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Epichloë endophytes have been used successfully in pastoral grasses providing protection against insect pests through the expression of secondary metabolites. This approach could be extended to other plant species, such as cereals, reducing reliance on pesticides. To be successful, the selected endophyte must express secondary metabolites that are active against cereal insect pests without any secondary metabolite, which is harmful to animals. Chanoclavine is of interest as it is commonly expressed by endophytes and has potential insecticidal activity. Investigation of possible mammalian toxicity is therefore required. An acute oral toxicity study showed the median lethal dose of chanoclavine to be >2000 mg/kg. This allows it to be classified as category 5 using the globally harmonized system of classification and labelling of chemicals, and category 6.1E using the New Zealand Hazardous Substances and New Organisms (HSNO) hazard classes, the lowest hazard class under both systems of classification. A three-week feeding study was also performed, which showed chanoclavine, at a dose rate of 123.9 mg/kg/day, initially reduced food consumption but was resolved by day seven. No toxicologically significant effects on gross pathology, histology, hematology, or blood chemistry were observed. These experiments showed chanoclavine to be of low toxicity and raised no food safety concerns.

Pharmacologic profiling of serotonin (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have altered responses to ergovaline, 5HT, 5HT2A, and 5HT7 agonists. To determine if 5HT receptor activity of tall fescue alkaloids is affected by grazing endophyte-free (EF), wild-type [Kentucky-31 (KY31)], novel endophyte AR542-infected (MAXQ), or novel endophyte AR584-infected (AR584) tall fescue, contractile responses of lateral saphenous veins biopsied from cattle grazing these different fescue-endophyte combinations were evaluated in presence or absence of antagonists for 5HT2A (ketanserin) or 5HT7 (SB-269970) receptors. Biopsies were conducted over 2 yr on 35 mixed-breed steers (361.5 ± 6.3 kg) grazing EF (n = 12), KY31 (n = 12), MAXQ (n = 6), or AR584 (n = 5) pasture treatments (3 ha) between 84 and 98 d (Yr 1) or 108 to 124 d (Yr 2). Segments (2 to 3 cm) of vein were surgically biopsied, sliced into 2- to 3-mm cross-sections, and suspended in a myograph chamber containing 5 mL of oxygenated Krebs-Henseleit buffer (95% O2/5% CO2; pH = 7.4; 37°C). Veins were exposed to increasing concentrations of 5HT, ergovaline, and ergovaline + 1 × 10(-5) M ketanserin or + 1 × 10(-6) M SB-269970 in Yr 1. In Yr 2, ergotamine and ergocornine were evaluated in presence or absence of 1 × 10(-5) M ketanserin. Contractile response data were normalized to a reference addition of 1 × 10(-4) M norepinephrine. In Yr 1, contractile response to 5HT and ergovaline were least (P < 0.05) in KY31 pastures and the presence of ketanserin greatly reduced (P < 0.05) the response to ergovaline in all pastures. However, presence of SB-269970 did not (P = 0.91) alter contractile response to ergovaline. In Yr 2, there was no difference in contractile response to ergotamine (P = 0.13) or ergocornine (P = 0.99) across pasture treatments, but ketanserin reduced (P < 0.05) the contractile response to both alkaloids. The 5HT2A receptor is involved in alkaloid-induced vascular contraction and alkaloid binding may be affected by exposure to different endophyte-fescue combinations.

