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At least 19 recordsLinked to original sources
PubMed1997

Determination of catecholamines in sheep plasma by high-performance liquid chromatography with electrochemical detection: comparison of deoxyepinephrine and 3,4-dihydroxybenzylamine as internal standard.

3,4-Dihydroxybenzylamine (DHBA) is commonly used as the internal standard in HPLC catecholamine assays. Sheep are frequently used in studies of cardiovascular physiology and in such studies measurement of catecholamines is important. The recovery of DHBA from sheep plasma is, however variable and poor. Therefore, we have developed a reliable and sensitive HPLC-ED method with alumina extraction for measurement of catecholamines in sheep plasma using deoxyepinephrine (epinine) as the internal standard. Separation was performed on a muBondapak C18 column (300x3.9 mm, 10 microm) with a mobile phase containing 2% acetonitrile and 98% buffer (0.05% sodium acetate-0.02% EDTA-0.013% sodium heptanesulfonate), pH 3.25. The extraction of epinine from water, human plasma, dog plasma and sheep plasma did not differ (p>0.05), but extraction of DHBA from sheep plasma was significantly impaired (p<0.0001). The R2 of regression curves (n=5) of norepinephrine (NE) (25.02 pg/ml-1.00 ng/ml) and epinephrine (E) (25.82 pg/ml-1.03 ng/ml), using epinine as internal standard were greater than 0.99. The intra- and inter-day coefficients of variation were 2.11-11.15 and 0.88-12.60% for NE and 1.12-10.91 and 2.88-12.60% for E, respectively. The detection limits for NE and E are 12 pg/ml. The technique described has the advantage that it allows the simultaneous determination of both endogenous and [3H]norepinephrine in sheep plasma using a sensitive and reproducible HPLC technique.

Animals↗
PubMedDate not supplied

Analysis of the positive inotropic effect of ibopamine in the blood-perfused canine papillary muscle.

The positive inotropic effect of ibopamine, an orally active dopamine analogue, was examined in an isolated canine papillary muscle perfused with blood of a donor dog through the anterior septal artery (ASA). Administered intraduodenally (25 mg/kg) in the donor dog, ibopamine increased the left ventricular dP/dtmax as well as the contractile force of the isolated papillary muscle. Injected into the ASA (10 micrograms) it had only a slight positive inotropic effect, which was greatly enhanced by preincubation of the drug in plasma. Addition of physostigmine to the plasma prevented this enhancement. Propranolol (0.2 mg/kg i.v.) shifted the dose-response curves for the positive inotropic effect of plasma-dissolved (PD) ibopamine (0.3-10 micrograms), norepinephrine (NE; 1-100 ng), and deoxyepinephrine (Epinine; 0.3-10 micrograms) to the right. At 3 micrograms/min cocaine enhanced the response to NE, but enhanced only slightly the responses to Epinine and PD ibopamine; at 10 micrograms/ml it enhanced the response to NE, but depressed slightly the responses to Epinine and PD ibopamine. The positive inotropic effect of intraduodenally administered ibopamine may be caused by active metabolite(s), possibly epinine, from its hydrolysis by esterases, and may be mediated by both direct and indirect stimulation of beta-adrenoceptors in the canine heart.

Animals↗
PubMed1990

Lung epinephrine synthesis.

We studied in vitro and in vivo epinephrine (E) synthesis by rat lung. Nine days after removal of the adrenal medullas, circulating E was reduced to 7% of levels found in sham-operated rats but 30% of lung E remained. Treatment of demedullated rats with 6 hydroxydopamine plus reserpine did not further reduce lung E. In the presence of S-[3H]adenosylmethionine lung homogenates readily N-methylated norepinephrine (NE) to form [3H]E. The rate of E synthesis by lung homogenates was progressively more rapid with increasing NE up to a concentration of 3 mM, above which it declined. The rate of E formation was optimal at an incubation pH of 8 and at temperatures of approximately 55 degrees C. We compared the E-forming enzyme(s) of lung homogenates with those of adrenal and cardiac ventricle. The adrenal contains mainly phenylethanolamine N-methyltransferase (PNMT), which is readily inhibited by SKF 29661 and methylates dopamine (DA) very poorly. Cardiac ventricles contain mainly nonspecific N-methyltransferase (NMT), which is poorly inhibited by SKF 29661 and readily methylates both DA and NE. Lung homogenates were inhibited by SKF 29661 about half as well as adrenal but more than ventricle. We used the rate of E formation from NE as an index of PNMT-like activity and deoxyepinephrine synthesis from DA as an index of NMT-like activity. PNMT and NMT activity in rat lung homogenates were not correlated with each other, displayed different responses to change in temperature, and were affected differently by glucocorticoids.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1978

