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At least 19 recordsLinked to original sources
PubMed1987

Peripheral dopamine receptors in the antihypertensive action of dihydroergotoxine in humans.

The effect of the intravenous administration of dihydroergotoxine (6 micrograms/kg) on arterial blood pressure, heart rate, and plasma concentrations of norepinephrine and 3,4-dihydroxyphenylacetic acid (the deaminated dopamine metabolite) was studied in 20 subjects with essential hypertension (8 men and 12 women aged 32-68 years old, World Health Organization Class I-II). In supine resting subjects, dihydroergotoxine significantly decreased systolic blood pressure (from 175 +/- 5 to 156 +/- 4 mm Hg; p less than 0.001), diastolic blood pressure (from 109 +/- 4 to 95 +/- 3 mm Hg; p less than 0.001), and heart rate (from 71 +/- 2 to 63 +/- 2 beats/min; p less than 0.001) as compared with the results of placebo treatment. Moreover, dihydroergotoxine reduced plasma levels of norepinephrine (from 368 +/- 39 to 238 +/- 33 pg/ml; p less than 0.001) and 3,4-dihydroxyphenylacetic acid (from 1.57 +/- 0.21 to 1.22 +/- 0.13 ng/ml; p less than 0.01). The time course of the blood pressure decrease paralleled that of plasma norepinephrine concentration. Dihydroergotoxine did not suppress the cardiovascular and plasma norepinephrine concentration. Dihydroergotoxine did not suppress the cardiovascular and plasma norepinephrine response to standing. The effect of domperidone, a peripheral presynaptic dopamine receptor antagonist, on dihydroergotoxine response was studied in six of the 20 subjects (3 men and 3 women 48-64 years old). The intravenous administration of domperidone (0.3 mg/kg) prevented the dihydroergotoxine-induced reduction in blood pressure and heart rate and the fall in plasma norepinephrine and 3,4-dihydroxyphenylacetic acid levels. Domperidone administered alone failed to significantly modify any measured variables.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Dual effect of dihydroergotamine and dihydroergotoxin in isolated human femoral veins and arteries.

In human femoral vein strips, dihydroergotamine and dihydroergotoxin caused a slowly proceeding, long-lasting increase in tone. Dihydroergotamine had markedly higher affinity than noradrenaline, it possessed nearly the same intrinsic activity as noradrenaline. Dihydroergotoxin was less effective than dihydroergotamine. In isolated femoral artery strips, dihydroergotamine showed lower affinity and lower intrinsic activity in terms of noradrenaline. Dihydroergotoxin had negligible vasoconstrictor effects in arteries. In veins, dihydroergotoxin had a stronger alpha-adrenolytic effect than in arteries. In isolated arteries, dihydroergotoxin was equieffective to dihydroergotamine whose alpha-adrenoceptor blocking effect did not significantly differ in veins and arteries. Our results show that dihydroergotamine at very low concentrations exerted predominantly venoconstrictor effects and, therefore, it is more suited to increase the venous tone than dihydroergotoxin which at low concentrations showed alpha-adrenoceptor blocking activity.

Dihydroergotamine↗
PubMed1983

Effect of dihydroergotoxine on the susceptibility of rats to convulsions produced by different convulsant agents.

The study was undertaken to test further whether diminished GABAergic transmission might be responsible for the increased susceptibility of rats to picrotoxin-induced convulsions. In rats kept individually in cages in a noise-free room, the time between the intraperitoneal injection of the convulsant agent and the onset of convulsions was measured. Acute and subacute treatment with low doses of dihydroergotoxine (0.01-1.0 mg/kg) increased the occurrence and decreased the latency of picrotoxin-induced convulsions. Acute administration of dihydroergotoxine, 1.0 mg/kg, caused convulsions in animals injected with the subconvulsive dose (3 mg/kg) of bicuculline and of 10.0 mg/kg dihydroergotoxine in animals injected with the subconvulsive dose (1.5 mg/kg) of strychnine. Some of the animals injected with the 100% convulsive dose of strychnine were protected by dihydroergotoxine pretreatment (1.0 mg/kg) as evidenced by the lower occurrence of convulsions and fewer animals dying, as well as by a delay in the appearance of convulsions at 10.0 mg/kg. These results together with the previous findings on the GABA system suggest that dihydroergotoxine potentiates the appearance of picrotoxin and bicuculline-induced convulsions by a diminution of GABAergic transmission.