Introduction: Chronic low-dose cabergoline treatment for microprolactinoma may cause cardiac valve pathology, but the evidence is contradictory. We investigated whether the expectation of the echocardiographer could influence the report., Methods: Transthoracic echocardiograms from 40 patients aged 49·3 ± 9·6 (mean ± SD) years (Men:Women 7:33) on long-term cabergoline and bromocriptine therapy (duration 9·94 ± 4·5 years) were randomly assigned to two groups of echocardiographers so that each echocardiogram was reported twice. One group was told that 'the patients were control subjects' (Group A) and the other that 'the patients were on dopamine agonist therapy which is known to cause valve disease' (Group B). An observer who was blind to the group scored the reports for regurgitation at each valve (scores 0-4; max 16 per case)., Results: Mean total regurgitation score was significantly higher in Group B (1·43 ± 1·28; P = 0·014) than in Group A (0·73 ± 1·30). The difference was mainly from reporting trivial regurgitation: (mitral 16 vs 5, P = 0·005; tricuspid 17 vs 6, P = 0·007 and pulmonary 8 vs 1, P = 0·013). Mild regurgitation was uncommon (mitral 1 vs 1 and tricuspid 3 vs 6). Moderate regurgitation occurred in only one case and was associated with restriction of the leaflets consistent with the effects of cabergoline. Valve thickening was not reported in Group A, but in 9 (23%) mitral and 4 (10%) aortic valves in Group B., Conclusion: Long-term, low-dose dopamine agonist therapy rarely causes cardiac valve disease, but operator bias can lead to over-reporting of both valve thickening and trivial regurgitation., (© 2011 Blackwell Publishing Ltd.)

Ergot alkaloids cause fescue toxicosis when livestock graze endophyte-infected tall fescue. It is generally accepted that ergovaline is the toxic component of endophyte-infected tall fescue, but there is no direct evidence to support this hypothesis. The objective of this study was to examine relative and potential transport of ergoline and ergopeptine alkaloids across isolated gastric tissues in vitro. Sheep ruminal and omasal tissues were surgically removed and placed in parabiotic chambers. Equimolar concentrations of lysergic acid, lysergol, ergonovine, ergotamine, and ergocryptine were added to a Kreb's Ringer phosphate (KRP) solution on the mucosal side of the tissue. Tissue was incubated in near-physiological conditions for 240 min. Samples were taken from KRP on the serosal side of the chambers at times 0, 30, 60, 120, 180, and 240 min and analyzed for ergot alkaloids by competitive ELISA. The serosal KRP remaining after incubation was freeze-dried and the alkaloid species quantified by HPLC. The area of ruminal and omasal tissues was measured and the potential transportable alkaloids calculated by multiplying the moles of transported alkaloids per square centimeter of each tissue type by the surface area of the tissue. Studies were conducted to compare alkaloid transport in reticular, ruminal, and omasal tissues and to determine whether transport was active or passive. Ruminal tissue had greater ergot alkaloid transport potential than omasal tissue (85 vs 60 mmol) because of a larger surface area. The ruminal posterior dorsal sac had the greatest potential for alkaloid transport, but the other ruminal tissues were not different from one another. Alkaloid transport was less among reticular tissues than among ruminal tissues. Transport of alkaloids seemed to be an active process. The alkaloids with greatest transport potential were lysergic acid and lysergol. Ergopeptine alkaloids tended to pass across omasal tissues in greater quantities than across ruminal tissues, but their transport was minimal compared to lysergic acid and lysergol.

Agroclavine is a natural, clavine type of ergot alkaloid with D1 dopamine and a-adrenoceptor agonistic properties. We showed previously that in vitro agroclavine enhances natural killer (NK) cell activity, increases interleukin-2 and interferon-gamma production and prolongs the survival time of tumor-bearing mice. The aim of this study was 1) to test the effect of agroclavine on NK activity in vivo, and 2) to assess the potential toxicity of high doses of agroclavine on cardiac and liver functions using creatine kinase MB (CKMB) and alanine aminotransferase (ALT) as biochemical markers in normal and stressed animals. The effect of stress was studied because we examined promising anticancer properties of agroclavine and malignant diseases are supposed to be a potent stressful event for patients. In our experiments 3-month-old male rats of the Wistar-Kyoto strain were used. Agroclavine was injected intraperitoneally (0.5 mg/kg or 0.05 mg/kg) 30 min before stress (four hours' restraint and immersion in 23 degrees C water). The animals were killed 30 min after stress, blood was collected and the spleen was removed. Non-stressed animals treated with agroclavine were killed 5 h after the drug administration. The results confirmed our previous in vitro results and showed that also in vivo agroclavine increases NK cell activity under non-stress conditions. Agroclavine only slightly increased CKMB and had no influence on ALT in non-stressed animals. These promising results are limited by the fact that agroclavine (0.5 mg/kg) diminished NK cell activity and significantly increased ALT and CKMB under stress conditions.

