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Rabbits were fed Moringa oleifera (200mg/kg/day, p.o.) or lovastatin (6mg/kg/day, p.o.) in banana pulp along with standard laboratory diet and hypercholesterolaemic diet for 120 days. Moringa oleifera and lovastatin were found to lower the serum cholesterol, phospholipid, triglyceride, VLDL, LDL, cholesterol to phospholipid ratio and atherogenic index, but were found to increase the HDL ratio (HDL/HDL-total cholesterol) as compared to the corresponding control groups. Treatment with M. oleifera or lovastatin in normal rabbits decreased the HDL levels. However, HDL levels were significantly increased or decreased in M. oleifera- or lovastatin-treated hypercholesterolaemic rabbits, respectively. Lovastatin- or M. oleifera-treated hypercholesterolaemic rabbits showed decrease in lipid profile of liver, heart and aorta while similar treatment of normal animals did not produce significant reduction in heart. Moringa oleifera was found to increase the excretion of faecal cholesterol. Thus, the study demonstrates that M. oleifera possesses a hypolipidaemic effect.

Influence of chronic treatment of rats with and calcium channel blockers (CCBs) and isoprenaline (ISP) on responses to noradrenaline (NA) was investigated on electrically--driven isolated right ventricle preparations. The ventricles were obtained from animals treated with chronic ISP or CCBs alone and chronic nifedipine, verapamil, diltiazem or nimodipine plus chronic ISP. A decreased response to NA as evidenced by an increase in EC50 for contraction which was observed in chronic ISP- treated preparations may be due to development of desensitisation (down-regulation) of beta-adrenoceptors. In chronic CCB-treated preparations there was a significant decrease in the EC50 of NA and decreased contractile response suggesting an increase in the beta-adrenoceptors and decreased availability of calcium, respectively. In chronic CCBs + ISP treated preparations further decreases in the EC50 values were observed suggesting that the voltage gated L-type Ca2+ channels may be affected directly or indirectly by change in beta-adrenoceptor activity. By the above results a proposed mechanism of interrelationship of beta-adrenoceptors with voltage gated L-type calcium channels in cardiac muscle is supported.

The interactions of calcium channel blockers (CCBs) with noradrenaline (NA), phenylephrine (PE), dopamine (DA) and KCl have been investigated in rat isolated aortic strip. In preparations from control and hypertensive (DOCA-saline) rats chronically treated with verapamil, nifedipine and diltiazem, there was partial inhibition of contractions to NA, PE and DA. However, with nimodipine, there was potentiation of responses. This could be related to the occurrence of different isoforms of L-type calcium channels. In preparations obtained from hyperthyroid rats the concentration-response curves of NA, PE and KCl were shifted to the right with depressed maximal response which could be secondary to the primary effect exerted on the heart. In preparations from L-thyroxine + nimodipine/nifedipine treated rats the concentration-response curves of NA, PE and KCl were shifted to the right and the maxima was depressed suggesting that this may be due to decreased alpha receptor density (NA and PE) and down-regulation of voltage operated channels (KCl).

The present study attempts to investigate the interaction of calcium channel blockers (CCBs) with histamine (H) and 5-hydroxytryptamine (5-HT) in rat isolated aortic strip preparations. In preparations obtained from rats chronically treated with various CCBs the contractile responses to H were completely blocked suggesting that this may be due to inhibition of the voltage-dependent channels and inositol 1,4,5-triphosphate induced release of calcium from intracellular stores. The decreased contractions of the aortic strip preparations with 5-HT obtained from rats chronically treated with various CCBs implies a decrease in 5-HT receptor density. DOCA-saline hypertensive rats chronically treated with various CCBs showed variable responses to H and 5-HT suggesting that these changes may be due to different isoforms of L-type calcium channels. In L-thyroxine-treated preparations or those simultaneously treated with L-thyroxine and CCBs the responses to H were abolished and those to 5-HT were partially blocked with decrease in maxima which could be secondary to the primary effect on the heart and to generalised reduced senstivity of the rat aorta.

