Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells.

Department of Animal Sciences, University of Missouri, Columbia 65201, USA.
Journal of Animal Science (Impact Factor: 1.92). 06/1995; 73(5):1396-400.
Source: PubMed

ABSTRACT Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation.

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    ABSTRACT: The objectives of these experiments were to characterize rumen motility patterns of cattle fed once daily using a real-time wireless telemetry system, determine when to measure rumen motility with this system, and determine the effect of ruminal dosing of ergot alkaloids on rumen motility. Ruminally cannulated Holstein steers (n = 8) were fed a basal diet of alfalfa cubes once daily. Rumen motility was measured by monitoring real-time pressure changes within the rumen using wireless telemetry and pressure transducers. Experiment 1 consisted of three 24-h rumen pressure collections beginning immediately after feeding. Data were recorded, stored, and analyzed using iox2 software and the rhythmic analyzer. All motility variables differed (P < 0.01) between hours and thirds (8-h periods) of the day. There were no differences between days for most variables. The variance of the second 8-h period of the day was less than (P < 0.01) the first for area and less than the third for amplitude, frequency, duration, and area (P < 0.05). These data demonstrated that the second 8-h period of the day was the least variable for many measures of motility and would provide the best opportunity for testing differences in motility due to treatments. In Experiment 2, the steers (n = 8) were pair-fed the basal diet of Experiment 1 and dosed with endophyte-free (E-) or endophyte-infected (E+; 0 or 10 μg ergovaline + ergovalinine/kg BW; respectively) tall fescue seed before feeding for 15 d. Rumen motility was measured for 8 h beginning 8 h after feeding for the first 14 d of seed dosing. Blood samples were taken on d 1, 7, and 15, and rumen content samples were taken on d 15. Baseline (P = 0.06) and peak (P = 0.04) pressure were lower for E+ steers. Water intake tended (P = 0.10) to be less for E+ steers the first 8 h period after feeding. The E+ seed treatment at this dosage under thermoneutral conditions did not significantly affect rumen motility, ruminal fill, or dry matter of rumen contents.
    Frontiers in Chemistry 10/2014; 2:90. DOI:10.3389/fchem.2014.00090
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    ABSTRACT: Ergot alkaloids are psychoactive and vasoconstricting agents of the fungus Claviceps purpurea causing poisoning such as ergotism in medieval times (St. Anthony's Fire). This class of substances also inhibits tumor growth in vitro and in vivo, though the underlying mechanisms are unclear as yet. We investigated six ergot alkaloids (agroclavine, ergosterol, ergocornin E, ergotamine, dihydroergocristine, and 1-propylagroclavine tartrate) for their cytotoxicity towards tumor cell lines of the National Cancer Institute, USA. 1-Propylagroclavine tartrate (1-PAT) revealed the strongest cytotoxicity. Out of 76 clinically established anticancer drugs, cross-resistance was found between the ergot alkaloids and 6/7 anti-hormonal drugs (=85.7 %) and 5/15 DNA-alkylating drugs (=33.3 %). The IC50 values for the six alkaloids were not correlated to well-known determinants of drug resistance, such as proliferative activity (as measured by cell doubling times, PCNA expression, and cell cycle distribution), the multidrug resistance-mediating P-glycoprotein/MDR1 and expression or mutations of oncogenes and tumor suppressor genes (EGFR, RAS, TP53). While resistance of control drugs (daunorubicin, cisplatin, erlotinib) correlated with these classical resistance mechanisms, ergot alkaloids did not. Furthermore, COMPARE and hierarchical cluster analyses were performed of mRNA microarray data to identify genes correlating with sensitivity or resistance to 1-PAT. Twenty-three genes were found with different biological functions (signal transducers, RNA metabolism, ribosome constituents, cell cycle and apoptosis regulators etc.). The expression of only 3/66 neuroreceptor genes correlated with the IC50 values for 1-PAT, suggesting that the psychoactive effects of ergot alkaloids may not play a major role for the cytotoxic activity against cancer cells. In conclusion, the cytotoxicity of ergot alkaloids is not involved in classical mechanisms of drug resistance opening the possibility to bypass resistance and to treat otherwise drug-resistant and refractory tumors. The modes of action are multifactorial, which is a typical feature of many natural compounds.
    Investigational New Drugs 10/2014; 33(1). DOI:10.1007/s10637-014-0168-4 · 2.93 Impact Factor
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    ABSTRACT: Six stallions were used in this study to determine the effects of endophyte-infected tall fescue on reproductive parameters. One experimental diet consisted of endophyte-infected tall fescue and the other consisted of a non-toxic endophyte tall fescue, Flecha AR-542, known as MaxQ. Stallions were fed one of two diets at 45% of the grain diet, at a rate of 1% of their body weight. Three stallions were blindly assigned each experimental diet and fed each diet for 70 days. After a seventy day rest period treatments were switched and fed for another 70 days. Stallions were supplied with fresh water, Common Bermuda, and Annual Ryegrass ad libitum. Results showed no differences in stallion reproductive parameters measured when feed endophyte-infected or MaxQ. Urinary alkaloid and creatinine tests were performed on urine samples to make sure stallions were receiving toxic levels of ergot alkaloids. Stallions consuming endophyte-infected seed had higher (P<0.0002) alkaloid/creatinine levels.

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