Bromocriptine/SKF38393 ameliorates islet dysfunction in the diabetic (db/db) mouse

Dysfunction of pancreatic islets plays a crucial role in the etiology of type II diabetes. Chronic hyperglycaemia or hyperlipidaemia may impair islet function. Previous studies by our laboratory have demonstrated that dopaminergic agonists ameliorated hyperglycaemia and hyperlipidaemia in obese and diabetic rodents. In the present study, we investigated the effect of a treatment with the dopamine D₂ /D₁ receptor agonists (bromocriptine/SKF38393, BC/SKF) on islet dysfunction in db/db mice. Our results show that a 2-week BC/SKF treatment markedly reduced hyperglycaemia and hyperlipidaemia, and significantly improved islet dysfunction demonstrated by an increase of secretagogue-stimulated insulin release from islets of db/db mice to levels observed in islets from lean mice. There was also a fourfold increase of insulin content in the pancreas of BC/SKF-treated db/db mice compared with that in untreated controls. The effect of BC/SKF on islet function cannot be mimicked in pair-fed animals. BC/SKF had no direct stimulatory effect on islet insulin secretion, suggesting BC/SKF treatment improved islet function via an indirect mechanism. This treatment markedly improved the abnormally elevated daily levels of corticosterone, blood glucose and plasma lipids, supporting the view that BC/SKF may affect the neuroendocrine system that in turn regulates peripheral metabolism and thereby improves islet function. Received 3 April 1998; accepted 27 April 1998     

The effect of L-dopa on pupillary diameter in mice

Summary Injection of L-dopa in mice produces dose-dependent mydriasis. Pre-treatment with peripheral dopa-decarboxylase inhibitors (carbidopa and benserazide) or with an alpha-adrenergic blocking agent (phentolamine) abolishes the pupillary dilation caused by L-dopa. Pretreatment with fusaric acid, an inhibitor of dopamine-beta-hydroxylase, also antagonizes the mydriatic effect of L-dopa. Thus, our results suggest that the mydriasis produced in mice following the injection of L-dopa is caused by its peripheral conversion to noradrenaline, which stimulates alpha-adrenergic receptors in the dilator iridis. There was no evidence that stimulation of specific dopaminergic receptors was involved.We are grateful to N. Rothschild, Head of Laboratory Animal Department, Sackler School of Medicine, for his help.     

Reduction of body fat stores by inhibition of prolactin secretion

Summary Reductions of prolactin secretion by bromocriptine treatment for 24 days reduced fat stores (abdominal and epididymal fat depots) in hamsters by 25–49% compared with control animals. However, body weights and food consumption were not affected. These results further substantiate an important role for prolactin in regulation of fat metabolism and indicate that bromocriptine might be used to decrease fat stores.     

Lack of pressor effect of dopamine in the pentobarbital-anesthetized rat

Summary The blood pressure and heart rate responses to intravenous dopamine infusion at 2.5, 5.0 and 10.0 g·min^–1·100 g^–1 were studied in conscious and pentobarbital-anesthetized Sprague — Dawley rats. In the conscious rats, dopamine caused a significant dose-related increase in the mean arterial blood pressure which was abolished in the anesthetized rats. The heart rate increased significantly only at the highest dose infused. The responses to equipressor doses of noradrenaline (40 ng·min^–1·100 g^–1) and phenylephrine (1.0 g·min^–1·100 g^–1) were also suppressed in the anesthetized rats. The results suggest that pentobarbital anesthesia depresses the blood pressure response to dopamine infusion in the rat through a depression of activation of alpha-adrenoceptors.16 June 1986     

Platelet monoamine oxidase B: use and misuse

The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.     

Platelet monoamine oxidase B: Use and misuse

The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.     

Timed bromocriptine administration reduces body fat stores in obese subjects and hyperglycemia in type II diabetics

Obese postmenopausal female volunteers were given timed daily oral dosages of bromocriptine, and tested for reduction of body fat stores. This dopamine agonist has been shown to reset circadian rhythms that are altered in obese animals and to reduce body fat levels in several animal models. The participants were instructed not to alter their existing exercise and eating behavior during treatment. Skinfold measurements were taken on 33 subjects as indices of body fat. The measurements (e.g., suprailiac) were reduced after six weeks by about 25%, which represents a reduction of 11.7% of the total body fat. These dramatic decreases in body fat, which are equivalent to that produced by severe caloric restriction, were accompanied by more modest reductions of body weight (2.5%), indicating a possible conservation of protein that is usually lost as a consequence of such caloric restriction. The effects of bromocriptine treatment on body fat and hyperglycemia were also examined in non-insulin dependent diabetics being treated with oral hypoglycemics (7 subjects) or insulin (7 subjects). Total body fat was reduced by 10.7% and 5.1% in diabetics on oral hypoglycemics and insulin, respectively, without any significant reductions in body weight.Hyperglycemia was reduced in most of the 15 diabetic subjects treated leading to euglycemia and even cessation of hypoglycemic drugs in 3 of the 7 subjects during 4–8 weeks of bromocriptine treatment. These findings support the hypothesis that obesity and type II diabetes may be treated effectively with bromocriptine when administered at the proper times and dosages.This is a process patented by Louisiana State University and licensed to Ergo, Inc., Newport, Rhode island. A. H. Meier and A. H. Cincotta have financial interest in the process.     