Xanthotoxol (XT), 8-hydroxypsoralen, exhibited dose-graded sedative activity in dogs, cats, rats, mice and hamsters. At doses of 5-20 mg/kg intraperitoneally (i.p.) in cats and 3-100 mg/kg orally (p.o.) in dogs, XT blocked predatory mouse/rat killing behavior. In mice, XT (10-300 mg/kg i.p.) exhibited a dose-dependent reduction in locomotor activity but was less potent in this regard than reference diazepam (10-100 mg/kg i.p.). XT in mice (0.1-10.0 mg/kg i.p.) and in hamsters (0.1-10.0 mg/kg p.o.) antagonized amphetamine-induced hypermobility but was less potent than diazepam. XT elevated the electrical threshold in foot-shock-induced fighting behavior in rats. XT (0.1-30.0 mg/kg p.o.) potentiated pentobarbital-induced narcosis in hamsters at otherwise subeffective doses of pentobarbital. Conditioned avoidance responses in rats were not significantly altered with 1-3 mg/kg i.p. and 30-100 mg/kg p.o. doses of XT but 300 mg/kg p.o. blocked both conditioned and unconditioned response. Doses of 100-1000 mg/kg i.p. of XT in mice were used to study 48-h acute toxicity of XT and its LD50 was estimated to be 468 mg/kg. Doses of 10, 40 and 80 mg/kg p.o. were used to study the chronic toxicity of XT in rats for 6 months and no side effects or abnormalities in reproductive activity or endocrine integrity were noted. The F1 generation of rats from 6-month XT-treated parents were free of teratogenic effects.

In rat isolated aorta low concentration of CdCl2 (4.8 x 10(-8) M) produced a significant increase in pD2 value of KCl and noradrenaline (NA) with an increase in the maxima, while higher concentration of CdCl2 (1.44 x 10(-5) M) produced a significant rightward shift of the dose-response curve with a depression of maxima. In rat isolated portal vein 4.8 x 10(-7) M CdCl2 produced a significant increase in the pD2 value of KCl with an increase in the maxima, while higher concentration of CdCl2 (4.8 x 10(-5) M) produced a significant rightward shift of the dose-response curve of KCl and NA with a depression of maxima. In rat isolated vas deferens and anococcygeus muscle 4.8 x 10(-8) M CdCl2 produced a significant increase in pD2 value of KCl with an increase in the maxima, while higher concentrations of CdCl2 (4.8 x 10(-6) M and 1.44 x 10(-5) M) produced a significant rightward shift of the dose-response curve of KCl and NA. It is suggested that enhancement and reduction of response to KCl and NA, in presence of different concentrations of CdCl2 might be due to the alteration in the fluxes of calcium ion since these spasmogens produce their action by increasing the availability of calcium ions for the contractile machinery.

1 Stimulation of periarterial nerves to the ileum of 1 to 12 day old rabbits with supramaximal voltages and frequencies of 1, 2, 5, 10 and 20 Hz with square wave pulses of 2--5 ms duration for 30--40 s produced responses that were initially contractor. In the course of the first week, the responses changed from motor to inhibitory, the change occurring first at the highest rates of stimulation. By the 7th day of life, almost all responses were inhibitory. 2 The motor responses were potentiated by physostigmine and blocked by hyoscine suggesting that they were mediated by acetylcholine. 3 In preparations from rabbits older than 3 days, motor responses could be converted to inhibitory ones by prior exposure to noradrenaline (NA, 1 microgram/ml) for 20 min. This procedure also significantly increased the responses which were already inhibitory. 4 The ability of the ileum to take up NA increased with age. This uptake was blocked by cocaine. 5 The following explanations are possible: (a) changeover from cholinergic to adrenergic transmission in sympathetic fibres; (b) existence of 'parasympathetic' splanchnic nerves or a permanent cholinergic 'sympathetic' component of splanchnic nerves and (c) temporal delay in the development of adrenergic nerves (compared with cholinergic nerves) in the intestine.

In anococcygeus muscle and vas deferens preparations of rat, guanidinomethyl-2-benzo-(1,4)-dioxane (guanoxan) potentiated responses to norepinephrine (NF) in concentrations which exerted a neurone blocking effect. The potentiation was significantly reduced in reserpinized preparations and was abolished in the presence of nialamide. The possible mechanisms of potentiation have been discussed. Higher concentrations of guanoxan produced concentration-related contractions. The contractions were significantly less in reserpinized preparations. Phentolamine both prevented and reversed the contractions while methysergide was ineffective in this respect. Thus the effect of guanoxan appears to be mediated through the activation of alpha-receptors by the released NE.

In anesthetized rats intravenously infused, norepinephrine (NE) was accumulated by the heart, the spleen and the lung in a dose-related manner. With the lower dose of NE (2.5 mg/kg) the organ/blood ratios were more than unity and were generally greater than with higher doses (5 and 10 mg/kg), indicating that accumulation occurred by active uptake. Nialamide and pyrogallol treatment increased accumulation in the three organs. In animals receiving nialamide and pyrogallol treatment, normetanephrine (uptake2 inhibitor) and desmethylimipramine (uptake1 inhibitor) inhibited accumulation in all the organs and the entire accumulation of NE could be ascribed to uptake1 and uptake2 processes. In these animals, phenoxybenzamine and bilateral adrenalectomy inhibited and enhanced, respectively, the accumulation in the heart and the spleen only. NE accumulated in hearts of animals in vivo could be partly washed out by perfusion with NE-free medium in vitro. Washout was prevented by normetanephrine, indicating that this effect was not a passive diffusional leakage.

