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Inhibition of reserpine, guanethidine and imiparmine of the uptake of 5-hydroxytryptamine by rat peritoneal mast cells in vitro.

The effect of reserpine, guanethidine and imipramine of the uptake of tritiated 5-hydroxytryptamine by rat peritoneal mast cells was studied in vitro. The Km value for uptake of 5-hydroxytryptamine was 3 x 10(-7) M in this study. Kinetic analysis of the data obtained suggests that the drugs inhibits the uptake in a competitive manner, in the order of decreasing potency: reserpine, imipramine, guanethidine. For reserpine the Dixon plot resulted in two curves, each composed of 2 linear components suggesting inhibition of uptake of 5-hydroxytryptamine at 2 different levels or by 2 different mechanisms with different K1 values. It is suggested that the higher K1 value, representing an immediate effect of reserpine, stands for inhibition of uptake at the cell membrane. The lower K1 value possibly represents inhibition at the level of the membrane surrounding the intracellular storage organelles.

Animals↗

Effects of reserpine and isoproterenol on elemental distribution in submandibular gland of rat.

The effects of a single dose of reserpine or isoproterenol on the acinar cells of rat submandibular gland were investigated by electron microscopy and X-ray microanalysis. About 4 h after injection of reserpine, the cellular Ca concentration started to increase and at 24 h a level two to three times the control value was reached. The mucus content of the cells increased in parallel with the Ca concentrations. Isoproterenol stimulation depleted the acinar cells of their mucus. Resynthesis of mucus was visible at 8-12 h after injection. Changes in cellular Ca concentrations followed the mucus content of the cells. After 24 h both the mucus content and the Ca concentration were significantly increased over the control values. High-resolution X-ray microanalysis on thin cryosections showed that the calcium was accumulated in the mucus granules, both after reserpine and after isoproterenol administration. The newly synthesized mucus was also more calcium-rich than the original mucus. The effect of a single isoproterenol stimulation on elemental content of rat submandibular gland acinar cells was not significantly different from that of chronic isoproterenol treatment. Chronic treatment with reserpine resulted in a higher cellular Na/K ratio than a single dose.

Animals↗

The effect of reserpine treatment on choline acetyltransferase activity in rat submaxillary glands.

Rats were treated daily with a low dose of reserpine (0.1 mg kg-1) injected subcutaneously for 3 weeks. In the submaxillary glands the noradrenaline content was reduced by about 95%. The total activity of the acetylcholine-synthesizing enzyme choline acetyltransferase remained unchanged. However, the activity of this enzyme was found to be increased when the reserpine treatment was followed by surgical sympathetic denervation and the glands were analysed 3 weeks post-operatively. The enzyme activity also increased in the glands when the surgical sympathetic denervation was performed on the day of the start of the reserpine treatment. The lack of effect of reserpine on choline acetyltransferase activity in the glands seems to exclude the possibility that it is the depletion of neuronal noradrenaline stores that initiates the events giving rise to increases in choline acetyltransferase activity after sympathetic denervation.

Animals↗

Neuropeptide Y and noradrenaline mechanisms in relation to reserpine induced impairment of sympathetic neurotransmission in the cat spleen.

The mechanisms underlying the reserpine-induced impairment of the functional responses to sympathetic nerve stimulation and output of noradrenaline (NA) and neuropeptide Y (NPY)-like immunoreactivity (-LI) were studied using the isolated blood-perfused cat spleen. Splenic nerve stimulation (10 Hz for 2 min) during control conditions caused perfusion-pressure increase, volume reduction and an increased output of NA and NPY-LI. After administration of phenoxybenzamine, the nerve stimulation-induced perfusion-pressure increase was almost abolished, the volume reduction inhibited and the output of NPY-LI enhanced. After subsequent addition of propranolol, a clear-cut increase in perfusion pressure upon nerve stimulation reappeared. Local infusion of NPY caused a potent, long-lasting, adrenoceptor-resistant increase in perfusion pressure and a relatively smaller volume reduction of the spleen. Twenty-four hours after reserpine pretreatment (1 mg kg-1 i.v.), which depleted the splenic content of NA greater than 95% and NPY-LI by about 50%, the functional responses upon nerve stimulation were markedly reduced. Preganglionic denervation or pretreatment with the ganglionic-blocking agent chlorisondamine did not influence the NA depletion after reserpine treatment. A considerable, adrenoceptor antagonist-resistant, long-lasting functional response as well as a markedly enhanced output of NPY-LI then occurred upon nerve stimulation. In conclusion, reserpine treatment combined with interruption of preganglionic impulse flow reveals non-adrenergic, nerve stimulation evoked splenic functional responses which could be mediated by release of a cotransmitter peptide like NPY.

