/kg) antagonized the effects of anandamide on memory consolidation in both strains. These results strongly suggest that endogenous cannabinoids affect memory processes through opioid systems. The possible involvement of other neurotransmitter systems, such as dopamine, in strain-dependent effects of anandamide in memory consolidation is discussed.     

(R)-Methanandamide and delta9-tetrahydrocannabinol-induced operant rate decreases in rats are not readily antagonized by SR-141716A

The current study examined the interaction between the cannabinoid CB(1) receptor agonists Delta(9)-tetrahydrocannabinol and (R)-methanandamide in combination with the cannabinoid CB(1) receptor antagonist SR-141716A (N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl) in rats responding for food on a fixed ratio (FR-10) schedule of food reinforcement. The study provided only limited evidence for antagonism by SR-141716A (at 1 mg/kg but not with 0.3, 3 and 10 mg/kg) of the rate suppressant effects induced by the cannabinoid CB(1) receptor agonist Delta(9)-tetrahydrocannabinol (and only at the single dose of 5.6 mg/kg Delta(9)-tetrahydrocannabinol). (R)-Methanandamide in combination with SR-141716A resulted in a greater rate suppression compared to that induced by (R)-methanandamide alone. Thus, SR-141716A augmented the rate-decreasing effects of (R)-methanandamide and only minimally altered the rate-decreasing effects of Delta(9)-tetrahydrocannabinol. Additionally, high doses (10 and 30 mg/kg) of SR-141716 singly consistently suppressed the rate of responding. The current results coupled with our previous data examining combinations of Delta(9)-tetrahydrocannabinol or (R)-methanandamide and SR-141716 (see text) underscore pharmacological/behavioral differences (whether quantitative or qualitative) between the cannabinoid CB(1) agonists (R)-methanandamide and Delta(9)-tetrahydrocannabinol revealed by their interactions with the cannabinoid CB(1) antagonist SR-141716.     

Pressor and vasoconstrictor effects of methylene blue in endotoxaemic rats

Nitric oxide (NO) is a primary mediator of hypotension in sepsis. We examined the effects of methylene blue (MB), an inhibitor of the NO/cGMP pathway, on mean arterial pressure (MAP), cardiac output (CO), total peripheral resistance (TPR), mesenteric blood flow (MBF) and renal blood flow (RBF) in pentobarbitone-anaesthetised rats injected with lipopolysaccharide (LPS, 7.5 mg/kg). MB (1, 3 or 10 mg/kg.h) or vehicle was i.v. infused into four groups at 2.5 h after i.v. injection of LPS. Two other groups received MB or vehicle at 2.5 h after receiving saline. LPS reduced MAP, CO, RBF as well as MBF at 2.5 and 4 h, and increased TPR at 2.5 but not 4 h. Whereas MB alone had no effects on measured variables in control rats at 4 h, in LPS-treated rats, it elevated TPR at all doses and attenuated the fall in MAP at the two low doses. CO was unaltered by low doses of MB but reduced by the high dose. MBF was unaltered, but RBF was increased by the lowest dose but decreased by the highest dose of MB. Therefore, in endotoxaemia, a low dose of MB increases MAP and TPR but does not alter CO; a high dose of MB does not raise MAP but increases TPR and reduces CO. Received: 13 December 1997 / Accepted: 23 February 1998     

Impaired renal vascular response to a D1-like receptor agonist but not to an ACE inhibitor in conscious spontaneously hypertensive rats.

The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D1-like receptor is impaired in SHR, we examined the effect of a continuous infusion of the D1-like receptor agonist fenoldopam (2 microg/kg/min) on systemic and renal hemodynamics in conscious SHRs and Wistar-Kyoto (WKY) rats. As an active control, we used an equivalent antihypertensive dosage of captopril (10 mg/kg). Fenoldopam significantly increased effective renal plasma flow (ERPF) in WKY rats (+22 +/- 5%; p < 0.01), whereas this response was absent in SHRs (+7 +/- 3%; NS). Mean arterial pressure (MAP) was significantly reduced in SHRs (-11 +/- 2%; p < 0.001), demonstrating a systemic vasodilator response to fenoldopam in SHRs. The reduction in renal vascular resistance (RVR) was more pronounced in WKY rats (-24 +/- 2%) than in SHRs (-13 +/- 4%; p < 0.05). Captopril significantly increased ERPF in SHRs (+16 +/- 3%; p < 0.001), demonstrating a preserved renal vasodilatory capacity in SHRs. The blunting of the renal vasodilatory response to fenoldopam in SHRs is present during a high as well as a low sodium intake. In conscious SHRs, the renal vasodilatory response to a D1-like receptor agonist is impaired, whereas the blood pressure response is more pronounced. The preserved renal vasodilatory response to captopril indicates that the defective vasodilatory response in SHRs is functional rather than due to altered structural properties of the renal vascular bed.     

Antagonism of diazepam's anticonflict effects in rats by nicotine,but not by arecoline

The purpose of the present study was to determine the possible role of cholinergic mechanisms in the anticonflict effects of the anxiolytic diazepam. Male Sprague-Dawley rats were tested with a modified Geller-Seifter procedure using a multiple reinforcement schedule in which unpunished responding in one component was reinforced according to a fixed-interval 60-sec schedule, and punished responding in the other component resulted in both food and a brief electric shock presentation according to a fixed-ratio 1 schedule. In Experiment 1 (?)-nicotine antagonized the increase in punished responding that was produced by diazepam. In Experiment 2 diazepam produced selective increases in punished responding that again was antagonized by (?)-nicotine, a nicotinic cholinergic agonist, whereas arecoline, a muscarinic cholinergic agonist, did not antagonize diazepam's increase in punished responding. Neither drug produced any significant changes in unpunished responding. In Experiment 3 it was shown that the centrally acting nicotinic antagonist, mecamylamine, was able to block nicotine's antagonism of diazepam. These results suggest that there is an interaction between central nicotinic cholinergic mechanisms and diazepam's anticonflict effects in this animal model for anxiolytics, and support clinical observations that smoking can reduce some effects of benzodiazepines. © 1994 Wiley-Liss, Inc.     