Activation by S-adenosylhomocysteine of norepinephrine and serotonin in vitro uptake in synaptosomal preparations from rat brain

Summary S-Adenosylhomocysteine (10^–7–10^–5 M) activated norepinephrine (NE) and serotonin (5HT) in vitro uptake in synaptosomal preparations from rat brain, but did not affect dopamine (DA) uptake. When administered to rats (7 mg/kg i.p.), it had the same effect on in vitro NE and 5HT uptake. It did not affect NE and 5HT release.Work achieved within the frame of the research contract institut Mérieux., Institut National des Sciences Appliquées.     

Role of adenosine A1 and A2 receptors in the regulation of aldosterone production in rat adrenal glands

Summary To investigate the roles of adenosine A₁ and A₂ receptors in the regulation of aldosterone production, we examined the effects of adenosine and adenosine agonists (N⁶-cyclohexyl adenosine; selective adenosine A₁ receptor agonist and 5-N-ethylcarboxamine adenosine; selective adenosine A₂ receptor agonist) on aldosterone and cyclic AMP production in rat adrenal capsular cells. Neither adenosine nor 5-N-ethylcarboxamine adenosine caused significant effects on basal aldosterone or cyclic AMP production. Also, adenosine (10^–3M) showed no consistent effects on aldosterone and cyclic AMP production induced by ACTH. On the other hand, N⁶-cyclohexyl adenosine exhibited a significant inhibition of basal aldosterone and cyclic AMP production at doses of 10^–4 M and 10^–3 M; furthermore, 10^–3 M N⁶-cyclohexyl adenosine inhibited aldosterone and cyclic AMP production stimulated by ACTH. These results suggest that adenosine A₁ receptors are coupled to and inhibit adenylate cyclase and may be involved in the inhibition of aldosterone production.     

Effect of substitution of glycine by D- or L-alanine on the activity of the C-terminal hexapeptide analogue of substance P on isolated guinea-pig ileum

Summary Two new C-terminal hexapeptide analogues of substance P having D- or L-alanine in position 9 were synthetized. Their contracting activities on isolated guinea-pig ileum were considerably lower than that of 7–11.     

Hypothalamo-hypophyseal-gonadal function in the rat following administration of the novel and selective D-1 agonist CY 208-243

The effects of the novel and selective dopamine D-1 agonist CY 208-243 on the rat hypothalamo-hypophyseal-gonadal (HHG) axis were studied. CY 208-243 did not modify the concentration of luteinizing hormone (LH) in serum from female or male rats, and had no effect upon opiate antagonist-induced stimulation of LH secretion in male rats. CY 208-243 did not inhibit ovulation in cycling female rats. Thus, D-1 receptor activation by systemic drug administration does not alter HHG function in rats.     

Hypothalamo-hypophyseal-gonadal function in the rat following administration of the novel and selective D-1 agonist CY 208-243

Summary The effects of the novel and selective dopamine D-1 agonist CY 208-243 on the rat hypothalamo-hypophyseal-gonadal (HHG) axis were studied. CY 208-243 did not modify the concentration of luteinizing hormone (LH) in serum from female or male rats, and had no effect upon opiate antagonist-induced stimulation of LH secretion in male rats. CY 208-243 did not inhibit ovulation in cycling female rats. Thus, D-1 receptor activation by systemic drug administration does not alter HHG function in rats.     

The role of parathyroid hormone and calcitonin in magnesium absorption in the rat small intestine

Summary We studied duodenal and ileal magnesium (Mg) absorption in intact, parathyroidectomized (PTX), thyroid-(TX) and thyroparathyroidectomized (TPTX) rats with iodine hormones replaced, and, additionally, in PTX rats receiving bovine parathyroid hormone 1–34 and 1,25-dihydroxyvitamin D₃, respectively. Ma absorption was reduced after PTX and TPTX in the duodenum, but not in the ileum, whereas TX had no influence on duodenal or ileal Mg absorption. Both bovine parathyroid hormone 1–34 and 1,25-dihydroxyvitamin D₃ increased Mg absorption in the duodenum and the ileum in PTX rats.Acknowledgments. We are grateful to B. Schreiber, K. Schwille and I. Goldberg for technical and secretarial help. Supported by Deutsche Forschungsgemeinschaft (Schw 210/3). Reprint requests to P.O.S., University Hospital, Maximiliansplatz, D-8520 Erlangen.     

