Effect of fruits of Moringa oleifera on the lipid profile of normal and hypercholesterolaemic rabbits.

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 isoprenaline and calcium channel blockers on response of isolated right ventricle to noradrenaline.

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.

Interaction of calcium channel blockers with different agonists in aorta from normal and diseased rats.

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).

Interaction of calcium channel blockers (CCBs) with histamine and 5-hydroxytryptamine in aorta from normal and diseased rats.

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.

Evaluation of xanthotoxol for central nervous system activity.

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.

Effect of cadmium on contractile response to spasmogens in vascular and nonvascular tissues.

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.

The acute pressor response to cadmium in rats.

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.

Modification of the antihypertensive effect of indapamide by indomethacin.

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.

Cadmium-induced hypertension in rats.

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.

Effects of Abana, an Ayurvedic preparation, on rabbit atrium and intestine.

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.

Evidence for multiple prejunctional receptor sites in rat isolated anococcygeus muscle.

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.

Action of some amides of substituted ethylenediamines on central nervous system.

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.

The role of the sympathetic nervous system in oestrogen-induced hypertension in rats.

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.

Investigation of some effects of levamisole on dog blood pressure.

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.

Interactions of levamisole with some autonomic drugs on guinea-pig vas deferens.

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.

Investigation of the muscle relaxant activity of nitrazepam.

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.

Effect of clozapine and molindone on plasma and brain levels of mescaline in mice.

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.

Role of opioidergic component in the antihypertensive effect of clonidine.

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.

influence of Mg++ and reserpine on the reactivity of rat seminal vesicle to 5-hydroxytryptamine.

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).