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Synthesis of collagen in the vasculature and other tissues of normotensive rats is markedly reduced by reserpine. Hypophysectomy produces similar effects. The effects of reserpine on collagen biosynthesis may be mediated through the hypothalamus.
Adrenal medullary chromaffin cells maintained in a chemically defined, serum-free medium retain high levels of both catecholamines and opiate-like peptides. At least 25% of the opioid activity as measured by radioreceptor assay is present as [Met]- and [Leu]enkephalin. Incubation of chromaffin cells with [3H]tyrosine and [35S]methionine for 3 days results in incorporation of 3H and 35S into [Met]enkephalin and 3H incorporation into [Leu]enkephalin, demonstrating de novo enkephalin synthesis. Addition of 100 nM reserpine to the culture medium causes an 80% depletion of catecholamines and a 100% increase in opioid peptide content 3-4 days later. [Met]Enkephalin content is preferentially induced (290% above control) compared with [Leu]enkephalin (70%) Reserpine increases the fractional radiolabeling of [Met]- and [Leu]enkephalin in excess of control cultures, suggesting that the increase in opiate-like peptides results from an increased rate of synthesis rather than decreased degradation, decreased secretion, or increased processing of preformed precursor(s).
The toxin N-methyl-1,2,3,6-tetrahydropyridine produces a model of neural degeneration very similar to idiopathic Parkinson disease. To understand the cellular mechanisms that modulate susceptibility to its active metabolite N-methyl-4-phenylpyridinium (MPP+), we have transfected a cDNA expression library from the relatively MPP(+)-resistant rat pheochromocytoma PC12 cells into MPP(+)-sensitive Chinese hamster ovary (CHO) fibroblasts. Selection of the stable transformants in high concentrations of MPP+ has yielded a clone extremely resistant to the toxin. Reserpine reverses the resistance to MPP+, suggesting that a transport activity protects against this form of toxicity, perhaps by sequestering the toxin within an intracellular compartment. In support of this hypothesis, dopamine loaded into the CHO transformant shows a localized distribution that is distinct from the pattern observed in wild-type cells and is also reversed by reserpine.
Reserpine was found to inhibit the secretion of luteinising hormone when injected into intact and gonadectomised fowl at a dose rate which caused heavy sedation. This could indicate that reserpine or its derivatives should not be used for breeding poultry.
Hourly release of Prolactin by pituitary constructs 1 whole pituitary (PI), adenohypophysis (P-N) and pituitary-hypothalamus co-incubate (PHC) were compared. Adenohypophysis secreted significantly more prolactin than PI and PHC, while PHC secreted significantly less than PI. Co-incubation of (P-N) with posterior pituitary reduced the elevated secretion of prolactin. Addition of dopamine (10(-7) M), bromocriptine (10(-7) M) and apomorphine (5 x 10(-8) M) to these constructs did not affect the release of prolactin from PI but inhibited the same from (P-N) and PHC. Treatment with reserpine increased serum prolactin levels but intrapituitary prolactin contents were decreased. Hourly release of prolactin from pituitary constructs derived from reserpine-treated rats was significantly reduced as compared to ascorbic acid--treated controls. Inclusion of dopamine (10(-7) M), bromocriptine (10(-7) M) and apomorphine (5 x 10(-8) M) in these constructs inhibited prolactin secretion further. In vitro addition of perphenazine stimulated the release of prolactin by PHC but was without any effect on PI and (P-N). The data are interpreted to suggest that dopamine in posterior pituitary may be an important determinant of hypothalamic modulation of prolactin secretion.
Tissue levels of nineteen amino acids and total free amino acids, were assayed by gas-liquid chromatography in cytosols of rat atrial and ventricular muscle cardiomyocytes. The tissues were assayed after the rats had been administered IP with the three cardioactive drugs, exerting a significant effect on their heart action: propranolol, pentylenetetrazol and reserpine. It was demonstrated that while in the atrial and ventricular cardiac muscle cytosols of control rats, arginine, glutamine and cysteine were detected in high levels (35.1% and 17.6%; 14.8% and 51.6%; 9.9% and 0.25% of the total free amino acids, respectively), all three drugs significantly reduced the total amounts of cytosolic free amino acids in both atrial and ventricular heart muscles. All three drugs (with reserpine in particular) modified the levels of arginine, cysteine, phenylalanine, tryptophan, isoleucine and tyrosine. The role of these amino acids in the heart muscle cytosol, and their involvement in the mechanism of action of these three cardioactive drugs, is discussed.
