Effects of chronic levodopa on D1 and D2 receptor-mediated striatal output.
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Animals↗
Biomedical subjects
J R Walters
Publications and source records attributed to J R Walters.
Combination therapy with oral ursodeoxycholic and chenodeoxycholic acids: pretreatment computed tomography of the gall bladder improves gall stone dissolution efficacy.
In a five year study, 55 patients with radiolucent gall stones were treated with the combination of 7.5 mg chenodeoxycholic acid (CDCA) and 5.0 mg ursodeoxycholic acid (UDCA)/kg/day--that is, half the monotherapeutic doses. Side effects were few but four patients could not tolerate the prescribed bile acids because of diarrhoea or nausea. Analysis of fasting duodenal bile confirmed that CDCA+UDCA converted supersaturated into unsaturated bile but the saturation indices did not predict the dissolution response. By actuarial analysis, the confirmed (by ultrasound x2) complete gall stone dissolution rates in all 55 patients were mean (SEM) 29 (7)% at 12 and 44 (8)% at 24 months. The advent of routine computed tomography before treatment enabled comparison of dissolution efficacy in those screened by computed tomography (n = 24), whose maximum gall stone attenuation was less than 100 Hounsfield units, with that in those not screened (n = 29). Although stone size and number were comparable, patients screened by computed tomography had significantly better dissolution rates (p less than 0.025) than those not screened in this way. At 12 months, partial or complete gall stone dissolution rates were 93 (7)% in the screened and 55 (11)% in the non-screened patients. At 18 months, complete dissolution rates were 64 (12%) and 20 (9)% respectively. Computed tomography before treatment is cost effective in selecting those patients likely to achieve gall stone dissolution on treatment with UDCA+CDCA.
Adult↗
Addisonian crisis presenting with a normal short tetracosactrin stimulation test.
We report the case of a 70 year old man who presented with physical and biochemical features suggestive of Addison's disease, but had a normal short tetracosactrin (Synacthen) test. Six months later he re-presented with similar clinical features but with an abnormal response to tetracosactrin confirming the diagnosis of Addison's disease. We recommend that if adrenal insufficiency is strongly suggested further investigation should be performed to exclude this diagnosis.
Addison Disease↗
D1 receptor stimulation inhibits dopamine cell activity after reserpine treatment but not after chronic SCH 23390: an effect blocked by N-methyl-D-aspartate antagonists.
Single unit recordings were conducted to examine the effects of systemic D1 agonist SKF 38393 on the firing rate of substantia nigra pars compacta dopamine (DA) neurons in rats pretreated subchronically with reserpine or chronically with a D1 antagonist. The effect of N-methyl-D-aspartate receptor antagonists on these processes was also investigated. An i.v. injection of SKF 38393 (10 mg/kg) significantly inhibited DA cell activity by approximately 70% in rats pretreated with reserpine (1 mg/kg, s.c.) for 6 days and studied under conditions of local anesthesia. SKF 38393 exerted no effect in reserpinized rats anesthetized with chloral hydrate. The SKF 38393-induced inhibition was reversed by the D1 antagonist SCH 23390, but not by the preferential D2 antagonist haloperidol. This effect of SKF 38393 was observed in 60% of the rats as early as 3 to 8 hr after the first reserpine injection, and the inhibition remained significant 5 to 15 days (averaging 64 and 58%) after termination of the 6-day reserpine treatment. The N-methyl-D-aspartate antagonists ketamine, at anesthetic doses (100 mg/kg, i.p.), and MK 801, at a nonanesthetic dose (0.15 mg/kg, i.v.), completely blocked the inhibitory effect of SKF 38393. In contrast, DA cells recorded in rats pretreated with SCH 23390 for 7 to 21 days, followed by a 4-day washout period, failed to respond to SKF 38393. Because nigrostriatal DA neurons do not appear to express D1 receptors, these results suggest that D1 receptors can exert an indirect inhibitory effect on the activity of nigral DA neurons, presumably through striatonigral neuronal pathways.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cholestasis associated with cinnarizine.