Incubation of rat brain homogenates or 14,500 g pellet isolated from the homogenate with (14C)-mescaline was associated with accumulation of (14C)-mescaline in the pellet. 1.33 mumol/ml of chlorpromazine, trifluoperazine, fluphenazine, imipramine, desmethylimipramine, nortriptyline and amitriptyline inhibited the accumulation of mescaline. Lower concentrations (0.133-0.44 mumol/ml) of the psychotropic drugs were less effective. The tricyclic antidepressants were less potent than the tranquilizers. Although the trimethoxyphenylacetic acid (TMPA) levels of the pellet were also reduced by the psychotropic drugs, the TMPA:mescaline ratios were unchanged indicating that the drugs had no effect on the metabolism of mescaline. The inhibition of accumulation of mescaline by the high concentrations of tranquilizers may divert more of the hallucinogen to the receptor site. Thus, an explanation for the reported worsening of clinical syndrome of hallucinogenic poisoning by tranquilizers is provided.

The effects of varying the concentration of Mg++ in the incubation medium on the contractile responses of rat isolated seminal vesicle to 5-hydroxytryptamine (5-HT) were investigated in the absence and presence of EDTA. Preparations incubated in Mg++-free and Mg++ excess media showed supersensitivity and subsensitivity to 5-HT respectively. In the presence of EDTA alterations in the sensitivity to 5-HT produced by varying the concentrations of Mg++ were comparatively less. Preparations obtained from reserpinized animals showed subsensitivity in normal and Mg++ excess media and supersensitivity in Mg++-free medium. In the presence of EDTA, reserpinized preparations showed slight supersensitivity in normal Mg++ medium, marked supersensitivity in Mg++-free medium and lesser subsensitivity in Mg++ excess medium. Probably EDTA by more effectively removing Mg++ from the membrane binding sites by chelation makes the membrane permeable to Ca++ leading to supersensitivity to 5-HT (observed only in the presence of EDTA). These results suggest that the failure of reserpine to induce supersensitivity to 5-HT in rat seminal vesicle may be due to an enhanced antagonism of Mg++ on Ca++ movements in this preparation due to the poor capacity of rat tissue to retain Ca++ (Krishnamurty and Grollman, 1976).

The rectal temperature of male rats was measured in a thermoneutral environment (25 degrees C) and at ambient temperatures of 15 and 35 degrees C. Unless otherwise specified all drugs were administered intracerebroventricularly (i.c.v.) and all results are reported for the thermoneutral environment. Exposure to 15 degrees C did not affect the rectal temperature but exposure to 35 degrees C produced hyperthermia. At 15 and 25 degrees C, 20 mug GABA produced hyperthermia which was longer lasting at the former ambient temperature. GABA (20 mug) prevented the hyperthermic effect of exposure to 35 degrees C and produced hypothermia in animals maintained at this temperature for 1 hr. A low dose (1 mug) of NA produced hyperthermia and a higher dose (mug) hypothermia. In rats pretreated with sodium salicylate (i.p.), 20 mug GABA and 1 mug NA produced hypothermia instead of hyperthermia, suggesting the release of PGE in mediating hyperthermia. The hypothermic effect of 10 mug NA and of GABA observed at 35 degrees C was blocked by phentolamine, an indication of the possibility of alpha-adrenoceptor mediation.

Rat aorta became supersensitive and subsensitive to noradrenaline (NA), respectively, in Mg++-free and 3.6 mM Mg++ media reserpine treatment reduced the sensitivity in normal or high (3.6 mM) Mg++ media but had no effect in Mg++-free medium. Incubation of aortae in Mg++-free medium enchanced 45Ca++ uptake and efflux in rat aorta, whereas, it reduced 45Ca++ efflux without a change in 45Ca++ uptake by rabbit aorta. Reserpine pretreatment enhanced 45Ca++ efflux from rat aorta without a changed in 45Ca++ uptake in normal Mg++-free medium. Unlike in rat aorta, reserpine enhanced 45Ca++ uptake by and reduced efflux from rabbit aorta in Mg++-free medium but not in normal medium. These results suggest that the failure of reserpine to induce supersensitivity in rat aorta to NA may be due to poor capacity of the muscle to retain Ca++ and probably also due to an enhanced antagonism of Mg++ on Ca++ movements.