Animals↗
PubMed1991

Effect of dihydroergotoxine, a cerebral vasodilator, on cognitive deficits induced by prenatal undernutrition and environmental impoverishment in young rats.

The study was conducted on 64 Charles Foster strain albino rats, which were equally distributed into 8 evenly matched groups, following a 2 x 2 x 2 factorial design, by varying three independent factors at two levels: nutrition--normal and undernutrition; environment--enrichment and impoverishment, and drug treatment--vehicle and dihydroergotoxine (3 mg/kg, i.p.). Prenatal undernutrition was induced by restricting the mother's food intake. The environmental enrichment/impoverishment and the vehicle/dihydroergotoxine treatments were given during the postweaning period of the pups. The rats were subjected to original and subsequent reversal brightness discrimination learning tests in a single unit T-maze at 8-9 weeks of age. Thereafter, the animals were tested for passive avoidance learning. The results indicate that undernutrition caused significant original and reversal discrimination learning, deficits whereas environmental deprivation attenuated only the original discrimination learning performance. Dihydroergotoxine treatment facilitated the learning performance of rats in both the original and reversal learning tests. Nutritional, environmental and dihydroergotoxine treatments had no effect on the retention of the passive avoidance learning, both at 24 hr and 1 week intervals. Dihydroergotoxine treatment attenuated the learning deficits induced by prenatal undernutrition. The results indicate that dihydroergotoxine is not likely to be useful in cognitive deficits, induced by malnutrition, though it facilitated learning acquisition, since it had no effect on retention.

Animals↗
PubMed1982

A comparative plethysmographic study of the venoconstrictor effect of dihydroergotamine and dihydroergotoxine on the deep veins of the calf in healthy subjects and patients suffering from varicosis.

The venoconstrictor effect of dihydroergotamine and dihydroergotoxine was compared in ten volunteers and in tne patients suffering from varicosis of the leg veins. The dihydrogenated ergot alkaloids were administered subcutaneously in a dose of 0.5 mg each. The influence on the capacitance reaction was determined by occlusion plethysmography of the calf. In addition, the arterial resistance was measured in the same region. Dihydroergotamine reduces the capacitance reaction in volunteers only at the high occlusion pressure levels 8.0 and 10.7 kPa after a lag of 40 min, whereas dihydroergotoxine does not show any significant influence. On the other hand, dihydroergotamine and dihydroergotoxine lead to a significant decrease in capacitance reaction in the patients after 20 and 60 min, respectively. However, the effect if dihydroergotamine (2.1 ml/100 ml tissue) is significantly greater than that of dihydroergotoxine (1.2 ml/100 ml tissue) and nearly normalizes the increased capacitance reaction. The two drugs increase the arterial resistance more clearly in the volunteers than in the patients, and dihydroergotoxine more often than dihydroergotamine tends to decrease resistance when the pre-existent resistance value is low.

Adult↗
PubMed1990

Effects of dihydroergotoxine on some dopamine-related behaviors in rats.

1. The effects of dihydroergotoxine on open-field behavior, apomorphine-induced stereotype and haloperidol-induced catalepsy were studied quantitatively in rats. 2. Dihydroergotoxine decreased the open-field behavior of rats, in a dose-dependent manner; this effect remained at least for 8 hr. 3. Dihydroergotoxine (10.0 mg/kg) caused a 1.40 leftward displacement of the dose-response curve constructed for apomorphine-induced stereotypy; the ED50 for apomorphine was reduced from 0.40 (+/- 0.05) to 0.29 (+/- 0.03). 4. Dihydroergotoxine (10.0 mg/kg) was unable to change haloperidol-induced catalepsy. 5. Results were discussed in the light of a possible interference of central noradrenergic systems with the expression of dopaminergic behaviors.

Animals↗
PubMed1985

Alpha-adrenergic agonist and antagonist activity of dihydroergotoxine in rats.