The present study describes the metabolic changes observed in a dietary subacute toxicity experiment with the ergot alkaloid alpha-ergocryptine in Sprague-Dawley rats. The observed effects on metabolic and hormonal parameters were described separately from the general toxicological effects, in view of the important role of dopamine agonists in metabolism (e.g. ergot alkaloids in fescue toxicosis). The rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28-32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). Total cholesterol and high-density lipoprotein (HDL)-cholesterol were decreased dose dependently in females but the ratio HDL-cholesterol/total cholesterol was only decreased at 20 mg/kg body weight. Triglycerides and glucose concentrations were decreased in the highest dose groups of both sexes. Serum urea concentrations were increased in the 20, 100 and 500 mg/kg dose groups. Insulin, glucagon and liver glycogen were increased in the highest dose group at the end of the study, when the animals were allowed to eat prior to blood sampling and necropsy. Prolactin, T4 and FT4 were decreased in the 20, 100 and 500 mg/kg dose groups of both sexes. Follicle-stimulating hormone (FSH) was decreased in the 20, 100 and 500 mg/kg female dose groups and luteinizing hormone (LH) was increased in the 20, 100 and 500 mg/kg male dose groups. It is postulated that the observed effects on food intake, metabolism (lipid and carbohydrate) and hormonal parameters are due to an interaction of ergocryptine with central dopaminergic activities, which comprise a major functional component of a central regulatory system for metabolism.

The dietary subacute toxicity of the ergot alkaloid alpha-ergocryptine was studied in Sprague-Dawley rats. Rats were fed 0, 4, 20, 100 or 500 mg ergocryptine/kg diet for 28-32 days (equal to 0, 0.36, 1.7, 8.9 and 60 mg ergocryptine/kg body weight/day for females and 0, 0.34, 1.4, 6.6 and 44 mg ergocryptine/kg body weight/day for males). The present study describes the general toxicological effects; the effects on metabolic and hormonal parameters will be reported separately. Body weight, body weight gain, food intake and food efficiency were all decreased with a U-shaped dose-response curve, as in both sexes the ranking severity of effects was in the order 100-20-500 and 4 mg/kg diet. Other changes with a U-shaped dose-response relationship included: hematological parameters (decreased MCV and MCH), serum enzyme activities (slightly increased/decreased ALAT, ASAT, GGT), increased serum urea concentrations, decreased glomular filtration (creatinine and urea clearances), decreased absolute organ weights, increased and decreased relative organ weights, atrophy of thymus and in females atrophy of ovary and uterus with in the mid-dose groups no detectable morphological features of an oestric cycle in the uterus. Other parameters, including increased relative liver, heart and ovarian weights and necrosis of the tail, were influenced in a dose-related manner or only in the high dose group. The U-shaped changes for the parameters mentioned above might be caused by the U-shaped dose-response relationship for food intake, which may be explained by the dopaminergic properties of alpha-ergocryptine. It is concluded that in rats fed ergocryptine for 28 days the dose-effect curve is rather steep and that the NOAEL is 4 mg/kg diet.