The effects of papaverine MgCl2, cocaine, DNP, KCN and khellin on responses of some rabbit and rat tissues to CaCl2 were studied in vitro in a depolarizing medium. Guinea pig taenia coli preparation was used for comparison. In rabbit tracheal chain and vas deferens and guinea pig taenia coli preparations all spasmolytics shifted the concentration-response curves of CaCl2 to the right without affecting the maxima or slopes. In rat tracheal chain and vas deferens preparations all spasmolytics shifted the concentration-response curves of CaCl2 to the right. Furthermore all agents (except cocaine in tracheal chain preparations) depressed the maximum responses. The slopes were unaffected in either preparations. The initial competition and subsequent noncompetition observed in certain tissues is discussed in the light of the reported poor capacity of some tissues to retain Ca++ and the absence of releasable firmly bound Ca++ (11).

The sensitivity to isoprenaline of beta inhibitory adrenoceptors of tracheal chain preparations from guinea-pig, rabbit and rat was compared. For this purpose the tracheal chain preparations were contracted either with KCl or pilocarpine. Isoprenaline (1.0 X 10(-7)M--6.4 X 10(-6)M) caused concentration-related relaxation of guinea-pig trachea, whereas the rabbit and the rat trachea remained insensitive even at very high concentrations of isoprenaline (2.5 X 10(-3)M). Phenoxybenzamine (2.6 X 10(-6)M) potentiated or unmasked the relaxant effects of isoprenaline respectively in the guinea-pig or the rabbit and the rat trachea contracted with KCl. Phentolamine was ineffective in potentiating or unmasking the relaxant effects of isoprenaline. The potentiating or unmasking effects of phenoxybenzamine were absent in reserpinized preparations and lidocaine treated preparations from both guinea-pig and rat. Normetanephrine (5.4 X 10(-7)M) potentiated responses to isoprenaline only in the guinea-pig trachea. Even a 10-fold higher concentration of normetanephrine was ineffective in the rabbit or the rat rachea.

The amine releasing action of mescaline was investigated in rat isolated hypothalamus labeled with 3H-metaraminol. Mescaline had no effect on the uptake of 3H-metaraminol but produced its release in a concentration-related manner. 4 x 10(-4) M mescaline, which produced submaximal effects was used for subsequent experiments. 3 x 10(-5) M cocaine had no effect on the 3H-metaraminol releasing action of mescaline. Mescaline was fully effective in Ca2+-free medium while 6 x 10(-2) M KCl was ineffective. 3 x 10(-7) M tetrodotoxin or 6 x 10(-5) M lidocaine partially blocked mescaline-induced release but substantially or completely blocked 3 x 10(-2) M KCl-induced release. Prior exposure of hypothalamus to 3 x 10(-4) M tyramine reduced the releasing action of mescaline. Thus, mescaline appears to release 3H-metaraminol both by Ca2+-independent (tyramine-like) and Ca2+-dependent (lidocaine-sensitive) mechanisms. 3 x 10(-4) M tyramine and 6 x 10(-2) M KCl released 14C from control hypothalamus labelled with 14C-mescaline, but not from reserpinized hypothalamus. The amounts of 14C recovered in 14C-mescaline labeled control and reserpinized hypothalamus at the end of 50 min of efflux were similar suggesting a poor retention of 14C-mescaline by storage particles.

The effects of levamisole on responses to various agonists were studied in guinea-pig vas deferens. Levamisole did not itself exhibit any contractile or relaxant effect on guinea-pig vas deferens but in the presence of levamisole the concentration-response curve of noradrenaline (NA) was shifted to the left and the maximal response was increased. Responses to field-stimulation at 5 and 10 Hz were potentiated by levamisole. Cocaine and denervation caused potentiation of NA responses and these enhanced responses remained unchanged in the presence of levamisole. Acetylcholine (ACh) responses were potentiated by levamisole whereas responses to histamine, KCl and methoxamine remained unaltered. These results suggest that levamisole does not have any action at postsynaptic alpha-adrenoreceptors. The increased responses to NA and ACh in the presence of levamisole may be due to its uptake1, blocking and anticholinesterase activities respectively.

Administered intravenously in decerebrate cats nitrazepam or diazepam (0.0625 to 0.5 mg/kg) produced dose-related inhibition of the ipsilateral extensor reflex. Nitrazepam (0.25 mg/kg i.v.) produced a significantly greater (P less than 0.001) inhibition than that produced by diazepam (0.25 mg/kg i.v.). Nitrazepam or diazepam (0.0625-4 mg/kg i.v.) had no effect on the contractions of directly stimulated (120 V, 5 msec, 0.1 Hz) quadriceps femoris muscle and on the contractions of tibialis anterior muscle produced by stimulating the cut peripheral end of the lateral popliteal nerve (8 V, 1.5 msec, 0.1 Hz). Nitrazepam or diazepam (0.125-0.5 mg/kg i.v.) produced dose-related depressor responses in cats anaesthetized with chloralose or pentobarbitone. Nitrazepam produced a depressor response at 0.0625 mg/kg dose while diazepam did not. The drugs did not appear to have any deleterious effect on the veins removed 6 hr after the first exposure to the drugs as evidenced by lack of histological changes. It is concluded that nitrazepam and diazepam produce central muscle relaxation by inhibiting polysynaptic pathways in the spinal cord. The potency of nitrazepam appears to be greater than that of diazepam. Definitive evidence has been provided that the peripheral neuromuscular or direct muscular actions are not involved in the muscular relaxation produced by the two drugs.