The alpha-adrenergic activity of dihydroergotoxine had been studied in both pithed and urethane or pentobarbitone anaesthetized rats. In anaesthetized rats, blood pressure effects varied with the anaesthetic agent: hypotension with urethane, hypertension with pentobarbitone. This latter pressor response was a peripheral effect. In pithed rats, the vasopressor response to dihydroergotoxine was reduced competitively by yohimbine, and non-competitively by nifedipine, but not by prazosin or methysergide, showing that the vasoconstriction is mediated by alpha 2-adrenoceptors. Dihydroergotoxine decreases the tachycardia elicited by stimulation of the cardioaccelerator nerves, this effect being antagonized by yohimbine. It also reduced the pressor response to (-)-phenylephrine. These results indicated that, on the peripheral vascular system of the rat, dihydroergotoxine acts as an alpha 1-adrenoceptor blocker and an alpha 2-adrenoceptor agonist.

Adrenergic alpha-Agonists↗
PubMed1988

Dihydroergotoxine-induced bradycardia in rats.

Dihydroergotoxine (0.01-0.3 mg kg-1 i.v.) decreased heart rate in pentobarbitone-anaesthetized rats. The bradycardia was reduced but not blocked by pre-treatment with guanethidine, yohimbine, propranolol or pithing. It was not prevented by bivagotomy, atropine, sulpiride or haloperidol. Dihydroergotoxine failed to affect, either the bradycardia produced by electrical stimulation of the vagus, or the cardioacceleration induced by i.v. isoprenaline. The increase in heart rate elicited in pithed rats by electrical stimulation of the spinal cord was reduced by dihydroergotoxine; this effect being inhibited by yohimbine but not by sulpiride. In conclusion, the main mechanism by which dihydroergotoxine (i.v.) induces bradycardia in the rat involves stimulation of alpha 2-adrenoceptors located predominantly at the cardiac sympathetic nerve endings.

Animals↗
PubMed1981

Determination of methylergometrine and dihydroergotoxine in biological fluids.

New hapten-carrier conjugates were prepared from 9,10-dihydro-N-[1-(hydroxymethyl)propyl]-6-methylergoline-8-carboxamide 1-hemisuccinate (dihydromethylergometrine hemisuccinate) by coupling with bovine serum albumin employing the mixed anhydride technique. The specificity of anti-dihydromethylergometrine antiserum elicited in the rabbits by immunization with this antigen was tested by cross-reaction studies with methylergometrine, dihydroergotoxine, dihydroergocristine and dihydroergotamine employing [9,10-3H]-dihydromethylergometrine and [9,10-3H]-dihydroergocryptine in the radioimmunoassay procedure. These cross reactivities were observed 100% for methylergometrine, 48.3% for dihydroergotamine, 16.6% for dihydroergotoxine and 6.6% for dihydroergocristine using labeled dihydromethylergometrine. When labeled dihydroergocriptine was the results were 18.3%, 112.1%, 100% and 63.8%, respectively. Methylergometrine concentrations in the postpartal plasma and milk at 2 hr after oral administration of methylergometrine maleate (0.75 mg) to woman were 5.1 ng/ml and 1.3 ng/ml, respectively. Dihydroergotoxine concentrations in the rabbit sera after oral administration of dihydroergotoxine methanesulfonate (4 mg) were studied. The assay was satisfactory to permit the measurement of ergot alkaloid levels in the biological fluids.

Animals↗
PubMed1987

Bioavailability of slow-release co-dergocrine mesylate (dihydroergotoxine) formulations.

The relative bioavailability and plasma concentration profile of dihydroergotoxine as a solution, standard tablets and slow-release formulations have been compared in 12 healthy subjects following the application of 4-5 mg as a single dose or as 2-3 smaller dose units given at 5 h intervals. Plasma dihydroergotoxine concentrations were measured using a sensitive and highly specific radioimmunoassay procedure. The plasma concentration profile after a single 4.5 mg SR-capsule with relative bioavailability 92% (Oral solution, 4.5 mg as single dose = 100%), releasing 80% of the capsule contents within 8 h, was similar to that achieved following the application of 2-3 divided doses at 5 h intervals of a solution (relative bioavailability = 85%), standard tablet (relative bioavailability = 99%) or SR-tablets (relative bioavailability 78%). Slow-release formulations of dihydroergotoxine do not lead to high postdose concentrations as seen with solutions and standard tablets. Application of a single 4.5 mg SR-capsule can maintain prolonged plateau concentrations exceeding 100 pg/ml over 10 h. Reducing the rate of presentation of dihydroergotoxine to the body in the form of slow release formulations or by using spaced doses does not markedly affect bioavailability when compared to a solution.