Vascular spasm may complicate both traumatic injuries and disease processes. It may be severe enough that thrombosis and vascular compromise occur, causing tissue necrosis. Transient relief may be obtained by proximal sympathetic blocks, but these are not well tolerated by the patient and require repeated injections. This study shows that a single intra-arterial injection of 1.25 mg of reserpine into the branchial artery of human volunteers with a No. 25 needle produces a prolonged sympathectomy distal to the site of injection, with cutaneous flushing, increased temperature, and increased digital pulse wave recordings. It also eliminates the vasoconstriction normally caused by a cold stimulus. Using this dose, the side effects were minimal. No complications were encountered as a result of the technique. Low-dose intra-arterial reserpine is recommended for the treatment of reversible vascular spasm.
Maternal deprivation for 24 hr is known to produce hyperactivity in 2-week-old infant rats kept at nest temperature. Pretreatment with reserpine (0.5 mg/kg), at the time of separation, prevented the development of hyperactivity over the ensuing 24-hr, whereas the same dose in mothered littermates had no residual effects on behavior the next day. d-Amphetamine (0.25 and 2.0 mg/kg) produced dose-dependent increases in locomotion and rearing and decreases in self-grooming behavior, which were of comparable magnitude whether the pups were separated and kept warm, normally mothered, or separated at room temperature, a condition known to produce decreased activity levels. Cardiac rates were not affected by either drug; reserpine lowered respiratory rates slightly, amphetamine increased body temperature following behavior testing. Altered accumulation of catecholamines at presynaptic terminals is discussed as a possible neurochemical mechanism for behavior changes following maternal separation in this model system.
The reserpine model and the reduced monoamine hypothesis of the depressive symptom spectrum suggest that the reserpine-sensitive brain vesicular monoamine transporter (VMT) is a candidate for susceptibility to affective disorder. VMT nonselectively accumulates cytoplasmic biogenic monoamine neurotransmitters into the storage vesicles of presynaptic neurons and blood platelets. Complementary DNA (cDNA) synthesized from platelet VMT mRNA was analyzed in 17 patients meeting DSM-III-R diagnostic criteria for major depressive or bipolar disorder and in four healthy controls, using polymerase chain reaction (PCR) amplification and direct sequencing. PCR sequencing of the protein coding region failed to reveal changes in the deduced amino acid sequence of the platelet/brain VMT (approximately 36,000 base pairs sequence screened). The results indicate that alterations in the primary structure of the VMT are not generally involved in the pathogenesis of unipolar depression and manic depressive illness.
The involvement of mast cells in the elicitation of contact photosensitivity (CPS) was examined in mice treated with pharmacologic agents and in genetically mast cell-deficient W/Wv mice. Contact photosensitivity responses were diminished by pretreatment with reserpine, which may have been due to depletion of vasoactive amines in mast cells. This inhibition was almost reversed by the monoamine oxidase inhibitor, pargyline-HCl, which prevented reserpine-induced depletion of vasoactive amines such as serotonin. Defective CPS was also found in W/Wv mice, but not in their congenic littermates (+/+). Abnormal CPS in mast cell-deficient mice was due to a defect in the elicitation of CPS rather than a defect in the induction of effector T cells, since the ability to elicit CPS could be transferred to normal +/+ mice by photosensitized cells from mast cell-deficient mice. These findings favor the view that mast cells are involved in the elicitation of CPS.
The case is presented of a hypertensive patient on reserpine, who developed ventricular irritability after administration of alfentanil, a new ultra-short-acting narcotic used in anesthesia. The dysrhythmias resolved after cessation of the offending agent. There are no reported cases of interaction of reserpine and alfentanil in the literature.
We have studied the effect of a single injection of reserpine (5 mg/kg, s.c.) on the synaptic vesicle monoamine transporter (VMAT) density in the rat striatum, using two labelling procedures: radioimmunolabelling with an antibody against VMAT, and binding of the specific ligand [(3)H]dihydrotetrabenazine ([(3)H]TBZOH). In the rostral and medial striatum, the distribution of VMAT immunoreactivity displayed the highest density in the lateral subregions. In the caudal part of the striatum, VMAT immunoreactivity showed increasing density from dorsal to ventral subregions. The VMAT immunoreactivity was not altered 2 and 30 days after the reserpine injection, whereas [(3)H]TBZOH binding site density, measured on adjacent slices, showed a dramatic decrease at day 2 and a moderate recovery at day 30, suggesting that despite a persistent blockade of [(3)H]TBZOH binding sites, VMAT protein density was unchanged.
Electroconvulsive shock (ECS) administered once daily for up to 14 days decreases beta-adrenergic receptor binding in the cortex and hippocampus in a time-dependent manner. The decrease in binding in the cortex lasts at least 1 week after the last shock. In the striatum, hypothalamus, or cerebellum, 14 days of ECS did not produce significant changes in beta-adrenergic receptor binding. The brain regional pattern of beta-adrenergic receptor changes suggests that repeated ECS affects beta 1-adrenergic receptors in brain regions that receive a noradrenergic innervation activated by ECS. The effects of ECS on neurotransmitter receptor binding appear to be highly selective. Of five receptors in the cortex and three receptors in the hippocampus measured, only beta-adrenergic receptor binding is decreased. Chronic footshock stress does not alter beta-adrenergic receptor binding sites in the cortex, indicating that the effects of ECS are not due to stress alone. The effects of ECS on reserpine-induced alterations in beta-adrenergic receptor binding sites were also examined. Ten days of ECS following chronic reserpine injections reverses the increased binding of beta-adrenergic receptors.