In rat isolated anococcygeus muscle, dopamine (2.6 x 10(-11) M to 8.3 x 10(-10) M) produced a concentration-dependent inhibitory effect on field stimulated contractions. The effect of dopamine was blocked by pimozide (2.2 x 10(-8) M) but not by yohimbine (2.6 x 10(-10) M) or propranolol (1.0 x 10(-7) M), suggesting a specific prejunctional inhibitory effect. Higher concentrations of dopamine (1.4 x 10(-7) M to 1.4 x 10(-4) M) elicited concentration-dependent contractions which were blocked competitively with higher concentrations of pimozide (2.2 x 10(-7) M to 1.4 x 10(-4) M) and 2.2 x 10(-6) M), suggesting a postjunctional activity. ACh in very low concentrations (2.8 x 10(-11) M to 4.4 x 10(-10) M) blocked the field stimulated contractions. Atropine (2.6 x 10(-9) M) per se augmented them and also antagonized the inhibitory effects of ACh, suggesting a prejunctional activity of ACh. Higher concentrations of ACh (5.5 x 10(-7) M to 7.0 x 10(-5) M) produced contractions which were not altered by atropine in a concentration (2.6 x 10(-9) M) which antagonized the prejunctional activity of ACh. Histamine, in a wide range (3.1 x 10(-12) M to 2.6 x 10(-8) M), did not modify field stimulated contractions. Very low concentrations of 5-HT (1.2 x 10(-11) M to 3.8 x 10(-10) M) had an inhibitory effect on field stimulated contractions. Methysergide (2.8 x 10(-9) M) enhanced the responses to electrical stimulation and antagonized the 5-HT-induced inhibitory effect. Still higher concentrations of 5-HT (1.9 x 10(-6) M to 1.0 x 10(-3) M) produced concentration-dependent contractions. Methysergide (8.5 x 10(-7) M) failed to antagonize, whereas phentolamine (1.0 x 10(-6) M) antagonized 5-HT competitively. Dopamine (8.3 x 10(-10) M), ACh (4.4 x 10(-10) M) or 5-HT (3.9 x 10(-10) M), in concentrations which produced a maximal prejunctional inhibitory effect, did not alter the EC50 value of NA, ruling out a post-junctional effect. Moreover, the concentration ratios of these agents for EC50 pre to EC50 post were less than 1, suggesting their preferential prejunctional site of action. It is concluded that multiple prejunctional site of action. It is concluded that multiple prejunctional receptor activities for DA, ACh (muscarinic) and 5-HT, which modify the release of neurotransmitter, may be operative in this preparation.

Oral treatment with indapamide was found to reduce blood pressure of hypertensive rats but not of normotensive rats. Chronic indomethacin treatment had no effect on blood pressure of untreated normotensive and hypertensive rats. Also indomethacin did not modify the antihypertensive effect of indapamide excluding the direct involvement of PGs in the antihypertensive effect of indapamide. Vascular reactivity to pressor agents NA, ADR and ANG was significantly increased after indomethacin treatment. This may be due to the blockade of the actions of PG in modifying vascular reactivity to vasoconstrictor agents or may be a direct effect of indomethacin on calcium fluxes. Indapamide reduced the reactivity to NA and ANG in the presence of indomethacin suggesting that the antihypertensive effect of indapamide may be through a decrease in reactivity to pressor agents which is independent of increase in the synthesis of vasodilator PGs.

In rats, acute i.v. administration of CdCl2 (0.5 and 1 mg/kg) produced a depressor response followed by a pressor response, while the acute i.p. administration of CdCl2 (0.5 and 1 mg/kg) produced only a pressor response. Phentolamine (5 mg/kg, i.v.), hexamethonium (10 mg/kg, i.v.), propranolol (2 mg/kg, i.v.) and indomethacin (20 mg/kg, i.p.) as well as bilateral adrenalectomy, acute reserpinization and chemical sympathectomy by guanethidine did not modify the acute pressor response to CdCl2. Verapamil (1 mg and 2 mg/kg, i.v.) and nifedipine (0.25 and 0.5 mg/kg, i.v.) prevented the acute pressor response to CdCl2 administered by either i.v. or i.p. route. Phentolamine (10 micrograms/ml) could not prevent the rise in perfusion pressure of the rat hindquarter due to intra-arterial CdCl2 administration. However, verapamil (50 and 100 micrograms/ml) prevented rise in perfusion pressure. It is concluded that cadmium ion might mimic calcium ion and produce a direct contractile effect on the vascular smooth muscle.

