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PubMed1993

Mutants of the Bacillus subtilis multidrug transporter Bmr with altered sensitivity to the antihypertensive alkaloid reserpine.

The Bacillus subtilis multidrug transporter Bmr effluxes structurally diverse toxic compounds out of bacterial cells. Antihypertensive alkaloid reserpine reverses Bmr-mediated multidrug resistance by inhibiting drug transport. We have obtained a mutant of the bmr gene that provides a normal level of multidrug resistance, which can, however, only be reversed by very high concentrations of reserpine. Reduction of Bmr sensitivity to reserpine has been caused by the substitution of Leu for Val286 in the Bmr molecule. This mutation also led to a dramatic decrease of [3H]reserpine binding to membrane vesicles prepared from the Bmr-overexpressing bacteria. Leucine is larger than valine by one methylene group. Substitution of Val286 with a smaller residue, glycine, had an opposite effect. It led to increased sensitivity of Bmr to reserpine and increased affinity of reserpine binding to the membranes prepared from Bmr-overexpressing bacteria. Neither of the mutations significantly changed the sensitivity of Bmr to rescinnamine, a structural analog of reserpine. The results suggest that Val286 is involved in the formation of the reserpine-binding site of the Bmr molecule.

Amino Acid Sequence↗
PubMed1976

Prevention by calcium administration of reserpine action on rat brain noradrenaline stores: a reappraisal.

The conditions under which pretreatment with a calcium salt may prevent the action of reserpine on brain noradrenaline stores in the rat were investigated. The results show that only after subcutaneous administration of reserpine in the same site as a previous CaCl2 injection, was the action of reserpine prevented and reduced levels of this drug were found in the brain. Conversely, the depletion of encephalic noradrenaline following reserpine, as well as the reserpine brain concentration, were not affected by subcutaneously administered calcium chloride, when reserpine was administered either intravenously, or subcutaneously in a site different from that selected for pretreatment with the calcium salt. In essence calcium chloride, a well known irritant, acts accordingly at the site of subcutaneous administration, thus limiting by a non specific mechanism the absorption of reserpine. Under similar conditions, in fact, the absorption of a different drug, i.e. harmaline, was likewise altered. In view of these findings the significance of some studies on calcium-reserpine interaction appearing in the literature requires a reappraisal.

Animals↗
PubMed1964

INFLUENCE OF METHYLDOPA ON CENTRAL EFFECTS OF RESERPINE.

Methyldopa potentiated hypnosis due to hexobarbitone in mice, as did reserpine, chlorpromazine and 5-hydroxytryptamine. Methyldopa antagonized the increase by reserpine of sleep due to hexobarbitone, but enhanced the potentiation by chlorpromazine and 5-hydroxytryptamine of hypnosis due to hexobarbitone. The sedative effect of reserpine in mice and the emetic effect in pigeons were also antagonized by methyldopa. However, the effects of reserpine on convulsions due to leptazol and in causing ptosis were not antagonized by methyldopa. It is suggested that some effects of reserpine (potentiation of hexobarbitone-sleeping time, sedation and emesis) are unrelated to changes in brain amine levels and that methyldopa, with its weak reserpine-like actions, is an antagonist to reserpine.

Anesthesia↗
PubMed1996

D1 dopamine receptor stimulation inhibits firing activity of midbrain dopamine neurons in reserpine treated rats: an effect eliminated after hemitransection of diencephalon.