The basal catecholamine content of rabbit retina was determined by liquid chromatography with electrochemical detection (LC-EC) and 3,4-dihydroxyphenylethylamine (dopamine, DA) found to be the major catecholamine. The immediate DA precursor, 3,4-dihydroxyphenylalanine (L-DOPA), and the metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), were also detected at about 2.8% and 17% of DA levels, respectively. When added exogenously, L-tyrosine did not increase the rate of DA synthesis over the basal level. In contrast, exogenous L-DOPA led to a 3.5-fold increase in DA, and to a 20-fold increase in DOPAC content. The monoamine oxidase inhibitors pargyline and (-)-deprenyl differentially affected the degradation of DA, since 100 microM pargyline was apparently more effective than 100 microM (-)-deprenyl. Reserpine and (+/-)-amphetamine each induced a Ca2+-independent decrease of DA stores. The separate actions of reserpine and (+/-)-amphetamine in lowering tissue DA levels were additive, suggesting two separate pools of DA available for release from presynaptic stores. The present study demonstrates that the LC-EC technique may be used to investigate the modulation of the synthesis and release of retinal DA in vitro, without the prior uptake of radiolabelled transmitter.
The effects of acute treatment with p-chloramphetamine, d-fenfluramine, and reserpine on intracellular (brain tissue and whole blood) and extracellular (CSF and platelet-free plasma) compartments of 5-hydroxytryptamine (5-HT) in the brain and blood of the same rats have been examined. These treatments affected 5-HT in brain tissue and whole blood similarly (r = 0.823). Reserpine significantly reduced both intracellular pools at 2 and 24 h. p-Chloroamphetamine and d-fenfluramine were more effective on brain tissue 5-HT. The concentration of 5-HT in CSF was significantly increased by all treatments. p-Chloroamphetamine induced a dramatic 70-fold increase of CSF 5-HT, paralleling a 42% decrease in brain tissue. d-Fenfluramine significantly increased CSF 5-HT to 212% of controls and reduced whole brain 5-HT (-23%). The effects of p-chloroamphetamine and d-fenfluramine on 5-HIAA in brain, CSF, and plasma were nonsignificant. Individual values of 5-hydroxyindoleacetic acid (5-HIAA) in CSF and brain were highly correlated (r = 0.855), indicating that CSF 5-HIAA reflects well the concentration of 5-HIAA in brain tissue. Yet the intra- and extracellular concentrations of 5-HIAA were unrelated to the 5-HT changes. This indicates that CSF 5-HIAA does not reflect the active (extracellular) compartment of 5-HT in brain.
Doses of 1 to 2.3 mg./kg. of reserpine given intravenously to rabbits raised the plasma adrenaline. The noradrenaline concentrations were too near the threshold of the method to decide whether any alterations followed the injection of reserpine. Control experiments, in which blood samples were taken from rabbits but no drug was given, showed only a very slight rise in adrenaline concentration after the first bleeding.
A single intraperitoneal injection of reserpine (2.5 mg./kg.) into rats produced a fall in the corticotrophin concentration of the pituitary to 30% of the resting value; recovery was not far from complete at 40 hr. A single injection of a nitrogen mustard caused an even greater loss of pituitary corticotrophin; 24 hr. after the injection the concentration was 10% of the resting value. There is no reason to assume that the effect of reserpine is due to an interference with storage of ACTH in the tissue and is not simply due to the fact that the drug acts as a stressing agent. The shape of the curve representing the fall in pituitary ACTH during the early phases of a sudden stress may be very similar to that of the fall in adrenal ascorbic acid produced by the released ACTH. This suggests that, under these circumstances, resynthesis is slow and the diminishing stores of ACTH in the pituitary reflect mainly the release of the hormone.
Dibenamine-like compounds sometimes caused an increase in blood pressure when injected intravenously in mammals. This response varied with species, with the preparation, and with the structure of the compound. The response became smaller after repeated injections. In spinal atropinized rats injected with hexamethonium 5 mg/kg this pressor effect produced by injection of the adrenaline antagonist, compound AT3 [ethylfluoren-9-yl(2-iodoethyl)amine hydriodide], was reduced by prior treatment for five days with 1 mg/kg reserpine. Acute adrenalectomy also reduced this effect of the adrenaline antagonist; reserpine plus adrenalectomy abolished it. Subsequent injection of adrenaline and noradrenaline restored it.