Dopamine agonists are known to increase the incidence of Leydig cell hyperplasia/adenomas when administered to rats over periods of 1-2 years. We have examined the early changes in factors affecting luteinizing hormone (LH)-controlled signal transduction pathways and steroidogenesis in Leydig cells in vitro after chronic oral administration of one of these dopamine agonists, Mesulergine (CU327-085) (N-(1-6,dimethylergolin-8a-yl)-N',N'-dimethylsulphamide hydrochloride) to Sprague-Dawley (SD) rats. Eight-week-old rats were given this dopamine agonist (2 mg/kg body wt/day) in food for 1, 5, or 12 weeks. The Leydig cells from control and treated rats were purified by elutriation and density gradient centrifugation. The dopamine agonist treatment was found to decrease the specific binding of 125I-human chorionic gonadotrophin (hCG) binding to the Leydig cells: a decrease was detected as early as 1 week after treatment and was more pronounced after 5 and 12 weeks. This was found to be due to a decrease in the LH/hCG receptor numbers and not to a decrease in LH/hCG-receptor binding affinity. Both basal and LH-stimulated cAMP and testosterone production were also decreased; cAMP production was decreased by approximately 50% by all concentrations of LH added whereas testosterone production was only decreased with submaximum stimulating concentrations of LH. The formation of testosterone in response to dibutyryl cAMP was also decreased by approximately 50%, indicating additional lesions in the signal transduction pathway. The addition of the cell permeant 22R-hydroxycholesterol (22R) demonstrated that testosterone but not pregnenolone production was decreased by treatment with the dopamine agonist, thus indicating that the 17 alpha-hydroxylase/C17-20 lyase may have been inhibited. Supporting evidence for this was found because the dopamine agonist also increased aromatase activity in the Leydig cells and thus the potential to produce estrogens; previous studies have shown that estradiol is an inhibitor of the 17-20 lyase enzyme. The addition of the dopamine agonist directly to the Leydig cells did not inhibit cAMP production or testosterone production except at high concentrations. It is concluded that treatment of rats with the dopamine agonist indirectly (i.e., via the pituitary) affects Leydig cell function resulting in a rapid decrease in LH receptors and cAMP and testosterone production. Aromatase activity is increased and thus the capacity to produce estrogens. These early changes in the signal transduction pathways and steroidogenesis may be involved in the Leydig cell hyperplasia/adenoma formation that subsequently occurs.

Dopamine agonists are known to increase the incidence of Leydig cell hyperplasia/adenomas when administered to rats over periods of 1-2 years. We have examined the early changes in factors affecting Leydig cell growth/hyperplasia after chronic oral administration of one of these dopamine agonists, Mesulergine (CU32-085) [N-(1-6-dimethylergolin-8 alpha-yl)-N,N-dimethylsulphamide hydrochloride), to Sprague-Dawley (SD) rats. Eight-week-old rats were given the dopamine agonist (2 mg/kg body weight/day) in food for 5 or 57 weeks. The dopamine agonist treatment had no significant effect on food intake, body weight, and testis and seminal vesicle size, but significantly decreased testicular interstitial fluid volume at 5 weeks (by 51%). Leydig cells isolated from rats treated with the dopamine agonist for 5 weeks exhibited an increase in the rate of protein synthesis compared with the controls (by 28%). This treatment, however, had no significant effect on the number of Leydig cells or macrophages as assessed by histological examination of testicular sections. Treatment with the dopamine agonist for 57 weeks caused a 36 and 28% increase in the number of Leydig cells and macrophages, respectively. Nodules of Leydig cells, indicating the first signs of tumor development, were present in testes from the 57- but not the 5-week-treated animals or the controls of both groups, although an increase in the number of Leydig cells occurred with aging. Thick-walled arterioles were found in the intertubular spaces of the testis sections from rats treated for 57 weeks. These findings suggest that chronic treatment of male SD rats with the dopamine agonist causes hypertrophy of Leydig cells within 5 weeks (as assessed by [3H]methionine incorporation), followed by hyperplasia within 2 years, prior to the development of Leydig cell adenomas, which occur within 1-2 years after the initiation of treatment.