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Aged↗
Stimulation of intestinal basolateral membrane calcium-pump activity by recombinant synthetic calbindin-D9k and specific mutants.
Calcium transport by the Ca2(+)-pumping ATPase in rat duodenal basolateral-enriched membrane vesicles was stimulated by synthetic calbindin-D9k in a similar fashion to the purified natural protein. In order to elucidate the mechanism of this effect, various synthetic mutant proteins were studied. Proteins with modifications to the N-terminal Ca2(+)-binding domain, or to a cluster of negatively-charged surface residues had altered Ca2(+)-binding but these changes did not affect the stimulation of vesicular Ca2+ transport. It appears that these domains are not essential for the interaction between calbindin-D9k and the intestinal basolateral Ca2(+)-pump.
Animals↗
Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6-hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration.
Systemic administration of the selective D1 agonist, SKF 38393, to rats with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway induces contralateral turning and reduces firing rates of substantia nigra pars reticulata neurons. Previous studies have shown that chronically administered levodopa diminishes the contralateral turning induced by SKF 38393 in these animals. The present study demonstrates that twice daily injections (45-50 mg/kg, i.p.) of levodopa for 19 days also diminishes the effects of SKF 38393 on substantia nigra pars reticulata activity. Concomitant with this change, chronic levodopa injections reversed the lesion-induced supersensitivity of substantia nigra pars reticulata neurons to iontophoresed GABA. Neither of these effects were produced by the continuous infusion of levodopa (90-100 mg/kg/day, i.p. by osmotic pump) for 19 days, a treatment that produces average daily blood levodopa levels similar to those produced by chronic levodopa injection. These results suggest that large variations in circulating levodopa levels in 6-hydroxydopamine lesioned rats may desensitize the behavioral responses to D1 dopamine agonist administration by down-regulating D1 and GABA receptor-mediated mechanisms of basal ganglia output through the substantia nigra pars reticulata.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Nigrostriatal lesion alters neurophysiological responses to selective and nonselective D-1 and D-2 dopamine agonists in rat globus pallidus.
The effects of the selective D-1 dopamine agonist SKF 38393, the selective D-2 agonist quinpirole, and the nonselective D-1/D-2 agonist apomorphine on spontaneous activity of globus pallidus neurons were compared in normal control rats and rats with unilateral 6-hydroxydopamine induced lesions of the nigrostriatal pathway. In control, unlesioned rats, SKF 38393 (0.4 and 10 mg/kg, i.v.) caused no significant net change in the activity of globus pallidus neurons, although some individual cells showed significant increases or decreases in discharge rates following 10 mg/kg SKF 38393 administration. In animals with unilateral 6-hydroxydopamine induced lesions, SKF 38393 caused greater increases and decreases in the discharge rates of a larger percentage of pallidal cells recorded on the ipsilateral side than in control, unlesioned animals. These rate changes were effectively reversed by the D-1 antagonist SCH 23390, but not by the D-2 antagonist YM-09151-2. Quinpirole (0.3 mg/kg, i.v.) produced modest rate increases in control, unlesioned animals and significantly larger rate increases in nigrostriatal lesioned animals. YM-09151-2, but not SCH 23390, effectively reversed quinpirole's effects in the lesioned animals. As previously reported, the nonselective D-1/D-2 agonist apomorphine (0.3 mg/kg, i.v.) produced large increases in discharge rates of pallidal cells in control, unlesioned rats. In contrast, in nigrostriatal lesioned rats, the discharge rates of some ipsilateral pallidal neurons were markedly increased, others were decreased, and some were unaffected following apomorphine administration. The dopamine antagonist spiroperidol partially to fully reversed these rate changes. In summary, apomorphine's neurophysiological profile appears to be an exaggeration of the D-1 agonist profile in the globus pallidus of these lesioned animals. The degree of change observed after apomorphine administration is consistent with results from other studies that have indicated that a synergistic interaction between effects triggered by stimulation of the two receptor subtypes can occur in these animals, as in control, unlesioned animals. However, these results further show that in rats with unilateral nigrostriatal lesions, the denervated dopamine receptors or the processes they mediate are altered so that they no longer have the requirement seen in controls for concurrent stimulation of the complementary dopamine receptor subtype for expression of the selective agonist effects.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
The effects of striatal lesion on turning behavior and globus pallidus single unit response to dopamine agonist administration.