Dopamine D2 autoreceptors in rats are behaviorally functional at 21 but not 10 days of age

Previous studies used either racemic 3-(3-hydroxyphenyl)-N-n-propylpiperidine [(±)-3-PPP] or lower doses of the mixed dopamine (DA) D₁/D₂ agonist apomorphine (APO) to conclude that brain DA D₂ autoreceptors are not behaviorally functional until 28 days of age. The purpose of this study was to provide behavioral evidence for functional D₂ autoreceptors before 28 days of age using DA agonists with greater selectivity for D₂ autoreceptors. The locomotor activity of 10-, 21-, 35-day-old and adult rats was monitored after injection of a D₂ autoreceptor agonist. There were significant decreases in the locomotor activity of 21-, 35-day-old, and adult rats injected with (-)-3-PPP, SND 919, or PD 128483. Lower doses of APO significantly decreased the activity of adult and 35-day-old rats but not younger rats. The only significant effect on the locomotor activity of 10-day-old rats was an increase in activity after injection of APO, 0.01 mg/kg or higher, or B-HT 920, 0.01 mg/kg. The results suggest that brain DA D₂ autoreceptors are behaviorally functional at 21, but not 10, days of age.     

Behavioural and ECoG spectrum changes induced by intracerebral infusion of interferons and interleukin 2 in rats are antagonized by naloxone.

Rat interferon, alpha-interferon, interleukin 2 and recombinant interleukin-2 injected into the third cerebral ventricle produced typical behavioural sedation and/or sleep and ECoG synchronization in rats while beta-interferon produced no behavioural sleep or ECoG synchronization. A slight sedation was observed after the largest dose of beta-interferon only. During sleep induced by lymphokines, a dose-dependent increase in total voltage power as well as in the 0.5-3, 4-7 and 12-16 Hz frequent bands was observed. Much smaller doses were required to produce similar behavioural and ECoG spectrum effects after infusion of interferons and interleukin-2 into the locus coeruleus. No significant behavioural and ECoG changes were obtained after infusion of the same doses of interferons and interleukin-2 into other areas of the brain (caudate nucleus, dorsal hippocampus, substantia nigra pars compacta, ventromedial hypothalamus). The behavioural and ECoG effects of alpha-interferon, rat interferon and interleukin-2 were blocked in animals pretreated with naloxone. These results are consistent with the hypothesis that the behavioural and ECoG effects of these lymphokines are mediated at locus coeruleus level by stimulation of opiate receptors.     

Nomifensine enantiomers: Psychopharmacological effects in mice and rats in comparison with D,L-nomifensine

The D- and L-enantiomers of nomifensine (8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydrois-oquinoline) were tested for psychopharmacological effects in mice and rats with D,L-nomifensine hydrogen maleate as a reference drug. In tests on antidepressant activity (antagonism of tetrabenazine ptosis, reserpine hypothermia, oxotremorine hypothermia, “behavioral despair,” and potentiation of yohimbine toxicity), the D-enantiomer was on average 1.7 or 2.8 times more potent than the racemate with the intraperitoneal (i.p.) or oral route of administration, respectively. The L-enantiomer displayed slight ativity only when injected i.p. and was on average ≥ 30 times less potent than the racemate. In tests on dopaminergic acivity, D-nomifensine was about 3 times (motor stimulation in mice) or 1.5–1.9 times (induction of stereotyped behavior in rats) more potent than the racemate. The L-enantiomer was devoid of stimulant or stereotypic activity and had a rather sedative effect. In acute (24 h) toxicity studies, D-nomifensine proved 2.9 or 4.5 times more toxic, and L-nomifensine was 1.6 or 1.3 times less toxic than the racemate (i.p. or p.o., respectively). The results indicate that nomifensine acts by stereospecific mechanisms and that the D-enantiomer is the active component.     

Pressor response to beta 1- and beta 2-blockers in conscious rats treated with phentolamine

The purpose of this study was to examine the conditions whereby beta-blockers cause a pressor response in conscious, unrestrained rats: (1) whether beta-blockers cause a pressor response in rats subjected to, or not subjected to, nonselective alpha-blockade with phentolamine; (2) whether the pressor response to beta-blockers is due to the blockade of vasodilator beta 2-adrenoceptors, and (3) whether it is due to an acute increase in the release of adrenaline (A) and noradrenaline (NA). In the first series of experiments cumulative dose-response curves for propranolol, atenolol and ICI 118,551, nonselective beta-, beta 1- and beta 2-selective antagonists, respectively, were constructed in rats subjected to a continuous intravenous infusion of phentolamine. The administration of each of the beta-antagonists caused a significant dose-dependent increase in mean arterial pressure (MAP). The ED50 values for the increase in MAP were found to be 3.6 +/- 0.8, 10 +/- 2.6 and 4.6 +/- 0.8 micrograms/kg for propranolol, atenolol and ICI 118,551, respectively. In the second series of experiments, a single bolus injection of a selective or nonselective beta-antagonist or saline vehicle was given to rats subjected to a continuous intravenous infusion of phentolamine. Plasma levels of A and NA were determined in the control condition, during the infusion of phentolamine and again after the injection of a beta-antagonist. The infusion of phentolamine significantly decreased MAP and increased plasma levels of A and NA.(ABSTRACT TRUNCATED AT 250 WORDS)