Levels of unchanged mescaline were examined in the plasma and brain of albino Swiss-Webster mice pretreated with various doses of either clozapine or molindone. In clozapine treated mice, the mescaline levels were statistically significantly higher at 2 and 3 h with 7.5 and 15.0 mg/kg and at 1, 2 and 3 h with 30 mg/kg. Molindone at 4.0 and 8.0 mg/kg produced no significant effect; at 16.0 and 48.0 mg/kg, the levels were significantly higher at 1 and 2 h. Elevated brain levels of mescaline by clozapine and molindone indicate an adverse metabolic interaction between a hallucinogen and drugs that are commonly used to treat mescaline-induced psychosis.

The uptake of exogenously added noradrenaline (NA) (0.5-2.5 mug/ml) by the human umbilical artery was linear with time up to 10 minutes. The uptake was saturable and could be described by the Michaelis-Menten equation. The uptake was cocaine-resistant, normetanephrine-sensitive, was considerably inhibited in the cold and was partially inhibited by Na+- deficiency. Of NA accumulated in the artery 31% could be washed out by NA-free medium. It is concluded that the mechanism of uptake of NA by the human umbilical artery is similar to the uptake2 mechanism.

Effect of lithium on the contractile responses of rat isolated seminal vesicle to 5-hydroxytryptamine (5-HT) were investigated by varying the Ca++ and Mg++ concentrations of the incubation medium in the absence and presence of EDTA. Preparations incubated in excess Ca++ (4.2 mM) or in Ca++-free Krebs solution showed decrease in sensitivity to 5-HT, whereas the responses to 5-HT were potentiated in Mg++-free incubation media and reduced in media containing excess Mg++. Rezerpinization failed to induce supersensitivity to 5-HT in any Mg++ concentration in the medium. However, reserpinized tissue in Mg++-free solution with EDTA showed increased sensitivity to 5-HT. Li+ inhibited responses to 5-HT. The inhibitory action of Li+ was augmented in medium lacking in Ca++ and was antagonized in media containing excess Ca++ (4.2mM). Li+ reduced the sensitivity and decreased maximum responses to 5-HT in any Mg++ concentration in the medium. In the presence of EDTA, the inhibition observed with Li+ in excess Mg++ (3.6 mM) medium was comparatively much less in both non-reserpinized and reserpinized preparations. Thus Li+ may be inhibiting responses to 5-Ht by block of influx of Ca++ or delayed efflux of Ca++ or inhibition of uptake of Ca++ or a combination of two or more of these effects.

Five of the substituted ethylenediamine amides (LMG I to V) were tested for various CNS attributes and for acute toxicity (24 hr mortality). All compounds were potent analgesics in various animal tests, LMG V being most potent. All reduced spontaneous activity of mice and potentiated ether anaesthesia. However, CAR was not altered and anti-MES were not pronounced in rats. Compounds appear to have a wide safety margin considering ED50 and LD50 in mice.

Li+ is reported to reduce sensitivity of alpha-adrenergic receptors to NE. The present investigation was designed to investigate the mechanism of this decreased sensitivity on the rat isolated seminal vesicle. In innervated preparations, 1.35 X 10(-3) M Li+ (i) shifted the concentration-response curves of NE, methoxamine, ACh and BaCl2 to the right and reduced their maximum responses; (ii) antagonized the leftward shift and the enhancement of maximum responses to NE by cocaine (2.9 X 10(-4) M), and (iii) reduced only the maximum responses to KCl. In denervated preparations, 1.35 X 10 (-3) M Li+ shifted the concentration response curve of NE to the left without any change in the maximum responses. The antagonistic effects of Li+ on maximal responses to NE, ACh and KCl observed in innervated preparations were significantly increased in Ca++-free medium. Li+ (1.35 X 10(-3) M) increased NE uptake by the seminal vesicle significantly. It is concluded that decreased sensitivity of the seminal vesicle to NE by Li+ could be due to an increase in the uptake of NE and to a nonspecific postsynaptic spasmolytic action.

The effects of Abana, an Ayurvedic remedy, administered orally to rabbits was studied for its effects on isolated atria and intestine. Administration of Abana for 3 days increased the basal amplitude and reduced the responses of atria to isoprenaline and norepinephrine. Combined treatment with Abana and isoprenaline reduced this effect. It is possible that Abana treatment for 3 days has an action similar to that of chronic administration of isoprenaline (down regulation of beta receptors). A similar down regulation of beta receptors of smooth muscle of rabbit intestine also seems to occur. Abana pretreatment potentiated the inotropic responses of histamine and CaCl2. These effects may be due to a specific depressant effect of Abana on the adrenergic receptors and a direct sensitization of the atrium manifested by an increased response to CaCl2.