Adrenergic alpha-Antagonists↗

A comparison of the effects of morphine and pethidine upon body temperature and the reversal of reserpine's effects upon body temperature in the mouse.

The effects of morphine and pethidine upon body temperature and upon the reversal of reserpine hypothermia in the mouse were investigated. Both morphine and pethidine produced a dose-dependent fall in body temperature, that of morphine being totally antagonized by nalorphine and partially by naloxone, while that of pethidine was antagonised by naloxone and enhanced by nalorphine. Both drugs reversed reserpine-induced hypothermia. The reversal by morphine, but not by pethidine, was partially antagonized by naloxone. Adrenalectomy prevented the reversal of reserpine hypothermia by pethidine but morphine produced a partial reversal. Ganglion blockade and alpha-and beta-blockade all prevented reversal of reserpine hypothermia by both drugs. The results are discussed with regard to differences between pethidine and morphine and possible involvement of opiate receptors.

Adrenalectomy↗

Effect of reserpine pretreatment on brown fat iodothyronine 5'-deiodinase of mouse.

The effect of pretreatment with reserpine (1 mg kg-1 i.p. daily for 7 days) on the regulation of iodothyronine 5'-deiodinase (5'D) in mouse brown adipose tissue (BAT) has been examined. 5'D activity of BAT homogenate was assessed by the in-vitro formation of 3,5,3'-triiodothyronine from thyroxine and 3,3'-diiodothyronine from 3,3',5'-triiodothyronine in the presence of 20 mM dithiothreitol. Reserpine treatment decreased the stimulation of BAT 5'D induced by acute cold exposure (4 degrees C, 2 h) without a significant decrease in the basal 5'D activity, whereas stimulation of BAT 5'D elicited by noradrenaline (0.4 and 0.8 mg kg-1 s.c. 2 h previously) was not augmented after reserpine treatment. Although both noradrenaline and acute cold exposure increase BAT 5'D through alpha 1-adrenoceptors, our results show that chronic reserpine treatment prevents the effect of cold, but does not induce alpha 1-adrenoceptor supersensitivity in BAT.

Adipose Tissue, Brown↗

The effect of reserpine and stress on feeding behaviour in the light and dark phases of the diurnal cycle in rats.

The effect of reserpine (2.5 mg kg-1 subcutaneously) and stress (3 h restraint) on food and water consumption and body weight change in the light and dark phases of the diurnal cycle in rats was investigated. Reserpine increased water intake and body weight loss in the light phase (250 and 180% of the control, respectively). In the dark phase the reserpinized rats consumed less food and water (20 and 30% of the control, respectively) and body weight gain was reversed (-250% of the control). After stress, rats consumed more food and water (200 and 500% of the control, respectively) and their body weight loss was diminished (60% of the control) in the light phase. In the dark phase the consumption of food and water in the stressed rats was diminished (80 and 85% of the control, respectively) without any change in body weight gain. The dark/light phase ratio for food consumption, water intake and body weight change (gain/loss) was highly statistically significant in the stressed and reserpine-treated rats. The results indicate that evaluation of behaviour in animal models should be carried out during both phases of the diurnal cycle.

Animals↗

Release of [3H]noradrenaline from perfused rat hearts by potassium and its modifications by 6-hydroxydopamine and reserpine.