Cabergoline, a new dopaminergic ergot derivative with potent long-lasting prolactin (PRL)-lowering properties, was assessed using standard reproductive studies in the mouse, rat, and rabbit with oral administration. Because of the compound's pharmacologic activity, several aspects remain incompletely explored in the rat, in which prolactin is the luteotrophic hormone. A fertility study in female rats was possible only at very low doses (0.5, 1, and 2 micrograms/kg/d) because higher doses completely inhibited implantation. In male rats no adverse effects were seen on male reproductive performance or on the offspring at doses up to 320 micrograms/kg/d given for 10 weeks prior to mating with untreated females. In a developmental toxicity study in rats treated from day 6 to day 15 of gestation at doses (6.25, 12.5, and 25 micrograms/kg/d) not exceeding the active dose for inhibition of egg nidation (ED50 = 25 micrograms/kg), a high incidence of total litter loss occurred as a reflection of inhibition of egg nidation at the highest dose, but embryofetal development was not impaired in litters reaching term. An exploratory study at 30 or 1000 micrograms/kg/d with treatment from day 5 of gestation or later demonstrated that cabergoline did not affect the maintenance of pregnancy at 30 micrograms/kg/d given from day 7 or later, or at 1000 micrograms/kg/d given from day 9. Doses of 500, 2000, and 8000 micrograms/kg/d (treatment from day 6 to day 15 of gestation) did not inhibit egg nidation in mice and showed no adverse effects on intrauterine development. Doses ranging from 5 to 8000 micrograms/kg/d administered from day 6 to day 18 of gestation in the rabbit were associated with maternal effects, including a reduction in body weight gain and food and water intake starting from 500 micrograms/kg/d and increased reactivity at the highest doses (4000 and 8000 micrograms/kg/d). Effects on intrauterine development were restricted to a reduction in mean fetal and placental weights at 4000 and 8000 micrograms/kg/d. In peri- and postnatal studies in rats (treatment from day 15 or 17 of gestation to weaning) cabergoline did not affect fetal development and parturition up to 100 micrograms/kg/d, but strongly inhibited milk secretion starting from 10 micrograms/kg/d, thus leaving unexplored the postnatal phase at higher doses. When neonatal rats (born from untreated dams) were treated directly with cabergoline at 10, 30, and 90 micrograms/kg/d from day 7 to 13 after birth, treatment was well tolerated up to the highest dose tested (90 micrograms/kg/d). It was concluded that cabergoline did not impair fertility in the male rat, was not teratogenic in mice and rabbits, did not affect the latter phase of gestation or parturition in the rat, and was not toxic when administered directly to neonatal rats.

Amesergide is a selective serotonin 5-HTIC/2 receptor antagonist being developed for the treatment of depression. The potential developmental toxicity of amesergide was evaluated in CD rats and New Zealand white rabbits. Pregnant rats and rabbits were dosed once daily by gavage on Gestation Days 6-17 and 6-18, respectively. Doses for rats were 0, 3, 10, and 30 mg/kg; doses for rabbits and 0, 0.2, 2, and 15 mg/kg. Cesarean sections were performed on rats and rabbits on Gestation Days 20 and 28, respectively. In rats, maternal effects expressed as depression of body weight gain and food consumption were observed at the 30 mg/kg dose level. Fetal viability and morphology were not affected at any dose level. Fetal weight was depressed at the 30 mg/kg dose level. The no-observed-effect level (NOEL) in the rat was 10 mg/kg. In rabbits, maternal effects expressed as a decrease in food consumption occurred at the 2 and 15 mg/kg dose levels; weight gain was depressed at 15 mg/kg. Fetal viability, weight, and morphology were not affected at any dose level. The NOELs for maternal and developmental effects in the rabbit were 0.2 and 15 mg/kg, respectively.

A series of new (5R,8R,10R)-ergoline derivatives was synthesized, and their antihypertensive and dopaminergic activities were tested in conscious spontaneously hypertensive rats and in rats with unilateral 6-hydroxydopamine-induced lesions of the substantia nigra. (5R,8R,10R)-6-Alkyl-8-ergolinemethanols, prepared from the corresponding ergolinecarboxylates, were converted to the tosylates, which were treated with various five-membered heterocycles containing nitrogen atoms to afford the new ergolines. (5R,8R,10R)-8-(1,2,4-Triazol-1-ylmethyl)-6-methylergoline (4s, maleate: BAM-1110) exhibited potent dopaminergic activity, about 18-fold greater than that of bromocriptine mesylate. (5R,8R,10R)-8-(1,2,4-Triazol-1-ylmethyl)-6-propylergoline (8b, fumarate: BAM-1602) showed extremely potent dopaminergic activity, being about 220 and 1.15 times more active than bromocriptine mesylate and pergolide mesylate, respectively. Several compounds exhibited potent antihypertensive activity. Structure-activity relationships for antihypertensive and dopaminergic activities are discussed.