1 The cerebral ventricles of dogs under intravenous pentobarbitone sodium anaesthesia, were perfused with artificial cerebro-spinal fluid (CSF) at a rate of 0.4-0.5 ml/min from the ventricular to the aqueductal cannulae. The effluent was collected from the aqueductal cannula in 20 min samples. The animals' temperatures were recorded from the rectum.2 gamma-Aminobutyric acid (GABA) 0.1-5 mg when injected into the ventricles produced variable temperature effects. Doses of 0.1 and 0.5 mg always produced hyperthermia and 1 and 5 mg doses sometimes produced hyperthermia and sometimes hypothermia.3 Intraventricular perfusion with 2-bromolysergic acid diethylamide (BOL) and hyoscine did not block hyperthermia. Tests on the rat isolated stomach strip or the guinea-pig isolated superfused ileum for the possible release, respectively, of 5-hydroxytryptamine or acetylcholine by GABA were negative.4 When tested for the presence of prostaglandin E(PGE)-like substances on the isolated rat stomach strip, both the control effluent and the GABA effluent showed activity, the latter being much more potent. There was a temporal correlation between this effect and hyperthermia. Intraventricularly administered sodium salicylate converted the GABA-induced hyperthermia to hypothermia and blocked the release of PGE-like substances.5 Hypothermia induced by GABA alone or in the presence of sodium salicylate was associated with the release of noradrenaline into the effluent.6 Intraventricular administration of GABA in reserpinized dogs produced hyperthermia and not hypothermia. Similar results were obtained with phentolamine perfusion in normal dogs.7 Perfusion with calcium-free solution blocked both the noradrenaline-releasing and hypothermic actions of GABA.8 It is concluded that hyperthermia associated with intraventricular injections of GABA is due to the release of PGE-like substance and hypothermia is due to the release of noradrenaline.

The role of opioidergic system in the antihypertensive effect of clonidine was investigated in albino normotensive and renal-DOCA-salt hypertensive models of rats. Clonidine (2.5, 5 and 10.0 micrograms/kg, iv) produced a dose-related depressor response. Yohimbine (2 mg/kg, ip) blocked the clonidine-induced responses in both normotensive and hypertensive rats. Naloxone (2 mg/kg, iv) blocked the clonidine-induced depressor responses in hypertensive rats, but not in normotensive animals. Morphine (0.11 mg/kg, iv) produced a depressor response in both normotensive and hypertensive rats. Yohimbine (1 mg/kg, iv) did not affect the hypotensive effect of morphine in normotensive or hypertensive rats, whereas pretreatment with naloxone significantly blocked the hypotensive effect of morphine in both groups of animals. It is concluded that the hypotensive effect of clonidine in hypotensive rats could be due to an opioidergic mechanism since it is blocked by both naloxone and yohimbine.

Rat heart and spleen slices were incubated with 3,4-dimethoxyphenylethylamine-1-14C(14C-DMPEA) in Krebs medium at 37 C. At the end of 5-20 min of incubation, the heart did not take up the radioactivity while the spleen did. The Km and Vmax values of uptake in the spleen were 1 x 10(-4) M and 20 nmole/g per min, respectively, and the uptake was reduced to 16.0-35.1% in the cold (4 C) and to 40.3-64.0% in Na+-free medium. Thus, the uptake was an energy-dependent active process but was only partially Na+-dependent. Spleen slices incubated with 14C-DMPEA-free medium for 15 min following incubation with 14C-DMPEA retained 41.0-74.8% of radioactivity. The uptake was insensitive to norepinephrine (0.313 and 0.939 muM), dopamine (9.98 muM), 5-hydroxytryptamine (5 muM), cocaine (14.8 muM), 1-amphetamine (0.3 and 300 muM), d-amphetamine (300 muM), and normetanephrine (45.7 muM). 6-Hydroxydopamine treatment of rats, which produced 93% reduction in the splenic norepinephrine content, did not significantly reduce uptake. Thus, the uptake of DMPEA into the spleen is not by adrenergic neurones.

Albino rats of either sex received chronic ethinyl oestradiol (EO) treatment (1.5 mg kg-1 daily, i.m.) for 3 weeks. Untreated control rats received arachis oil vehicle alone. Chronic EO treatment resulted in elevation of blood pressure in both sexes. Female rats exhibited significantly greater elevation in blood pressure than males. In chronic EO-treated rats pressor responses to low doses (0.5 micrograms kg-1) of noradrenaline were significantly increased, while those to angiotensin II, acetylcholine and isoprenaline were unaltered. Chronic EO treatment also sensitized the vascular bed of the rats' hindquarters to noradrenaline. EO-induced hypertension was associated with significant increase in dopamine-beta-hydroxylase activity of adrenal glands. Complete bilateral adrenalectomy or chemical sympathectomy prevented the development of EO-induced hypertension. It is suggested that chronic treatment of rats with EO induces and maintains hypertension. The peripheral sympathetic system plays an important role in this phenomenon.