It has been reported that systemic administration of the D1 dopamine (DA) receptor agonist SKF 38393 inhibits the firing rate of substantia nigra pars compacta (SNC, A9) DA neurons after repeated reserpine treatment in locally anesthetized rats, although SKF 38393 induces little effect on the firing of midbrain DA neurons in normal rats. The present study found that local pressure microejection of SKF 38393 (10(-2) M, 20-100 nl) to SNC or substantia nigra pars reticulata (SNR) failed to influence the firing of SNC DA neurons in reserpinized rats (reserpine 1 mg/kg x 6 days, s.c.); subsequent intravenous (i.v.) injection of SKF 38393 (4 mg/kg), however, inhibited their firing and the inhibition was reversed by the D1 receptor antagonist SCH 23390. Similarly, systemic administration of SKF 38393 (4 mg/kg, i.v.) inhibited the firing of ventral tegmental area (VTA, A10) DA cells in reserpinized rats, while local microejection of SKF 38393 (10(-2) M, 30-60 nl) did not affect their firing. Furthermore, the inhibitory effect of systemic SKF 38393 on firing rate of either SNC or VTA DA neurons in reserpinized rats was eliminated after hemitransection of diencephalon. These results suggest that repeated reserpine treatment renders midbrain DA neurons responsive to D1 receptor stimulation and that D1 receptor agonist-induced inhibition of midbrain DA cell firing in reserpinized rats may require the involvement of long-loop feedback pathways.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1980

The fate of tritium-labeled reserpine in the chick embryo: a preliminary report.

After a single administration of EH-reserpine, 10 mugm 2.5 microCi, into the yolk of fertilized chicken eggs, gross radioactivity (reserpine plus degradation products) and the unchanged labeled drug, separated by thin layer chromatography, were assayed on the 8th and 19th day of incubation. Nanogram per gram concentrations of unchanged 3H-reserpine were recovered at both times. The 3H-reserpine recovered in the whole egg on the 8th day of incubation accounted for up to 20% of the administered dose. On the 19th day of incubation, brain showed the largest share (28%) of 3H-reserpine as a percentage of gross radioactivity of all organs investigated. Reserpine underwent considerable biodegradation in the developing chick embryo, but the concentrations of unchanged drug recovered in embryonal tissues throughout development were of the same order as those persisting in target organs of rats given a pharmacological dose of reserpine.

Animals↗
PubMed1988

Protection by procaine hydrochloride against reserpine-induced acute gastric mucosal injury in the rat: implications for stress-induced injury.

This study investigated whether oral procaine (1 mL of 5% solution) affords protection against reserpine-induced (5 mg/kg, ip) acute gastric mucosal injury in the rat. After 6 h, all rats in the reserpine-alone group developed mucosal injury confined to the glandular stomach (40.1 +/- 5.2 mm2, mean +/- SEM), and neither atropine (5 mg/kg, ip) or cimetidine (40 mg/kg ip) influenced this injury (38 +/- 4 and 40.5 +/- 4.6 mm2, respectively). Similarly, celiac ganglionectomy, to interrupt autonomic sympathetic delivery to the stomach, had no effect on the reserpine-induced injury (42 +/- 6 versus 40.1 +/- 5.2 mm2). Dose-dependent protection against the reserpine injury was produced by the alpha-adrenoceptor blocking drug phenoxybenzamine or phentolamine: a complete protection was noted with the 15-mg/kg dose. Vagotomy or procain completely protected the rat stomach against the reserpine injury. The data suggest that reserpine produces vagal adrenoceptor delivery to the rat stomach, resulting in mucosal injury, and that oral procaine blocks this delivery, thus achieving protection against injury development by a vagotomy action. The knowledge that the reserpine injury is a stress-induced injury indicates that oral procaine protects the rat stomach against stress-induced acute gastric mucosal injury.

Animals↗
PubMed1995

Time-course of modifications elicited by reserpine on the density and mRNA synthesis of the vesicular monoamine transporter, and on the density of the membrane dopamine uptake complex.