Adult↗
PubMed1983

[Specificity and precision of a radioimmunoassay of dihydroergotoxine in plasma].

For the quantitative and qualitative determination of dihydroergotoxine methanesulphonate (DCCK) a radioimmunoassay was developed. This method involves use of an antibody against the dihydrolysergic acid moiety and an 125I-labelled dihydrolysergic tracer. The differentiation of dihydroergopeptides, lysergic acid and the ergopeptides was obtained by modification of extraction methods already published. The assay procedure detects around 10 pg/ml dihydroergotoxine. Dihydrolysergic acid and lysergic acid are not detectable up to about 6 ng/ml. Ergometrine and alpha-ergocryptine show cross-reactivities of 14% and 7.5%, respectively. All dihydroergopeptides included in dihydroergotoxine show the same cross-reactivity as dihydroergotoxine itself. Intra- and inter-assay variations were approximately 12% and 13%, respectively.

Animals↗
PubMed1978

Dihydroergotoxine: separation and determination of four components by high-performance liquid chromatography.

The evaluation of a new high-performance liquid chromatographic method is described. It permits the separation and determination of the four components of dihydroergotoxine (dihydroergocristine, dihydroergocornine, dihydro-alpha-ergocryptine, and dihydro-beta-ergocryptine) in a single step. On reversed-phase microparticles, complete baseline separation is possible with different mobile phases containing about 10(-2) M base. The analysis of dihydroergotoxine mesylate drug substance or its dosage forms can be carried out in about 15 min. No reference substance is required for the determination of the proportions of the components. This method is simple and exhibits high accuracy, reproducibility, and selectivity. It permits the analytical control of dosage forms containing dihydroergotoxine mesylate to ensure that they comply with the specifications for the drug substance used in clinical and pharmacological studies.

Chemical Phenomena↗
PubMedDate not supplied

Dihydroergotoxine, an ergot alkaloid without marked hypotensive effect, improves blood flow and metabolism in the underperfused canine myocardium.

Regional myocardial blood flow was assessed in 6 anaesthetized dogs using radiolabelled microspheres. Lactate, H+, and O2 content were measured in arterial and local venous blood, obtained from the area supplied by the circumflex branch of the left coronary artery (LCX). Constriction of LCX by 67% led to considerable hemodynamic changes indicative of depressed global myocardial function. A significant release of lactate from the underperfused part of the left ventricle was recorded. Infusion of 0.7 micrograms/kg dihydroergotoxine over a period of 5 min induced a decrease in heart rate, left ventricular dp/dt max, and cardiac output, a sustained increase in total peripheral and femoral resistance and a transient increase in mean arterial blood pressure. Dihydroergotoxine markedly reduced lactate release and even, in some cases, induced lactate uptake and led to a significant increase in the endocardial blood flow both in the underperfused and normally perfused left ventricle. It is concluded that dihydroergotoxine, due to its ability to reduce myocardial oxygen demand and owing to its alpha-sympatholytic activity, which is not accompanied by any marked decrease in arterial blood pressure, causes improvement in blood flow in the underperfused myocardium and a marked amelioration of the impaired metabolic processes.

Animals↗
PubMed1987

Presynaptic inhibition by dihydroergotoxine of the response to peripheral sympathetic nerve stimulation in rats.

Dihydroergotoxine decreased the heart rate in both intact and pithed rats but increased blood pressure in pithed rats only. Dihydroergotoxine did not inhibit the postsynaptic effect of isoprenaline and noradrenaline but reduced the neurally induced pressor responses and tachycardia in the rat. The first effect was antagonized by sulpiride, and the second by yohimbine. It was concluded that dihydroergotoxine stimulates presynaptic alpha 2-adrenoceptors at the cardioaccelerator nerve endings, and presynaptic dopamine receptors at the sympathetic terminations innervating the vascular bed.