The effects of levamisole were investigated on the blood pressure of anaesthetized dog. Levamisole (0.5 to 4.0 mg/kg) elicited a biphasic effect, an initial brief depressor response followed by a pressor response. The pressor response was dose-related and was blocked by phenoxybenzamine. The residual depressor response was blocked by propranolol. Repeated administration of a high dose of levamisole produced tachyphylaxis. The pressor response to levamisole was not modified by either reserpinization, acute bilateral adrenalectomy or pretreatment with cocaine, whereas pretreatment with dexamethasone, nialamide or pyroaallol shifted the dose-response curve to the right. Levamisole potentiated the pressor responses to noradrenaline, angiotensin and acetylcholine. The effects of levamisole are ascribed to inhibition of monoamine oxidase, catechol-O-methyl transferase, catecholamine uptake2 mechanism and cholinesterase.

Chronic cadmium chloride (CdCl2, 0.5 and 1.0 mg/kg, i.p.) treatment in female albino rats for 2 weeks resulted in elevation of blood pressure. In chronic CdCl2-treated rats the pressor responses to different doses of noradrenaline, angiotensin II and depressor responses to acetylcholine and isoprenaline were unaltered. In rat hindquarter preparation there was elevation of perfusion pressure and the sensitivity of vascular bed to noradrenaline was increased in the CdCl2-induced hypertensive rats. Complete bilateral adrenalectomy or chemical sympathectomy or treatment with captopril did not prevent the development of CdCl2-induced hypertension. Treatment with verapamil (15 mg/kg/day, p.o.) or nifedipine (10 mg/kg/day, p.o.) for 2 weeks prevented the development of hypertension with chronic CdCl2 treatment. It is suggested that chronic treatment of rats with CdCl2 induces hypertension. It is possible that cadmium mimics the calcium ion for the induction of hypertension in rats.

Nicotine released 3H-radioactivity from rat hypothalamus labeled with 3H-metaraminol (3H-MA) in a concentration-related manner. The release was not blocked by hexamethonium (1.8 x 10(-5)M - 2.3 x 10(-3)m), tetrodotoxin (3 x 10(-7)M), lidocaine (6 x 10(-5)M or Ca++-free medium. Cocaine (3 x 10(-5)M) blocked the releasing action of nicotine. Nicotine failed to release 3H-MA in tissue exposed to tyramine. It is concluded that the nicotine-induced release of 3H-MA is intracellular.

1. The ability of alpha-methyl amino-acids and their corresponding amines to restore the sympathomimetic actions of tyramine, and the uptake of the amino-acids and the amines, were studied in isolated tissue preparations obtained from reserpine pretreated animals.2. Tyramine relaxed isolated rat ileum preparations from non-reserpinized rats but not from reserpine treated animals. alpha-Methyldopa, alpha-methylnoradrenaline and lower concentrations of metaraminol restored the responses of reserpinized preparations. alpha-Methyldopamine, alpha-methyl-m-tyrosine, alpha-methyl-p-tyrosine and higher concentrations of metaraminol did not do so. The restoring effect of alpha-methyldopa was blocked by disulphiram. alpha-Methyl-p-tyrosine or alpha-methyl-m-tyrosine blocked the restoring action of alpha-methyldopa but not of alpha-methylnoradrenaline. Cocaine blocked the restoration of responses to tyramine by alpha-methylnoradrenaline but not by alpha-methyldopa. alpha-Methyldopa and alpha-methylnoradrenaline failed to restore responses to tyramine in the presence of sodium-free Tyrode solution.3. Tyramine increased the perfusion pressure in isolated rabbit ear preparations obtained from non-reserpinized animals but was very much less active in preparations obtained from reserpine treated animals. alpha-Methyldopa, alpha-methyl-m-tyrosine, alpha-methylnoradrenaline, alpha-methyl-p-tyrosine and metaraminol restored the effects of tyramine. alpha-Methyldopamine did not do so. The restoring effect of alpha-methyldopa and alpha-methyl-m-tyrosine was blocked by disulfiram. alpha-Methyl-p-tyrosine blocked the restoring effect of alpha-methyl-m-tyrosine.4. Tyramine produced positive inotropic effects in isolated rabbit heart preparations. This was either reduced or absent in preparations obtained from reserpine pretreated animals. alpha-Methyldopa, alpha-methylnoradrenaline, alpha-methyl-m-tyrosine and metaraminol restored the responses to tyramine. alpha-Methyldopamine and alpha-methyl-p-tyrosine did not do so.