The sources of noradrenaline (NA) released by excess potassium from isolated perfused rat hearts were investigated by labelling the hearts from normal, reserpine-treated, and 6-hydroxydopamine-treated (6-OHDA-treated) rats with [3H]HA, and measuring the increased rate of efflux induced by perfusion with a Krebs solution containing varying amounts of excess potassium. The [3H]NA and its metabolites in the effluent were separated by adsorption on alumina and a cation-exchange resin (Dowex-50). The release induced by potassium was a linear function of the log of the increased potassium concentration. Following a 1-h efflux period after labelling with [3H]NA, the hearts from reserpine-treated rats retained 1/5 as much [3H]NA, and released, in response to a 56mM elevation in the potassium concentration, less than 1/6 as much tritium label as the hearts from untreated (control) animals. In contrast, the hearts form 6-OHDA-treated animals retained 1/15 of the amount of [3H]NA and released 1/50 of the 3H label as did the control hearts. The potassium-induced increase of 3H-labelled substances in the effluent from the control hearts showed a large (threefold) percentage increase in the [3H]NA fraction, whereas the effluents from the hearts of reserpine- and 6-OHDA-treated animals contained only small increases in the [3H]NA fraction. Based on the assumptions that reserpine prevented retention of NA in the storage granules whereas 6-OHDA prevented almost all neuronal storage, it was concluded that more than 80% of the NA released by potassium excess from perfused normal hearts originated from the storage vesicles of the nerves, the remainder being largely from the cytoplasm of the nerves, with only a small portion from extraneuronal sources.

Animals↗

Reserpine-induced changes in cardiac adrenergic receptors.

Using radioligand binding techniques, the effect of reserpine pretreatment on ventricular adrenergic receptors from guinea pig was studied. [3H]Prazosin and [3H]dihydroalprenolol were used to label alpha 1- and beta-adrenergic receptors, respectively. Administration of 2.5 mg/kg reserpine for 2 days caused a significant increase in the number of beta-adrenergic receptors with no effect on their affinity to respective ligands. Similar reserpine pretreatment did not affect either density or affinity of alpha 1-adrenergic receptors for ligands. The results may explain the previous report from our laboratory in which an identical reserpine pretreatment selectively enhanced the inotropic responsiveness of the working guinea pig heart to isoproterenol.

Animals↗

Effects of neonatally administered chlorpromazine and reserpine on the responsiveness of rat hepatic drug-metabolising enzymes to testosterone in adult life.

The effects of neonatally administered chlorpromazine and reserpine on the response of rat hepatic drug-metabolising enzymes to testosterone in adult life have been investigated using the chlorinated cyclodiene substrate DME. Neonatal treatment with chlorpromazine and reserpine had effects on the metabolism of DME similar to, but not as pronounced as, those of castration when adult. The effects of adult castration of male rats on hepatic microsomal metabolism of DME were fully reversed by treatment with testosterone propionate, with metabolism being restored to that of a control intact male. However, testosterone propionate treatment of either intact or castrated adult males that had received neonatal reserpine or chlorpromazine did not restore levels of metabolism to those characteristic of control adult male rats. These results suggest that neonatally administered chlorpromazine and reserpine alter the sensitivity of hepatic drug-metabolising enzymes to the actions of testosterone in adult life.

Aging↗

Effect of long-term use of reserpine, a sympathetic neuron blocker, on muscarinic cholinergic receptors in the guinea pig nasal mucosa.

To evaluate whether hypofunction of the sympathetic nervous system induced by long-term reserpine treatment affects the parasympathetic system in the nasal mucosa in the receptor level, a receptor binding assay was performed using the nasal mucosa of guinea pigs which had chemical denervation produced by intraperitoneal injection of 0.1 mg/body reserpine once daily for 4 weeks. The maximum number of muscarinic cholinergic receptor bindings to diquinuclidinyl benzilate (3H-QNB) in the nasal mucosa of the reserpine-treated guinea pigs was increased by 46% as compared with that in the control (p less than 0.05). The present experiment shows that hypofunction of the sympathetic system in the nasal mucosa induced by reserpine may affect the parasympathetic system in the nasal mucosa.

Animals↗

Treatment with reserpine of patients resistant to tricyclic antidepressants. A double-blind trial.

The literature concerning the therapeutic effects of the administration of reserpine to patients who fail to respond satisfactorily is discussed briefly. A double-blind study was conducted on 14 patients; eight were given 5 mg of reserpine i.m. and six were given 2 ml of normal saline on 2 successive days. The administration of the tricyclic antidepressants the patients had been taking, was continued. The Hamilton Depressive Rating Scale was administered on the day before treatment was commenced, and repeated on the fourth day. Statistical analysis revealed that the patients who received reserpine showed a highly significant improvement of a good quality. The mean fall in the Hamilton rating for the placebo group was 6 points, and in the reserpine group it was 18.87. The therapeutic significance of the findings is discussed.

Adolescent↗

The pathogenesis of interstitial pneumonitis induced by trehalose dimycolate. II. Reserpine prevents formation of lesions.