In normal rats, globus pallidus neurons are excited by the systemic administration of postsynaptically active doses of apomorphine. The role of the striatum in mediating this phenomenon was examined by investigating the effects of apomorphine on neuronal activity in the globus pallidus and on turning behavior in rats with unilateral quinolinic acid lesions of the striatum. The lesion markedly reduced striatal choline acetyltransferase activity and GABA content and significantly attenuated apomorphine's effect on the activity of pallidal neurons. Both the extent of attenuation of the electrophysiological response of pallidal neurons in lesioned animals and the neurotoxin-induced decreases in choline acetyltransferase activity and GABA content in the caudal striatum were correlated with the degree of apomorphine-induced turning. The data indicate that striatopallidal neurons contribute to apomorphine's excitatory effect on the activity of pallidal neurons in normal animals.
Animals↗
Calcium transport by intestinal epithelial cell basolateral membrane.
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Animals↗
Calbindin-D9k stimulates the calcium pump in rat enterocyte basolateral membranes.
Calbindin-D9k, a vitamin D-dependent Ca2+-binding protein, is closely associated with the transcellular absorption of calcium by mammalian enterocytes. Studies were performed to determine whether physiological concentrations of calbindin-D9k altered Ca2+ transport by the ATP-dependent Ca2+ pump in rat duodenal basolateral membrane vesicles. In solutions where free Ca2+ was buffered by EGTA, only a small stimulation of Ca2+ uptake rates could be demonstrated, and it was likely that this was secondary to changes in free Ca2+ concentration. However, a threefold stimulation of uptake by 30 microM calbindin-D9k was found when EGTA-free solutions were used, and changes in free Ca2+ activity or 45Ca2+ specific activity were avoided. The affinity for Ca2+ was reduced in this system but appeared to be stimulated by either calbindin-D9k or EGTA. Other Ca2+-binding proteins that bind Ca2+ in the micromolar range were found to increase Ca2+ uptake in the absence of EGTA. These experiments suggest that one of the actions of calbindin-D9k is to stimulate the rate of extrusion of Ca2+ from the enterocyte by increasing Ca2+ transport by the Ca2+ pump.
Adenosine Triphosphate↗
Identification and isolation of the phosphorylated intermediate of the calcium pump in rat intestinal basolateral membranes.
Transport of Ca2+ by the ATP-dependent Ca2+ pump has been demonstrated previously in rat intestinal basolateral-membrane vesicles. To identify the Ca2+-pump protein, duodenal basolateral membranes were phosphorylated with [gamma-32P]ATP in the presence of Ca2+ and La3+, under conditions conducive for maximal formation of the phosphorylated intermediate of the Ca2+ pump. Four major phosphoprotein bands were seen on autoradiograms of acidic SDS/polyacrylamide gels; the properties of a phosphoprotein (pp) at 130 kDa (pp130) were consistent with those expected for the plasma-membrane Ca2+ pump. This phosphoprotein was markedly enhanced by La3+, exhibited the characteristics of an acyl-phosphate bond, was preferentially phosphorylated from ATP and inhibited by micromolar concentrations of vanadate. Another phosphoprotein of 115 kDa possibly represented the endoplasmic reticulum Ca2+ pump or a fragment of pp130. Other phosphoproteins of 75 and 95 kDa were predominantly expressions of alkaline phosphatase. Formation of pp130 was highest in duodenal basolateral-membrane preparations when compared with those of jejunum and ileum or other subcellular fractions. A similar correlation between Ca2+-pump activity and pp130 formation was not found in membranes from villus-tip and crypt cells or in vitamin D-deficient animals. pp130 was isolated as a single phosphoprotein by calmodulin-affinity chromatography. We conclude that pp130 represents the phosphorylated intermediate of the rat intestinal basolateral-membrane Ca2+ pump, which can be separated from other phosphoproteins using its properties as a calmodulin-binding protein.