The long-term effects of a unique injection of reserpine (5 mg/kg s.c.) on the vesicular monoamine transporter and dopamine uptake complex have been investigated, in parallel with behavioral and neurochemical effects. Early after treatment, a dramatic decrease in locomotor activity, as well as a marked depletion in striatal dopamine (DA), associated with a prominent enhancement in dopaminergic turnover were observed in reserpine-treated rats. From 2 to 60 days after reserpine injection, a recovery in locomotor activity occurred, in parallel with an increased DA content in the striatum, reaching about 50% of controls at day 60. At this time, the dopamine turnover was quite normal. The density of the dopamine uptake sites in the striatum, studied with 3H GBR12783, was unchanged after reserpine treatment at any time studied up to 60 days. By contrast, the density of binding sites for 3H dihydrotetrabenazine (3H TBZOH), a marker for the vesicular monoamine transporter, remained dramatically decreased in the striatum all over the time of the study (> -90% of controls at day 2 and -80% at day 30 and 60). A lesser decrease (-60%) was observed in the substantia nigra pars compacta (SNc), 2 and 30 days after reserpine treatment. This suggests that at least 60% of the vesicular monoamine transporter is sensitive to reserpine in this cell bodies region, indicating that this proportion of the transporter is integrated in functional vesicles, a prerequisite for reserpine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Effect of prenatal reserpine exposure on development of the postnatal rat heart.

Previous studies have suggested that reserpine treatment may result in altered heart development. In order to more fully investigate this possibility, reserpine was administered s.c. at 0, 0.375, or 0.75 mg/kg/day to pregnant rats on gestation days 12-15. Maternal weight gain, as well as pup weight on postnatal day (PND) 1, was significantly reduced in a dose-dependent manner. Litter size was unaffected, but reserpine-treated dams had more dead pups than did control dams. On PND 1, litters were randomly standardized at ten pups each for analysis on PNDs 5, 8, 15, and 22. Pup body weight and heart weight were reduced in a dose-related manner at all ages measured. The decreased heart weights were probably due to decreases in cell number. Beta-adrenergic receptor concentration was significantly reduced only on PND 5, at the low reserpine dose, and was not considered to be a treatment effect. Prenatal reserpine exposure had no effect on levels of basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development. Cardiac ODC stimulation by insulin and isoproterenol also showed no effects of maternal reserpine treatment. The results suggest that maternal reserpine treatment may lead to adverse effects in the developing offspring.

Aging↗
PubMed1981

Kinetic characteristics of newly synthesized 3H-5-HT in the brain of control and reserpinized mice. Evidence for the heterogeneous distribution of 5-HT in serotoninergic neurons.

Following an intravenous administration of 3H-tryptophan to mice, 3H-serotonin rapidly accumulated in the brain, with a maximum around the 20th min after the injection. In mice whole monoamine oxidase activity was blocked by pargyline (75 mg/kg i.p.), reserpine pretreatment (5 mg/kg, 24 h before death) did not alter the initial accumulation of 3H-5-HT indicating that the rate of 5 HT synthesis was similar in control and reserpinized animals. When monoamine oxidase was not blocked, the accumulation of 3H-5-HT was significantly lower in reserpine-treated mice than in controls. However, the specific activity of 3H-5-HT accumulated in brain was 2-3 times higher in reserpinized (45 h) than in control mice. Since neither the specific activity of the precursor 3H-tryptophan, the reuptake process for 3H-5-HT nor the absolute synthesis rate of 5-HT was altered in the brain of reserpinized mice, it is proposed that the differences observed in the specific activity of 3H-5-HT reflected the presence of 3H-5-HT in different compartments in control and reserpinized mice. Serotonin would be distributed in a "storage" and a "functional" compartments in serotoninergic neurons under normal conditions whereas only the functional compartment would exist 18-48 h after the administration of reserpine.

Animals↗
PubMed1982

beta-Adrenoceptor ligand binding and supersensitivity to isoprenaline of ventricular muscle after chronic reserpine pretreatment.