High-performance liquid chromatographic assay of isoquinoline alkaloid formation from reaction of biogenic amines and aldehydes.

To understand the role that tetrahydroisoquinoline formation may play in alcoholism and drug toxicology, high-performance liquid chromatography with electrochemical detection was used to monitor the overall rate of reaction, in pH 7.4 buffer, between the catecholamines (dopamine, alpha-methyldopamine, dihydroxyphenylpropanolamine, deoxyepinephrine, levodopa, alpha-methyldopa, epinephrine, levarterenol, ans isoproterenol) and acetaldehyde. The observed overall rate of reaction varied from 0.38 to 0.0013 liter/mole sec. In addition, the reaction rate of the neurotransmitter dopamine was measured for various aldehydes (formaldehyde, acetaldehyde, glyoxylic acid, paraldehyde, malonaldehyde, glyceraldehyde, and chloral hydrate). The observed overall rate of reaction varied from 5.3 to 0.0011 liters/mol sec. Penicillamine prevented formation of the tetrahydroisoquinoline alkaloids when initially present in concentrations equal to or greater than the aldehyde concentration.

Aldehydes↗
PubMed1992

Preparation of an optimum mobile phase for the simultaneous determination of neurochemicals in mouse brain tissues by high-performance liquid chromatography with electrochemical detection.

A systematic method is described for the optimization of a mobile phase for the simultaneous determination of 24 neurochemicals consisting of catecholamine, serotonin, their precursors and metabolites and related materials. This mobile phase contained sodium acetate (0.04 M), citric acid (0.01 M), sodium chloride (0.0126 M), sodium octyl sulfate (91 mg/l), tetrasodium EDTA (50 mg/l) and 10% (v/v) methanol. When this optimum mobile phase was applied to the analysis of brain tissues of the Swiss male mouse, twelve neurochemicals were quantified in the free state: tyrosine, L-beta-3,4-dihydroxyphenylanine, dopamine, 3,4-dihydroxyphenylacetic acid, 4-hydroxy-3-methoxyphenylacetic acid, norepinephrine, 3-methoxy-4-hydroxyphenylglycol, DL-3,4-dihydroxymandelic acid, DL-4-hydroxy-3-methoxymandelic acid, serotonin, L-tryptophan, 5-hydroxyindole-3-acetic acid and DL-synephrine and normetanephrine, appearing as a fused peak. This fused peak was present on the chromatogram tracings of all the mouse brain tissues. The separable neurochemicals not found by this procedure in the Swiss male mouse tissues were DL-3,4-dihydroxyphenylglycol,5-hydroxytryptophan, epinephrine, DL-octopamine, metanephrine, deoxyepinephrine, homovanillyl alcohol, N-acetylserotonin, tyramine and 3-methyltyramine.

Animals↗
PubMed1983

Optically active catecholimidazolines: a study of steric interactions at alpha-adrenoreceptors.

The optical isomers and deoxy form of 2-(3,4, alpha-trihydroxybenzyl)imidazoline hydrochloride were examined for their alpha-adrenergic activity on rat aorta. The rank order of stimulant activity was deoxy (2) congruent to (R)-(-)-1 greater than (S)-(+)-1. This is in contrast to catecholamines in which the order of activity is (R)-(-)-epinephrine greater than (S)-(+)-epinephrine = epinine (deoxyepinephrine). The relative order of potency for the isomers of 2-(3,4, alpha-trihydroxybenzyl)imidazoline is different than that predicted by the Easson--Stedman theory for stereoisomers of catecholamines. Also, substitution of the deoxy compound 2 with substituents, methyl or benzyl, in the 4-position lowers the alpha-adrenergic agonist activity, and differences observed between optical isomers were small.