The objective of this research was to measure the effects of endophyte-infected tall fescue seed extract and various alkaloids associated with the endophyte on in vitro prolactin secretion by rat hemipituitaries. Rat anterior pituitaries (AP) were dissected into halves and placed in temperature-controlled culture chambers (37 degrees C). The tissue was perfused with culture media at a flow rate of 12 mL/h. After perfusion for at least 90 min with control media, AP halves were exposed to their respective treatments for 15 min before they were returned to the control media. The treatments for Exp. 1 were .01 micrograms of alpha-ergocryptine/mL of culture medium, .01 microgram of ergonovine/mL of culture medium, .01 gram-equivalents of endophyte-infected tall fescue seed/mL of culture medium, and .01 gram-equivalents of endophyte free tall fescue seed/mL of culture medium. Treatments for Exp. 2 consisted of 10(-4), 10(-6), and 10(-8) M concentrations of perloline, N-formyl loline, N-acetyl loline, N-methyl loline, and alpha-ergocryptine. alpha-Ergocryptine suppressed (P less than .10) prolactin secretion in both experiments. Ergonovine and perloline both stimulated (P less than .10) prolactin secretion. The loline alkaloids (N-formyl loline, N-acetyl loline, N-methyl loline) had no effect on prolactin secretion. The endophyte-infected seed extract treatment suppressed (P less than .10) prolactin secretion. The endophyte-free seed extract treatment had no effect on prolactin secretion. In Exp. 2, prolactin secretion from AP responded to alpha-ergocryptine treatment in a dose-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Male albino rats were tested for antinociception following injections (IP) with saline, quinpirole (Quin) (1 mg/kg), morphine sulfate (M.S.) (5 mg/kg), or both Quin and M.S. (1 mg/kg and 5 mg/kg, respectively). Quin reduced and M.S. increased tail-flick latency as compared to controls. Tail-flick latencies of the animals injected with both drugs were significantly reduced as compared M.S. alone. Quin increased blood glucose levels by 96 percent, as compared to saline controls. In competitive binding studies Quin displaced 3H-DAGO (IC50 = 29.8 microM). CD-1 mice demonstrated a naloxone-reversible analgesia following ICV Quin (100 micrograms). These data are consistent with the hypothesis that the hyperglycemic effects of Quin attenuate M.S. analgesia while the antinociceptive effects of Quin may be mediated through opioid receptors.

The D2 dopamine receptor agonist LY 171555 (0.5 to 5 mg/kg) induces dose-dependent catalepsy in C57BL/6, DBA/2 and BALB/c inbred strains of mice. This effect shows marked strain-dependent differences, since the response of C57BL/6 is significantly lower than those presented by the other two inbred strains at all doses tested. In previous studies we have shown that the D2 agonist at doses ranging from 0.5 to 5 mg/kg induces hyperdefensive responses toward nonaggressive opponents in mice of the C57BL/6 and BALB/c but not of the DBA/2 strain. Here we report that the outbred CD1 mice present both cataleptic and hyperdefensive responses when challenged with LY 171555. Forty-five percent of individuals presenting high defensive response and 11% high cataleptic scores. No correlation was found between catalepsy and hyperdefensiveness in CD1 mice following administration of 1 mg/kg of the D2 agonist. These results suggest that D2 receptor stimulation results in different behavioral responses, possibly mediated by different dopaminergic systems, depending on the genetic make up.