Animals↗
PubMed1992

Dihydroergotoxine modulation of the GABAA receptor-associated Cl- ionophore in mouse brain.

Dihydroergotoxine non-competitively displaced the binding of t-[3H]butylbicycloorthobenzoate ([3H]TBOB) to crude synaptosomal membranes from the mouse brain (cerebrum minus cortex), and gamma-aminobutyric acid (GABA) (10 microM) enhanced the displacement potency of dihydroergotoxine in a bicuculline-sensitive manner. The same ergot compound prolonged pentobarbital-induced sleeping in mice and diminished the convulsive potency of picrotoxin in the same animal species. The results are indicative of the positive coupling between GABA and dihydroergotoxine.

Animals↗
PubMed1983

Comparison between radioreceptor assay and radioimmunoassay for the determination of dihydroergotoxine in rabbit plasma samples.

Two analytical methods, radioreceptor assay and radioimmunoassay, for the determination of dihydroergotoxine have been developed. Antiserum, providing sufficient sensitivity for the radioimmunoassay, was produced by immunizing rabbits with D-lysergic acid coupled to bovine serum albumin. Radioreceptor assay utilizing dopamine receptor was carried out to determine dihydroergotoxine and its pharmacologically active metabolites in rabbit plasma, and the result was compared with that obtained by radioimmunoassay. The values obtained in both assays were almost identical; it was, therefore, assumed that the plasma concentrations of dihydroergotoxine determined by the present radioimmunoassay reflects the amount of unchanged drug and its active metabolites.

Animals↗
PubMed1985

Dihydroergotoxine decreases blood pressure in spontaneously hypertensive rats by interacting with peripheral dopamine receptors.

Dihydroergotoxine (10 micrograms/kg s.c.) decreased mean carotid blood pressure in urethane-anaesthetized spontaneously hypertensive rats but failed to modify the same parameter in normotensive rats. The effect was statistically significant 20 min after the injection and relatively long lasting (up to 90 min). Pharmacological characterization of the phenomenon indicated that it is mediated by stimulation of dopamine receptors, since pretreatment with haloperidol, cis-flupentixol but not with trans-flupentixol, completely prevent the reduction in blood pressure induced by dihydroergotoxine. Moreover, a challenge dose of dihydroergotoxine did not reduce mean blood pressure values in spontaneously hypertensive rats pretreated with domperidone or (-)sulpiride, but not with (+)sulpiride. These results suggest that the ergot derivative modifies the cardiovascular system by interaction with peripheral dopamine receptors of the DA2 type.

Animals↗
PubMed1995

Dopaminergic drugs in congestive heart failure: hemodynamic and neuroendocrine responses to ibopamine, dopamine, and dihydroergotoxine.

Ibopamine has hemodynamic and neurohumoral effects potentially useful for the treatment of congestive heart failure (CHF), but its mechanism of action is not completely clear. To evaluate the role of dopaminergic receptor stimulation in the hemodynamic and neurohumoral activity of ibopamine, we compared the effects of ibopamine, 100 mg orally (p.o.) with those of the dopamine 2, 4, and 6 micrograms/kg/min intravenously (i.v.) and of the DA2 agonist dihydroergotoxine 6 micrograms/kg i.v. in 13 patients with chronic CHF [left ventricular ejection fraction (LVEF) < or = 35%]. All patients underwent right heart Swan-Ganz catheterization with determination of hemodynamic parameters at baseline, after 30 min of infusion of each dose of dopamine (DA) and < or = 6 h after ibopamine and dihydroergotoxine administration. Blood samples for the assessment of plasma renin activity (PRA), aldosterone, norepinephrine (NE), and epinephrine (Epi) were also obtained. Ibopamine induced a peak 21% increase of cardiac index (CI) with a 23 and 25% increase in stroke volume (SV) and stroke work indexes (SWI), respectively, and an 18% reduction in systemic vascular resistance (SVR). Similar changes were observed after DA infused at the doses of 2 and 4 micrograms/kg/min, whereas with the dose of 6 micrograms/kg/min heart rate (HR) increased by 23% and SV index (SVI) did not change further. Dihydroergotoxine administration induced only a significant 9% decrease in mean arterial pressure (MAP), with a 13% reduction in SVR.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