Animals↗
PubMed1995

Dopaminergic transmission between identified neurons from the mollusk, Lymnaea stagnalis.

1. Dopaminergic transmission was investigated in the central nervous system (CNS) of the freshwater snail, Lymnaea stagnalis. 2. The giant pedal neuron, designated as right pedal dorsal one (RPeD1), makes chemical, monosynaptic connections with a number of identified follower cells in the CNS. Previous work has shown that RPeD1 is an interneuron and a important component of the Lymnaea respiratory central pattern generator. In this study, the hypothesis that RPeD1 uses dopamine as its neurotransmitter was tested by chromatographic, pharmacological, and electrophysiological methods. Characterization of RPeD1's transmitter pharmacology is essential to clearly understand its role in Lymnaea. 3. Earlier studies demonstrated that the soma of RPeD1 contains dopamine. This was quantitated in the present study by high-performance liquid chromatography (with electrochemical detection) of isolated RPeD1 somata and growth cones, which yielded 0.8 +/- 0.3 and 0.10 +/- 0.08 pmol of dopamine per soma and growth cone, respectively. 4. Bath or pressure application of dopamine to follower cells of RPeD1, in situ, mimicked the effects of RPeD1 stimulation. Dose-response curves were constructed for the excitatory effect of dopamine on follower cells, visceral dorsal two and three (VD2/3) (ED50 = 39 microM; Hill coefficient = 1.03), and the inhibitory effect of dopamine on follower cell, visceral dorsal four (ED50 = 33 microM; Hill coefficient = 0.92). 5. The following dopamine agonists (100 microM) were tested by bath application: 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN), apopmorphine, 2-bromo-alpha-ergocryptine, deoxyepinephrine (DE), mesulergine, (-) quinpirole, SKF 38393, and tyramine. Only the general dopamine agonists, ADTN and DE, mimicked RPeD1's effects on its follower cells. 6. When VD2/3 was isolated and plated in vitro, it maintained a depolarizing response to dopamine. This response was reduced by intracellular injection of the G-protein blocker, GDP-beta-S (2 mM in electrode). Similarly, incubation of VD2/3, in vitro for approximately 18 h, with pertussis toxin (PTX; 5 micrograms/ml), the G-protein inactivating exotoxin, also reduced the dopamine response. Injecting GDP or incubating in heat-inactivated PTX did not effect the response. 7. Several dopamine antagonists were used in an attempt to block RPeD1's synapses: chlorpromazine, ergonovine, fluphenazine, haloperidol, 6-hydroxydopamine, SCH 23390, (+/-) sulpiride, and tubocurarine. Only the D-2 dopamine receptor antagonist, (+/-) sulpiride, reversibly blocked synaptic transmission from RPeD1 to its follower cells. Both the (+) and the (-) enantiomer of sulpiride also antagonized synaptic transmission. A dose-inhibition curve for (+/-) sulpiride was constructed (IC50 = 47 microM).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

The active principles of plant extracts with antithyrotropic activity: oxidation products of derivatives of 3,4-dihydroxycinnamic acid.