1. Isolated papillary muscles from guinea-pig hearts were paced at a constant frequency and isometric contractions reported. 2. Guinea-pigs were either untreated or pretreated with reserpine. Three pretreatment schedules were used; a) 0.5 mg kg-1 i.p. at 24 h, b) 5.0 mg kg-1 at 72 h and 3.0 mg kg-1 at 48 and 24 h, or c) 0.1 mg kg-1 daily for 7 days. 3. Cumulative concentration-response curves for the isoprenaline-induced increases in tension were obtained. The geometric mean EC50 values after the 3 and 7 day reserpine pretreatment schedules were significantly (P less than 0.05) less than for untreated guinea-pigs indicating a supersensitivity. 4. EC50 values for the positive inotropic responses to histamine and calcium in papillary muscles from reserpine-pretreated guinea-pigs did not differ significantly (P less than 0.05) from those from untreated animals. This suggests that the supersensitivity to isoprenaline is beta-adrenoceptor specific. 5. Membrane fractions were prepared from the ventricles of the untreated and reserpine-pretreated guinea-pigs from which papillary muscles had been removed. Binding of [3H]-dihydroalprenolol ([3H]-DHA) to beta-adrenoceptors of these membranes was determined. Equilibrium dissociation constants (KD) and total numbers of binding sites (Bmax) were determined by Scatchard analysis of the saturation curves for [3H]-DHA binding. 6. There was no increase in affinity (fall in KD value) or change in the total number of binding sites associated with reserpine-induced supersensitivity. The equilibrium inhibition constant (Ki) for the displacement of [3H]-DHA binding by isoprenaline was also identical in membranes from untreated and reserpine-pretreated animals. Thus reserpine-induced supersensitivity to isoprenaline does not appear to involve a change in affinity for the beta-adrenoceptor or in receptor numbers as determined by [3H]-DHA binding.

Animals↗
PubMed1988

Effects of the sulfhydryl reagent N-ethylmaleimide on reserpine binding to the catecholamine transporter in chromaffin granule membranes.

1. Catecholamines are transported into chromaffin granules via a carrier-mediated, active-transport process which is inhibited by micromolar concentrations of the sulfhydryl reagent, N-ethylmaleimide (NEM). Reserpine is a very potent, competitive inhibitor of the catecholamine transporter and can be used to investigate the characteristics of the catecholamine transporter. 2. The purpose of this study was to determine whether [3H]reserpine binding to the catecholamine transporter present in chromaffin granule membranes isolated from bovine adrenal glands was also inhibited by NEM and, if so, whether this was a direct or an indirect effect of NEM on the catecholamine transporter. 3. Both [3H]norepinephrine transport into and [3H]reserpine binding to the chromaffin granule ghosts isolated from bovine adrenal glands are inhibited by NEM, with IC50 values of 0.63 +/- 0.02 and 2.8 +/- 0.66 microM, respectively. 4. Mg and ATP protected both the [3H]norepinephrine transport into the ghosts and the [3H]reserpine binding to the transporter from inhibition by NEM, shifting the IC50 values to 260 +/- 43 and 120 +/- 29 microM, respectively. 5. NEM inhibition of the catecholamine transport and reserpine binding appears to be due to an action on the proton translocator associated with the Mg ATPase enzyme rather than a direct action on the catecholamine transporter since (a) the concentration of NEM required to inhibit formation of a membrane potential is similar to that required to inhibit [3H]norepinephrine transport into and [3H]reserpine binding to the ghosts and (b) Mg and ATP protected the proton translocation and [3H]norepinephrine transport into the ghosts, and [3H]reserpine binding to the ghosts, from inhibition by NEM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1988

Changes in rat parotid saliva protein composition following chronic reserpine treatment and their relation to inanition.

Chronic administration of the catecholamine-depleting agent, reserpine (0.5 mg/kg), resulted in a reduction in food intake after 3 days. To differentiate effects of the drug from those of reduced food intake a pair-fed group, whose daily caloric intake was restricted to the amount consumed by the reserpine-treated rats, was included. After 7 days, both the reserpine-treated and pair-fed control exhibited a marked reduction in the volume of saliva collected in a 30 min interval following a secretory stimulus compared to untreated ad libitum-fed controls, and the proportion of salivary proteins attributable to acidic and basic proline-rich proteins and to minor 1b protein were decreased whereas deoxyribonuclease was increased. For two of the salivary proteins (fractions I and V) changes for the reserpine-treated and pair-fed groups were different. Fraction I was reduced in both groups, but exhibited a greater decrease in the pair-fed than in the reserpine-treated, whereas fraction V was significantly increased only in the pair-fed group. Thus many of the salivary changes associated with reserpine treatment may have resulted from the change in feeding habits and not from reserpine treatment per se. The study demonstrates the importance of controlling for food intake under experimental circumstances which may lead to a marked change in daily feeding habits.