The synthesis and the antihypertensive activity in rats of a series of 6-methylergolin-8 beta-yl-propionic acid derivatives are reported. The prolactin lowering activity (nidation inhibition test) in rats and the acute toxicity in mice were also studied as a measure of the specificity and safety of the potential antihypertensive compounds. From the structure-activity considerations reported here it is clear how modifications at the C8 side chain can improve the selectivity of the antihypertensive effects, whilst introducing substituents in other positions of the ergoline skeleton afforded unfavourable results in this respect. Compound 5, namely 2(R,S)-cyano-3-(6-methylergolin-8 beta-yl)-propionamide, emerged as the most interesting antihypertensive derivative.

This study was designed to compare at the same level of hypotension (-30%) nitroprusside (SNP) and nicergoline (NIC) effects on systemic haemodynamics and carotid haemodynamics (pulsed Doppler) and on plasma renin activity (PRA) in 20 anaesthetized dogs before and at the 20th minute of hypotension. In SNP group (n = 9) cardiac output (CO) and heart rate (HR) increased. Stroke volume (SV), pulmonary wedge pressure (PWP), central venous pressure (CVP) and systemic vascular resistance (SVR) decreased. Common carotid diameter (D) increased and blood flow velocity (V) decreased with constant common carotid blood flow (CCBF). CCBF/CO ratio was unchanged. PRA levels increased. In NIC group (n = II), HR, CO, SV were unchanged and PWP, CVP, SVR decreased. D, V and CCBF were unchanged. CCBF/CO ratio increased and PRA was unchanged. NIC provoked mild hypotension without reflex sympathetic activation unlike SNP. Only SNP dilated large arteries. The autoregulation of CCBF is maintained with both drugs but CCBF/CO ratio is increased only with NIC.

Novel ergolines were synthesized and screened in spontaneous hypertensive rats (SHR) with the aim of finding a new class of ergot related antihypertensives. Their prolactin inhibitory effect (measured as nidation inhibition in rats), acute toxicity (LD50) and interference with CNS function (Irwin test) were also evaluated as a measure of selectivity and safety. Modification of the C8 side-chain enhanced antihypertensive activity selectively, while the introduction of substituents in other positions of the ergoline skeleton generally yielded unfavourable results, either by decreasing selectivity or by increasing toxicity.

Cabergoline, a new ergoline derivative, is a potent prolactin inhibitor. In this review, results are combined from previously published and unpublished blind laboratory and open clinical studies with cabergoline in pseudopregnant, pregnant and lactating bitches, in bitches with normal and prolonged cycles, and in pregnant queens. Dose-response studies in nursing bitches, using puppy weight as an endpoint, revealed that a dose of 5 micrograms/kg/day orally (for 5 days) was the optimal dose with a minimum of side effects. This dose effectively lowered blood prolactin concentrations in pregnant bitches and was partly luteolytic during the 1st half of gestation, and fully luteolytic during the 2nd half of gestation. Consequently, pregnancies were terminated in the 2nd half of pregnancy in the bitch, and in the queen. Treatment successes with pseudopregnancy and true and false lactation, including cases of eclampsia, were greater than 90%. The same level of success was seen in bitches with prolonged cycles (anoestrus). A 7-10-day treatment period resulted almost uniformly in oestrus, and restored fertility in greater than 80% of all bitches mated. Cycles were occasionally shortened in bitches treated for false lactation. Attempts to shorten cycles routinely in beagle bitches, in a commercial breeding operation, with a dose of 5 micrograms/kg/day for 14 days during months 4, 5 or 6 of the cycle were unsuccessful.