We have recently reported that freeze-dried extracts (FDE) of certain plants form high molecular weight adducts with bovine TSH (bTSH), preventing it from binding to and stimulating adenylate cyclase in human thyroid membranes. We have now studied 34 pure compounds identical or structurally related to compounds present in FDE from Lycopus or Lithospermum, 2 of the 3 species of active plants studied previously. In studies conducted at 4 C in 20 mM Tris-HCl-0.5% BSA buffer, pH 7.45, eight 3,4-dihydroxylated compounds, all structurally related to cinnamic acid, inhibited the binding of [125I] bTSH to human thyroid membranes. Of these, 4 (caffeic, rosmarinic, chlorogenic, and ellagic acids) are present in the plants, and 4 (3,4-dihydroxyphenylacetic acid, deoxyepinephrine, adenochrome, and nordihydroguaretic acid) are structurally related thereto. These compounds were inactive when tested directly but became active when allowed to undergo auto-oxidation. With all 8 compounds, half-maximum inhibition of [125I]bTSH binding required quantities of oxidized product equivalent to 20-80 micrograms/ml (60-195 microM) of the original compound. Half-maximum inhibitory concentrations of oxidized caffeic and ellagic acids were increased 2- to 4-fold when experiments were performed at 37 C in medium containing 50 mM NaCl. Preincubation of membranes with active oxidation products in concentrations up to 100 micrograms/ml, followed by washing, had no effect on the subsequent binding of [125I]bTSH. As has been shown in the case of FDE, when [125I]bTSH was preincubated with oxidation products of caffeic and ellagic acids and was then chromatographed on Sephadex G-100, its elution pattern was advanced from an apparent mol wt of 30,000 to the void volume, and [125I]bTSH in the early eluting fractions displayed greatly reduced binding to thyroid membrane preparations. Addition of a large excess of unlabeled bTSH during preincubation prevented the shift in the elution pattern of [125I]bTSH produced by these oxidation products. To ascertain whether FDE and active compounds interact with the protein or carbohydrate moieties of bTSH, studies of their effects on the binding and chromatographic behavior of 125I-deglycosylated-bTSH (dg-bTSH) were also performed. Effects were similar to those observed for intact bTSH, suggesting that they do not interact with the carbohydrate moiety of TSH. Preincubation of both bTSH and dg-bTSH with either active FDE or oxidation products of caffeic or rosmarinic acid also greatly decreased their activity in the McKenzie mouse assay.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Variation in the interaction of some phenylethylamine and imidazoline derivatives with alpha-1 adrenoceptors in rabbit arteries: further evidence for the variable receptor affinity hypothesis.

This study was undertaken to determine whether the variation in the affinity of the alpha-1 adrenoceptors previously found for norepinephrine and phenylephrine in different arteries is also seen with other alpha-1 adrenoceptor agonists, and if so, if one part of the structure is particularly responsible for the variation. The potency and dissociation constants of eight agonists, both phenylethylamines and imidazolines, were determined in five rabbit arteries. In each artery the rank order of phenylethylamine agonist potency was epinephrine greater than norepinephrine greater than phenylephrine greater than deoxyepinephrine greater than methoxamine greater than dopamine. The same rank order of dissociation constants was found. For the imidazolines, the potency order was oxymetazoline greater than clonidine. For each agonist, there was a linear correlation between artery sensitivity and receptor affinity. None of the regression line slopes differed from each other. For each artery there was a linear correlation between phenylethylamine sensitivity and affinity. With the exception of the ovarian, which was lower, slopes of the regression lines in each group do not differ from each other. There were differences in the spread of the dissociation constants of the phenylethylamine derivatives among the arteries. The range of affinities was most marked with norepinephrine (greater than 40-fold) and least with epinephrine (approximately 4-fold). They suggest that agonist affinity governs the biological activity of at least the phenylethylamines on rabbit arteries mediated by the alpha-1 adrenoceptor. Variation in agonist affinity can explain the extent of the biological response. Differences in range of amine affinities in different arteries suggest that the agonist recognition site, although similar in the different arteries, is not identical and may be related particularly to some variation of the amine attachment site of the molecule. The results provide further support for the variable receptor affinity hypothesis.

Animals↗
PubMed1985

Hemodynamic advantage of combined administration of oral ibopamine and nitroprusside in patients with ischemic and idiopathic congestive cardiomyopathy.

The hemodynamic effects of combined administration of ibopamine (Ib) (150 mg orally) with nitroprusside (NP) (50-150 micrograms/min intravenously) were compared with those of NP alone in 17 patients with severe congestive heart failure due to coronary artery disease (7 patients) or idiopathic cardiomyopathy (10 patients). Hemodynamic measurements were obtained using a Swan-Ganz thermodilution catheter and a bedside thermodilution cardiac output computer. Nitroprusside alone produced a significant decrease (-12.4%) in mean arterial pressure, mean pulmonary arterial pressure (-28.3%), and systemic vascular resistance (-22.6%), and a significant increase in stroke volume index (23.1%). The administration of combined NP and Ib produced a further significant increase of stroke volume index (20.1%) with a concomitant and significant reduction of systemic vascular resistance (-19.4%); heart rate, mean systemic and pulmonary arterial pressures did not change significantly from the values observed with NP alone. Moreover, stroke work index, although not significantly modified with the vasodilator alone, was significantly increased over control values with NP + Ib association. Although NP alone induced similar effects in both the ischemic and idiopathic cardiomyopathies, the association of Ib gave a more favorable, though not significant, hemodynamic response in the subjects with primitive cardiomyopathy than in the ischemic ones. Thus, the association of Ib to NP therapy, in patients with congestive heart failure, further increases stroke volume index and stroke work index with a concomitant reduction of systemic vascular resistance, without any significant change in mean systemic and pulmonary arterial pressures, or heart rate. These results point out the possibility of associating Ib with other orally active vasodilators in the chronic treatment of congestive heart failure.