Animals↗
PubMed1982

[3H]Dopamine release by d-amphetamine from striatal synaptosomes of reserpinized rats.

The injection of reserpine, 5 mg/kg i.p. (ipRes), the regimen employed by a majority of investigators, results in synaptosomal and vesicular preparations which are incompletely reserpinized as determined by [3H]dopamine ([3H]DA) accumulation. Reserpine administered by the subcutaneous route, 5 mg/kg (scRes), appears to produce complete reserpinization. Release of [3H]DA by d-amphetamine (Amph) was observed from striatal synaptosomes prepared both from normal rats and those pretreated with reserpine intraperitoneally but not from those injected subcutaneously. In the more completely reserpinized scRes synaptosomes, so little [3H]DA had accumulated that release by Amph was not measurable, indicating that if a labile, reserpine-resistant, extravesicular DA storage pool releasable by Amph is present under these conditions, it must be extremely small. In scRes monoamine oxidase (MAO)-inhibited preparations, Amph released preloaded [3H]DA located in the cytosol in the absence of functional vesicles. Although chromatographic analysis of the superfusate from ipRes striatal synaptosomes showed that significant amounts of preloaded [3H]DA were released by Amph, the level of dihydroxyphenylacetic acid was not increased over controls, indicating that Amph releases only DA and not its metabolite and is also acting as a MAO inhibitor. No [3H]DA could be released by Amph from superfused hyposmotically shocked normal or ipRes synaptosomes, suggesting that an intact membrane is required for Amph-induced release.

Animals↗
PubMed1989

Reserpine enhances amphetamine stereotypies without increasing amphetamine-induced changes in striatal dialysate dopamine.

Indirect evidence suggests that amphetamine (AMPH) releases dopamine (DA) from an extravesicular, cytoplasmic pool. Disruption of vesicular DA storage by reserpine has been hypothesized to increase the concentration of extravesicular DA available for release by AMPH, which is consistent with the observation that reserpine does not prevent but augments the behavioral response to AMPH. In order to more directly test this hypothesis, the in vivo microdialysis technique was used to concurrently examine the behavioral and striatal dopaminergic response to AMPH (1.25 or 2.5 mg/kg) 24 h following reserpine pretreatment (2.5 mg/kg). Reserpine decreased tissue levels of DA by approximately 90% and reduced baseline dialysate DA concentrations by approximately 80%. Reserpine augmented the behavioural effects of AMPH, particularly increasing the occurrence and intensity of stereotypies. In contrast, reserpine did not alter the amount or duration of AMPH-induced DA release. This observation confirms that DA release by AMPH does not depend on vesicular stores but is inconsistent with the hypothesis that augmentation or behaviour by reserpine results from increased striatal DA release.

Amphetamines↗
PubMed1991

Reserpine-insensitive dopamine release in the substantia nigra?

Dopamine (DA) is synthesized and released not only from the terminals of the nigrostriatal dopaminergic pathway, but also from the dendrites in the substantia nigra (SN). Whether the DA release in the SN is sensitive to reserpine treatment, as it is in the stratum, has, however, not been clarified. We have determined the effects of reserpine on the concentrations of DA, serotonin and their metabolites in the SN and in the striatum and as an index of DA release in vivo we have assessed the accumulation of the DA metabolite 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase by pargyline. The effects of reserpine on the concentrations of DA and its metabolites were different in the SN as compared to in the striatum. In the striatum there was a maximal depletion of DA to 2% of controls, but in the SN the DA concentration decreased only to 17% of controls. In the SN, the increases of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were less pronounced than in the striatum. In the striatum reserpine treatment (given 15 h, 3.75 h, or 1.75 h before pargyline) decreased the pargyline-induced 3-MT accumulation to 30% of pargyline-treated controls. However, in the SN no effects of reserpine were observed. The results indicate that DA in the SN partly is situated in a reserpine insensitive pool and that the release of DA might be insensitive to reserpine. These differences between the SN and the striatum could be due to different storage mechanisms. In the striatum DA is stored in classical storage granulas but in SN DA is partly stored in storage granulas and partly in smooth endoplasmatic reticulum.