Animals↗
Acute reduction of dopamine levels alters responses of basal ganglia neurons to selective D-1 and D-2 dopamine receptor stimulation.
Extracellular single unit recording techniques were used to investigate dopamine agonist-induced changes in the tonic activity of globus pallidus neurons in normal control rats, and in rats in which dopamine levels were acutely reduced by alpha-methyl-para-tyrosine (AMPT) pretreatment. Systemic administration of the nonselective D-1/D-2 agonist apomorphine consistently induced large increases in the firing rates of globus pallidus neurons, as shown previously. The D-1 agonist SKF 38393 frequently induced no change in pallidal cell firing rates with doses up to 20 mg/kg; however, firing rates of 40% of the cells were stimulated by more than 20% of baseline and 14% were partially inhibited after 20 mg/kg SKF 38393. Following AMPT pretreatment, SKF 38393 induced only increases and no changes in activity; no decreases were observed. The D-2 agonist quinpirole typically increased pallidal neuron activity in a dose-dependent manner but was markedly less effective at stimulating pallidal neuron activity than apomorphine. In AMPT-treated rats, quinpirole's effects were significantly attenuated. Consistent with previous results, most cells showed large rate increases when SKF 38393 and quinpirole were coadministered to normal rats; these increases were similar in magnitude to those induced by apomorphine. In contrast to the observation that AMPT treatment altered the responses of globus pallidus neurons to individually administered quinpirole and SKF 38393, neither the increases in pallidal cell activity induced by apomorphine nor those induced by coadministration of SKF 38393 and quinpirole were significantly attenuated in AMPT-treated rats. The results support the idea that stimulation of both D-1 and D-2 receptors appears to be required to induce apomorphine-like changes in basal ganglia output. Moreover, the effects of individually administered D-1 and D-2 agonists observed in normal rats appear to depend upon the degree to which the complementary receptor subtype is stimulated by endogenous dopamine.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Unilateral lesion of the nigrostriatal pathway decreases the firing rate and alters the firing pattern of globus pallidus neurons in the rat.
Activities of spontaneously firing neurons in the globus pallidus of intact rats and rats that survived unilateral lesions of the nigrostriatal pathway for 3 days, 1 week, or 6-11 weeks were compared. No significant differences in neuronal firing rate, firing pattern, and number of cells per pass were observed between chloral hydrate-anesthetized control and lesioned animals. However, in locally anesthetized animals, pallidal cells fired significantly faster than in chloral hydrate-anesthetized animals, and the lesion caused a decrease in the firing rates of pallidal cells 1 week and 6-9 weeks postlesion. In addition, significant differences in the firing pattern of pallidal cells, as determined by the ratio of the mean to median interspike intervals, were seen between locally anesthetized controls and animals surviving 3 days, 1 week, and 6-9 weeks postlesion. This altered firing pattern tended to return to normal with time. The number of cells per pass was not significantly altered by the lesion. Data from this study suggest that, in locally anesthetized animals, the removal of the tonic dopaminergic input to the basal ganglia causes pallidal cells to decrease their firing rates in a time-dependent fashion and causes reversable firing pattern changes. This suggests that tonically active dopamine neurons, probably acting through the striatopallidal pathway, regulate the firing rate and mechanisms controlling the temporal ordering of spontaneous discharges of globus pallidus neurons.
Action Potentials↗
Neurophysiological examination of the role of D-1 dopamine receptors in the regulation of neuronal activity in the basal ganglia.
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Animals↗
Aromatase inhibition in the dog. I. Effect on serum LH, serum testosterone concentrations, testicular secretions and spermatogenesis.