Adult↗
PubMed1988

Effect of ibopamine on the failing heart at rest and during isometric exercise: a noninvasive study.

Eleven patients suffering from heart failure were treated with oral ibopamine, a di-isobutyric ester of N-methyldopamine, 100 mg three times a day for 1 week and 200 mg three times a day for 3 weeks. Therapy was discontinued by one patient because of tachycardia. Left ventricular performance was evaluated with echocardiography and systolic time intervals at rest and after 3 minutes of isometric exercise using a handgrip. Six of 10 patients completing the study were in New York Heart Association (NYHA) functional class III, 2 in class IV, and 2 in class II. All patients, except one who remained stable in class II, improved their subjective condition by one functional class during 4 weeks of therapy (p less than 0.01). There were no changes in heart rate, blood pressure, rate-pressure product, cardiac index, or total peripheral vascular resistance. The left ventricular end-systolic diameter decreased after four weeks from 71.2 +/- 12.7 (SD) to 65.9 +/- 13.0 mm (p less than 0.001); the left ventricular end-diastolic diameter did not change. The ejection fraction increased from 26 +/- 8 to 32 +/- 9% (p less than 0.01). Afterload, that is, left ventricular circumferential systolic wall stress, declined as a result of decreased systolic diameter. Systolic time intervals did not vary. There were no changes due to ibopamine during isometric exercise probably owing to increased beta-adrenergic stimulation induced by the handgrip. Neither urine volume nor body weight changed. Side effects were mild except for tachycardia of one patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Receptor systems involved in norepinephrine release in heart failure: focus on dopaminergic systems.

The sympathetic nervous system is under extraordinarily complex modulation, involving numerous presynaptic and postsynpatic control mechanisms. These highly conserved and very redundant control mechanisms allow for the sympathetic nervous system to adapt quickly and precisely to altered environmental stress or conditions. Heart failure (HF) is characterized by excessive sympathetic activity, with both enhanced "spillover" and reduced clearance of norepinephrine (NE). The normal inhibitor control mechanisms appear faulty, with unleashed sympathetic activity likely contributing to the pathophysiology of the clinical syndrome and being associated with excessive mortality. Attempts to attenuate pharmacologically the release or "spillover" of NE from sympathetic neurons in HF has remained an attractive therapeutic strategy, and various alpha 2 adrenergic agonists and dopaminergic agents have been studied in several small clinical trials. Agents designed to activate both presynaptic (DA2) and postsynaptic or vascular (DA1) receptors have demonstrated promise. Ibopamine, a prodrug that is converted metabolically to epinine, a DA1 > DA2 agonist, has potential for selective vasodilation of mesenteric, renal, cerebral, and coronary vascular beds while reducing NE release and aldosterone activity. Preliminary clinical trials with ibopamine are encouraging, but placebo-controlled multicenter studies will be necessary to establish its role in the treatment of HF.

Deoxyepinephrine↗
PubMed1995

Neurohormonal and hemodynamic effects of ibopamine.