Animals↗
PubMed1991

Neurochemical changes associated with the persistence of spontaneous oral dyskinesia in rats following chronic reserpine treatment.

Rats treated chronically with reserpine develop spontaneous oral dyskinesia. The present study examined the development of the oral dyskinesia during the course of reserpine treatment, and its persistence after termination of treatment. Rats were injected with either reserpine (1 mg/kg, s.c.) or vehicle once daily for 4 days and then every other day for 6 weeks. Oral dyskinesia developed rapidly, reaching a maximal level after 3 days. It persisted at a maximal level for up to 20 days after termination of reserpine treatment, and continued to persist above control level for at least 60 days. The reserpine-treated rats also exhibited stereotypy in response to acute injection of the D1-selective agonist SKF-38393 (10 mg/kg), which was not observed in control rats. In contrast to the oral dyskinesia, this altered sensitivity to SKF-38393 returned to normal within 20 days after terminating the reserpine treatment, suggesting that these two behavioral responses involve different neural mechanisms. Quantitative autoradiographic measurement of dopamine receptor subtypes revealed that both D1 and D2 receptors were increased in the caudate-putamen (Cpu) and nucleus accumbens. Only the increase in D2 receptor density in the CPu correlated with the persistence of the oral dyskinesia; both changes persisted following termination of the reserpine treatment, and their magnitude was less at 60 days than at 1 and 20 days post-treatment. These results may have important implications for tardive dyskinesia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1980

Reserpine-induced gastric ulcers: protection by lysosomal stabilization due to zinc.

The effects of graded doses of zinc sulfate pretreatment on reserpine-induced gastric ulceration and on lysosomal fragility both in vivo and in vitro, were studied in rats. Reserpine treatment (5 mg/kg, i.p., 18 h before sacrifice) induced marked gastric glandular ulceration and elicited the release of free beta-glucuronidase from lysosomes in the gastric mucosa. A similar effect on release of this enzyme from isolated rat hepatic lysosomes was observed after in vitro incubation with reserpine. Zinc sulfate (22, 44 or 88 mg/kg, i.p., 30 h before reserpinization, or 10(-3) M in vitro) inhibited the reserpine-induced response, and zinc sulfate alone (10(-11)--10(-3) M) also stabilized lysosomal membrane permeability to beta-glucuronidase. No direct effect of zinc or reserpine on purified beta-glucuronidase activity was observed. In conclusion, it is postulated that the stabilizing effect of zinc on lysosomal membranes, as manifest by reduced release of beta-glucuronidase from isolated lysosomes, is one of the protective mechanisms of zinc against reserpine-induced ulceration.

Animals↗
PubMed1996

Effects of amphetamine and 6-hydroxydopamine lesions on reserpine-induced oral dyskinesia.

The present study examined whether reserpine-induced oral dyskinesia is mediated by release of residual endogenous dopamine. Amphetamine produced a dose-dependent change in reserpine-induced oral dyskinesia in which the response was exacerbated by 0.6 mg/kg amphetamine and inhibited by 1 mg/kg. The latter dose also produced stereotypy that may have interfered with expression of reserpine-induced oral dyskinesia. Nigrostriatal 6-hydroxydopamine lesions attenuated expression of reserpine-induced oral dyskinesia. These lesions did not reduce locomotor activity, however, indicating that the attenuation of reserpine-induced oral dyskinesia was not due to a general depressant effect of the lesions on motor behavior. These results suggest that increasing dopamine release by administration of amphetamine exacerbates reserpine-induced oral dyskinesia, whereas decreasing the amount of releasable dopamine in the striatum by 6-hydroxydopamine lesions attenuates reserpine-induced oral dyskinsia. These findings may have implications for understanding tardive dyskinesia and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia.

Adrenergic Agents↗