Chronic treatment of intact male beagles with an orally active nonsteroidal aromatase inhibitor (4-(5,6,7,8-tetrahydroimidazo [1,5a] pyridin-5-yl) benzonitrile hydrochloride; CGS 16949; CIBA-GEIGY) at a dosage of 2.5 mg./kg. per day for six months resulted in increased (p less than 0.01) serum LH and testosterone concentrations compared to placebo-fed controls. The increases in serum LH and testosterone concentrations occurred by one week of treatment and were maintained over the six month period. Testes of CGS 16949A fed dogs obtained at termination of the experiment when perfused in vitro in the presence of a maximally stimulating concentration of LH secreted nondetectable amounts of estradiol and estrone and higher (p less than 0.01) amounts of testosterone, androstenedione and dihydrotestosterone than testes of control dogs. Despite these changes in androgen secretion there was no evidence on any effect of aromatase inhibition upon spermatogenesis. These data support the hypothesis that in the dog, estrogens play a major role in negative feedback of the hypothalamic-pituitary-testicular axis.
Animals↗
Aromatase inhibition in the dog. II. Effect on growth, function, and pathology of the prostate.
To evaluate the role of aromatase inhibitors in the treatment of benign prostatic hyperplasia (BPH), the effects of a potent, oral, nonsteroidal aromatase inhibitor [4-(5,6,7,8-tetrahydroimidazo[1,5a]pyridin-5yl)benzonitrile; CGS-16949A, CIBA-GEIGY] on canine BPH have been studied. Twelve mature beagles with enlarged prostates were divided into two groups of similar age, prostatic size, and prostatic histology. Dogs were given either CGS-16949A at a dosage of 2.5 mg./kg./day p.o. (n = 6) or an oral placebo (n = 6) for 25 weeks. Treatment with aromatase inhibitor had no significant effect on prostatic weight nor on total DNA content when compared to controls (p greater than 0.1). Semen volume did not change with treatment, and prostatic tissue concentrations of testosterone, dihydrotestosterone (DHT), and 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol) were similar for the treated and control beagles (p greater than 0.1). Protein concentration in the ejaculate, however, was significantly greater for the dogs receiving CGS-16949A (p less than 0.01). Histologically, there was no difference in the incidence or type of BPH between the two treatment groups. Beagles treated with aromatase inhibitor, however, did have a more severe inflammatory infiltrate of the prostatic parenchyma than the control dogs (p less than 0.01). The mean serum testosterone concentration for the beagles treated with aromatase inhibitor was 10 times greater than that for the control animals (p less than 0.01). The endocrine effect of this aromatase inhibitor in the male canine is presented in the preceding paper. Taken together, these results suggest that inhibition of endogenous aromatase activity is not an effective treatment for spontaneous BPH in the intact canine.
Animals↗
The effect of inhibition of aromatase enzyme activity on Leydig cell number and ultrastructure in beagles.
We have shown previously that administration of an orally active competitive aromatase inhibitor 4-(5,6,7,8-tetrahydroimidazo [1,5a] pyridin-5-yl) benzonitrile monohydrochloride to adult male beagles increases peripheral blood LH and testosterone concentrations, and that testes from treated dogs produce more testosterone when perfused in vitro than age-matched controls. In the present study we posed the question of whether the increased testosterone secretion by testes from these same aromatase-treated dogs was due to Leydig cell hypertrophy or hyperplasia, and if the latter, whether cytoplasmic organelles are increased. Beagles were treated with the inhibitor at a dosage of 2.5 mg/kg.day for 25 weeks and were euthanized by an overdose of iv sodium pentobarbital; testes were perfusion-fixed, embedded, and sectioned for stereological analysis. There were no significant differences in testis volume and absolute volumes of seminiferous tubules, blood vessels, lymphatic space, macrophage cells, and mesenchymal cells between the control and treated dogs. In contrast absolute interstitium volume and the absolute volume of Leydig cells per testis were significantly increased (P less than 0.05) in treated dogs. This increased Leydig cell volume per testis was due to increased volume of individual Leydig cells rather than to increases in Leydig cell number per testis. Additional studies showed that the surface area per Leydig cell of smooth endoplasmic reticulum, outer and inner mitochondrial membranes, and membranes of lipid droplets per testis were significantly higher (P less than 0.05) in the treated dogs as compared to the controls. In summary, the results of this study lead us to conclude that aromatase inhibition in the mature dog causes Leydig cell hypertrophy rather than hyperplasia and increased surface area per Leydig cell of subcellular organelles that contain enzymes involved in steroid biosynthesis.
Animals↗