A single intraperitoneal injection of 10 micrograms of trehalose dimycolate (TDM) produced interstitial and hemorrhagic pneumonitis in C57BL/6 mice. As a part of an investigation of a possible role for cell-mediated immunity in the pathogenesis of this disorder, we found that reserpine, 3 mg/kg, given before, at the same time, or on Day 5 after administration of TDM, significantly reduced development of interstitial pneumonitis by Day 7. Smaller doses were less effective. Administration of reserpine, 3 or 2 mg/kg, 1 to 3 days after administration of TDM was lethal to most mice. Reserpine has been shown to inhibit expression of cell-mediated immune responses in mice, probably by causing intercellular release and degradation of vasoactive amines. Inhibition of pulmonary lesions by reserpine in TDM-treated mice suggests that a similar mechanism may be involved in the pathogenesis of TDM-induced lung injury.

Animals↗

Abnormal 45Ca fluxes in dispersed submandibular acini of rats treated with reserpine.

The uptake and efflux of the isotopic tracer 45Ca were compared in dispersed submandibular acini of both control rats and rats treated with seven daily doses of reserpine (0.5 mg/kg, i.p.). Tracer uptake occurred in a time-dependent manner in both types of acini and reached 8.4 +/- 0.2 and 8.0 +/- 0.2 pmol/mg protein, respectively, in acini from control and treated animals after 60 min of incubation. Uptake of tracer was 2.35 nmol/mg DNA in control cells and 4 nmol/mg DNA in cells from treated rats at 60 min. 45Ca uptake (per mg protein) was enhanced in control acini 48% by 20 mumol/L epinephrine; 38% by 50 mumol/L carbachol; and 23% by 10 mumol/L isoproterenol. A similar order of potency was observed when uptake was expressed per mg DNA. In acini from reserpine-treated rats, 45Ca uptake (per mg protein) was increased 53% by epinephrine, 39% by isoproterenol, and only 8% by carbachol. The same enhanced effect of isoproterenol and lack of effect of carbachol were observed when uptake was calculated per mg DNA. In the absence of secretagogue, efflux of 45Ca from tracer-pre-loaded acini was larger in acini from reserpine-treated rats (53%) than in control acini (36%). Whether expressed in terms of mg protein or mg DNA, this efflux was increased in control acini 35% by epinephrine, from 25 to 28% by isoproterenol, and 17% by carbachol. In acini of reserpine-treated rats, epinephrine increased 45Ca efflux 20%, isoproterenol from 25 to 28%, and carbachol from 14 to 15%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Alprazolam reversal of reserpine-induced depression in patients with compensated tardive dyskinesia.

Two patients are described who developed neuroleptic drug-induced tardive dyskinesia (TD) secondary to the treatment of schizophrenia. In both patients, neuroleptic drug discontinuation brought about a decrease in the severity of the TD and an increase in schizophrenic symptomatology. Reserpine was added for both antipsychotic coverage and reported beneficial effects in the treatment of TD. The patients' schizophrenia was controlled using reserpine 1 mg/d; the TD dissipated in one patient and decreased in the other. After about seven weeks of reserpine therapy, both patients developed depressive symptoms that required the addition or alprazolam. Within a month of the initiation of alprazolam, the depressions had cleared. Alprazolam may block reserpine-induced increases in beta-adrenergic receptors in the brain and may account for the antidepressive effects in these two patients.

Adult↗

The chronically reserpinized rat as a possible model for cystic fibrosis. VI. Synergistic effects of isoproterenol on Ca++ and protein in the submaxillary gland.