Quantitative differences in the pharmacological effects of (+)- and (−)-cathinone

Summary The optically pure isomers of cathinone were prepared by separating synthetic cathinone racemate and used to study central and peripheral effects of these indirect sympathomimetics in rats and guinea pigs. The (–)-isomer was significantly more potent than the (+)-isomer in stimulating locomotor activity whereas no difference was observed with respect to their cardiac effects. In analogy to observations with (+)- and (–)-amphetamine such variable isomer discrimination may be due to different stereoselectivities of amine uptake mechanisms in the target tissues.     

Detailed molecular comparison between the inhibition mode of A/B-type carboxypeptidases in the zymogen state and by the endogenous inhibitor latexin

Treatment of advanced stages of prostate carcinoma with histone-deacetylase inhibitors entails expression of human procarboxypeptidase-A4 (hPCPA4). The three-dimensional structure of hPCPA4 has been solved and shows the features of related metallocarboxypeptidase zymogens, with a preformed α/β/-hydrolase active-enzyme moiety (hCPA4) and an inhibiting pro-domain (PD). The protease moiety recalls a sphere, out of which a spherical cone has been cut. This results in a funnel-like structure, at the bottom of which the active-site cleft resides. The border of this funnel is shaped by loops, which are responsible for the interaction with the PD, characterised by a large interface area and relatively few contacts. Such an inhibitory mode is evocative of the recently reported structure of the human inhibitor latexin in its complex with hCPA4. The main contacting structure of latexin is similar to the one employed for PD inhibition. In both cases, active-site blocking relies mainly on a loop provided by the central part of a β sheet.R. Garcia-Castellanos and R. Bonet-Figueredo contributed equally to this study and share first authorship.Received 28 April 2005; received after revision 1 June 2005; accepted 29 June 2005     

Induced recovery of defective membrane expression of a CC chemokine receptor 5 mutant by phytohemagglutinin

CC chemokine receptor 5 (CCR5) is a member of the G-protein-coupled receptor superfamily. It plays an important role in macrophage tropic human immunodeficiency virus-1 entry and in some inflammatory reactions. CCR5-893(–) is a single-nucleotide deletion that results in complete truncation of the C tail of the gene product. We detected CCR5-893(–) in a sample of patients infected with non-tuberculosis mycobacteria and found that it was maintained heterozygously with a frequency of 2%. There is no association between this mutation and any immunodeficiency. Membrane expression of CCR5-893(–) was substantially reduced compared to the wild type, but this defective surface presentation recovered greatly recovered in the presence of 2 mg l-1 phytohemagglutinin (PHA). However, PHA inducement did not affect the total intracellular expression of CCR5-893(–) or wild-type CCR5. Thus we suggest there exist some PHA-induced factor(s) that could mediate the presentation of truncated CCR5.Received 23 July 2003; accepted 18 August 2003     

Purification of the cytosol oestradiol-receptor complex from foetal guinea-pig uterus using electrofocusing on polyacrylamide plates

Summary The³H-oestradiol receptor complex obtained from the cytosol fraction of foetal guinea-pig uterus was purified by the following steps: column chromatography in Sephadex G-15 and Ultrogel, and by electrofocusing on polyacrylamide plates. In the final step a concentration of 15–17% of the foetal uterine oestradiol receptor protein was obtained. The isoelectric point (pl) of this receptor was determined to be 6.1–6.2.The expenses of the investigation were partially defrayed by a grant from the Centre National de la Recherche Scientifique (CNRS), France (Equipe de Recherche CNRS No. 187).     

Solubilization of prolactin receptor by a Zwitterionic detergent

Summary About 60% of the prolactin receptors were solubilized from rabbit mammary gland membranes by Zwittergent 3–12. The use of Zwittergent 3–12 resulted in increased sensitivity of the receptor assay and permitted use of ovine prolactin instead of human growth hormone in the receptor assay.Acknowledgments. This work was supported by grant AM 17476 from the National Institutes of Health.     

Effects of selective dopamine D1 and D2 antagonists on male rat sexual behavior

Summary The effects of selective dopamine (DA) D₁ and D₂ antagonists on male rat sexual behavior were investigated. The D₁ antagonist (+)SCH-23390, 25–100 g kg^–1 s.c. –20 min, and the D₂ antagonist raclopride, 0.1–1.6 mg kg^–1 s.c., –20 min, decreased both the number of mounts and intromissions preceding ejaculation. No statistically significant effects in the time up to ejaculation or in the time up to the first intromission were noted, whereas both compounds produced a statistically significant increase in the post-ejaculatory interval. The effect can generally be characterized as psychomotor inhibition, and no evidence was obtained for a specific role of DA D₁ or D₂ receptors in the mediation of male rat sexual behavior.The expert technical assistance of Ms Elisabeth Wallin is gratefully acknowledged. The figures were skilfully prepared by Ms Madelene Kröning at the Department of Psychology. This study received support from the Bank of Sweden tercentenary Foundation, The Swedish MRC and Wilhelm and Martina Lundgren Foundation.