Pharmacological investigations of the ergot alkaloid of the group of clavines, elymoclavine, isolated from Claviceps sp. cp. II showed the following results: The LD50 for mice for 24 h was 350 (228-535) mg/kg and for rats 145 (81-258) mg/kg. Elymoclavine induced a dose-dependent stereotypy (doses of 2 to 10 mg/kg) in rats and mice which was antagonized by haloperidol and pimozide. It prevented the development of haloperidol catalepsy in rats and produced rotations contralateral to the striatal lesions with 6-OHDA which were antagonized by pimozide and partly by cyproheptadine. Elymoclavine, like bromocriptine, decreased the plasma level of prolactin. Furthermore, elymoclavine increased the exploratory activity of rats in open field; this effect was antagonized by haloperidol and was essentially influenced by many substances acting on different transmitter systems (NA, DA, GABA). Elymoclavine inhibited the picrotoxin and electroshock convulsive seizures but potentiated the pentylenetetrazol ones in mice as these effects were differently influenced by pimozide, haloperidol, 5-HTP, atropine and phentolamine. 100 and 250 micrograms/kg of elymoclavine produced a considerable and persisting decrease of the blood pressure in anaesthetized cats. At 1 X 10(-6) M, without producing any per se effect, elyoclavine decreased the contractile effects of acetylcholine, nicotine, BaCl2 and PGE1 as well as the field electrical stimulation-induced contractions in an isolated segment from guinea-pig ileum. The observed effects of elymoclavine are mainly due to its dopaminergic agonist action. It seems, however, that influences on other transmitter receptors also underlie the mechanism of action of this ergot alkaloid.

We tested the mutagenic potential of crude extracts of 18 strains of Penicillium camemberti and 6 strains of P. roqueforti, which are used commercially in the production of mould ripened cheese in Switzerland. No mutagenic activity could be detected in any of the extracts. Roquefortine, a mycotoxin of P. roqueforti, often found in Blue cheese, was negative in the Amestest. The results obtained do not lead reasons for experting undesired long term effects from the consumption of mould ripened cheese.

The mammalian spot test has recently been demonstrated to be a promising method for the detection of somatic mutations induced by chemicals and is at present under validation as an in vivo screening test for carcinogenic potential. The pesticide chlordimeform, its principal metabolites N-formyl-4-chloro-o-toluidine and 4-chloro-o-toluidine, and the drug lisuride hydrogen maleate, as well as the known mutagens ethyl methanesulfonate (EMS) and N-ethyl-N-nitrosourea (ENU) were tested in the mammalian spot test. Female C57BL/6J mice were mated to T-stock males and treated by gavage with maximal tolerated doses of the test compounds, or by intraperitoneal injection with EMS and ENU at days 8, 9 and 10 of pregnancy. Mutation induction was monitored post-natally by checking the fur of the offspring for color spots that result from expression of a recessive gene involved in coat-color determination. Of the environmental chemicals tested, only 4-chloro-o-toluidine was mutagenic in the spot test. This positive result was in agreement with in vitro experiments and its carcinogenic potential in the mouse. However, the mouse carcinogens chlordimeform and N-formyl-4-chloro-o-toluidine were negative, as was the non-carcinogen lisuride hydrogen maleate. N-Formyl-4-chloro-o-toluidine and lisuride hydrogen maleate have been reported to be weakly positive in the Ames test. The positive controls EMS and ENU showed a clear mutagenic response.

The pharmacological investigation of the ergot alkaloid of the group of clavines elymoclavine isolated from Claviceps sp. cp. II showed the following: LD50 for mice for 24 hours was 350 (228 divided by 535) mg/kg and for rats--145 (81 divided by 258) mg/kg; elymoclavine induced a dose-dependent stereotypy in rats and mice which was antagonized by haloperidol and pimozide; it prevented the development of haloperidol catalepsy in rats and produced rotations contralateral to the striatal lesions with 6-OHDA which were antagonized by pimozide and partly by cyproheptadine. Elymoclavine increased the exploratory activity of rats in open field as this effect was antagonized by haloperidol and was essentially influenced by many substances acting on different transmitter systems (NA, DA, GABA). Elymoclavine inhibited the picroroxin and electroshock convulsive seizures but potentiated the pentylenetetrazol ones in mice as these effects were differently influenced by pimozide, haloperidol, 5-HT, atropine and phentolamine. The observed effects of elymoclavine are mainly due to its DAergic agonistic action. It seems, however, that influences on other transmitter receptors also underlie the mechanism of action of this ergot alkaloid.