Ibopamine is the prodrug of epinine or N-methyl dopamine. Ibopamine stimulates the DA1 and DA2 dopaminergic receptors, the beta 1 and beta 2 adrenoceptors, and the alpha 1 and alpha 2 adrenoceptors. Ibopamine has varying degrees of affinity for these various families, being the highest for the dopamine receptors and the lowest for the alpha adrenergic receptors. In the clinical setting, there is a dose-related hemodynamic and neurohormonal response. In patients with heart failure (HF), low doses appear to exert beneficial neurohormonal, hemodynamic, and renal effects, without increased inotropic effects. However, at higher doses (> 200 mg) ibopamine exerts effects that do not appear to be clinically useful in long-term treatment of chronic HF. Several small trials have suggested a benefit of ibopamine on exercise performance in patients with mild to moderate HF. On the basis of these studies, ibopamine is now being used in Europe to treat patients with mild to moderate congestive heart failure (CHF). At doses of 100 or 200 mg/t.i.d., there has been no evidence of significant safety problems. Ibopamine may have a role in the treatment of patients with more severe left ventricular dysfunction who remain symptomatic despite therapy with diuretics and angiotensin-converting enzyme (ACE) inhibitors. Preliminary data suggest the drug is well tolerated in this setting and can decrease sympathetic stimulation. Large placebo-controlled trials will assess the benefits of the optimal dose of the drug when added to ACE-inhibitor therapy, and the effect on survival.

Clinical Trials as Topic↗
PubMed1995

Clinical efficacy of ibopamine in patients with chronic heart failure.

Ibopamine, the most widely studied dopaminergic drug for the treatment of chronic heart failure, appears to have beneficial hemodynamic, renal, and neurohormonal effects in this setting. Angiotension-converting enzyme (ACE) inhibitors have become the recommended standard treatment for chronic heart failure; however, some patients may benefit from additional drugs to improve their symptoms and functional capacity. Ibopamine may be effective as an additive drug for patients with chronic heart failure. It is also possible that ibopamine will improve survival in these patients. Large-scale trials are needed to assess the effects on morbidity and mortality when ibopamine is added to ACE inhibitors, diuretics, and possibly digitalis.

Clinical Trials as Topic↗
PubMedDate not supplied

The hemodynamic effects of ibopamine, a dopamine congener, in patients with congestive heart failure.

Ten patients with congestive heart failure underwent noninvasive and invasive hemodynamic testing before and sequentially after the administration of ibopamine to determine the cardiovascular effects of this oral dopamine congener. Single doses of 200, 400 and 600 mg were administered to all patients and 5 repeated doses of 200 or 400 mg were studied in 8. Hemodynamic effects occurred as early as 30 minutes and lasted up to 4 hours after dosing. In general, ibopamine elicited statistically significant dose-related increases in cardiac output and reductions in the derived resistance of the systemic and pulmonary circulations. A biphasic response in central and peripheral pressures was observed; up to 1 hour after administration, ibopamine elevated mean right and left atrial pressures and pulmonary and systemic arterial pressures with a significant reduction of these measurements beyond 1 hour. It did not alter heart rate. Repeated doses qualitatively affected hemodynamics similar to the initial dose and did not appear to be accompanied by short-term tolerance. While oral ibopamine elicits some favorable hemodynamic effects in humans with cardiac failure, the biphasic hemodynamic response is generally undesirable in the majority of these patients.

Adult↗
PubMed1993

Ocular pharmacokinetics and pharmacodynamics in rabbits of ibopamine, a new mydriatic agent.

Ibopamine is an original dopamine analogue. The drug, instilled in the conjunctival sac, induces mydriasis and is well-tolerated. In the present study, we have investigated the pharmacokinetic and pharmacodynamic characteristics of ibopamine after ocular application. Ibopamine produces a dose-dependent mydriasis endowed with very interesting characteristics: rapid onset, marked pupil dilation and rapid return to normal pupillary diameter. Ibopamine is well absorbed through the cornea, it is rapidly hydrolysed by esterases to epinine and the mydriatic effect is correlated with the concentration of epinine in the aqueous humor. The results of the experiments with the alpha 1-antagonists bunazosin and thymoxamine, and with reserpine, suggest that the mydriatic effect of ibopamine is obtained by direct stimulation of the alpha 1-adrenergic receptors; pretreatment with bunazosin almost completely inhibits the mydriatic activity of ibopamine; the mydriasis is also antagonized by thymoxamine. Pretreatment with reserpine has no effect on the extent of the mydriasis induced by ibopamine.

Adrenergic alpha-Agonists↗