Elevated calcium and protein concentration are a consistent abnormality in submaxillary saliva from patients with cystic fibrosis (CF) and from experimental animal models developed by the chronic administration of either isoproterenol (IPR) or reserpine. The possibility that the effects of the two drugs may be additive was investigated by assessing their combined effects on glandular and salivary C++ and protein in the rat submaxillary gland. Individually, their effects were also assessed in relation to the dose used. Results indicate that: (1) treatment for 7 days with 0.05, 0.50, and 5.0 mg/kg daily dose of reserpine caused, respectively, a 45%, 95%, and 120% increase in glandular Ca++ and a 9.3%, 16.5%, and 37.4% increase in glandular protein; (2) treatment for 7 days with a 5.0 mg/kg daily dose of isoproterenol caused a 138% increase in gland Ca++ and a 12.38% increase in gland protein. Treatment with a 5.0 mg/rat daily dose of this drug caused increases of 166% and 10.3% in gland Ca++ and protein; (3) in experiments involving a combination of the two drugs, isoproterenol was administered in a 5.0 mg/kg daily dose from days 1-7 and reserpine in a 0.5 mg/kg daily dose from days 4-10 of the treatment schedule. This procedure resulted in (a) a 217% increase in gland Ca++ and a 25.7% increase in gland protein; (b) a marked accumulation of a granular, basophilic material in acinar cells and the development of intraductal precipitates; (c) the secretion of turbid saliva with high Ca++ and protein concentrations after a secretory dose of isoproterenol (this type of stimulation also reduced the gland Ca++ (50%) and protein (20%) contents and produced vacuolization in the acinar cells); (d) the secretion of saliva with elevated Ca++ and protein in response to pilocarpine (these elevated concentrations were, however, one-fifth of those obtained after isoproterenol stimulation); (e) the secretion of smaller volume of saliva after both types of stimulation. These findings indicate that both IPR and reserpine have a dose-related and significant effect on submaxillary gland Ca++ and protein and that their individual effects are synergistic. The implications of this synergism for the physiologic state of the submaxillary gland and for the secretory abnormality of cystic fibrosis are discussed.

Animals↗

Chronically reserpinized rat as a model for cystic fibrosis: Na+ transport inhibitory effect in submaxillary saliva.

The retrograde perfusion assay in the rat parotid gland was used to investigate the effects of salivary secretions from control and reserpine-treated rats on Na+ reabsorption. Results demonstrated that submaxillary saliva from the treated animals caused a 69% inhibition of Na+ reabsorption, accompanied by a 28% reduction in the volume of saliva secreted, and a 22% reduction in flow rate. By contrast, submaxillary saliva from control rats caused a 6% inhibition of Na+ reabsorption, a 6% reduction in volume, and a 5% reduction in flow rate. Parotid saliva from reserpine-treated rats also inhibited Na+ reabsorption to the extent of 39% and caused a 38% reduction in volume and a 33% reduction in flow. Parotid saliva from control rats only inhibited Na+ reabsorption to the extent of 2.7% and caused a 4--6% reduction in salivary volumes and flow rates. The inhibition of Na+ reabsorption and the reduction in salivary volume and flow rates caused by submaxillary saliva of reserpine-treated rats were either abolished or significantly reduced when the saliva was previously heated to 100 degrees C, frozen, and then thawed or kept in glass tubes at 4 degrees C for 24 hr. These results indicate that saliva from reserpine-treated rats have comparable effects in this assay system to those of saliva from cystic fibrosis (CF) patients and further support its use as an animal model for this disease.

Animals↗

The chronically reserpinized rat as a model for cystic fibrosis: abnormal Cl- transport as the basis for reduced salivary fluid secretion.

Saliva secretion induced by 10(-6) M acetylcholine was reduced 74% in isolated, perfused submandibular glands of control rats when the gland was perfused with solutions containing either furosemide (10(-3) M) or sulfate (instead of chloride) as the major anion. In regular (Cl-containing) perfusates without furosemide, saliva secretion was reduced 74% in isolated glands of rats treated with seven intraperitoneal doses of reserpine (0.5 mg/kg body weight). In the latter, addition of furosemide or replacement of perfusate Cl- with SO = 4 caused a further 35% drop in saliva volumes. Salivary Cl- concentrations were lower in saliva from the treated animals and were reduced further by furosemide, which also reduced the Cl- concentrations of control saliva. In submandibular acini isolated from control glands, acute exposure to 36Cl (1 mu Ci/ml) resulted in a rapid uptake of tracer so that a constant content of isotope (approximately 9.5 nM/mg protein) was attained in 4-5 min and maintained for 30 min. This basal uptake reached 8.4 nM/mg protein in acini isolated from glands of reserpine-treated rats and attainment of a steady state of tracer content was delayed and required 8-10 min. Exposure to acetylcholine reduced uptake and steady state tracer content by 35% in control acini, but had no effect in acini of reserpine-treated rats. Acetylcholine caused a rapid decrease (42% in 1 min) in 36Cl content of control acini which were preloaded with tracer for 12 min, but only a 23% decrease in acini of reserpine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