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PubMed1975

Fluorometric assay of bethanidine in plasma.

A fluorometric method for determining bethanidine in blood plasma is described. The bethanidine is extracted into chloroform, a drug-dye complex with eosin Y is formed, and the fluorescence is measured (excitation, 535 nm; fluorescence, 560 nm). The assay detects 0.02 muM bethanidine (4 ng/ml) in plasma. The relative fluorescence of several body constituents and antihypertensive drugs is negligible. The plasma levels of bethanidine in four hypertensive patients receiving this drug were measured.

Animals↗
PubMed1990

A dual electrophysiologic test for atrial antireentry and ventricular antifibrillatory studies. Effects of bethanidine, procainamide, and WY-48986.

We have developed a dual electrophysiologic test that allows measurement of both antireentry and antifibrillatory activities of potential antiarrhythmics in the same anesthetized dog. The reentry portion of the model was created surgically by a Y-shaped crushing around the tissue between the superior and inferior vena cava and tissue parallel to the AV groove. The pacing-induced tachycardia that results from circus movements around the tricuspid ring is very persistent in duration and regular in cycle length. The antifibrillatory activities were assessed by determination of the ventricular fibrillation threshold (VFT) using train-stimuli method. Control VFT was measured every 15-20 min in duplicate and followed by induction of atrial reentry. A drug was infused to intervene the atrial tachycardia. After the conversion of the arrhythmia (either by drug regimens or pacing), postdrug VFT was measured, again in duplicate. Bethanidine (20 mg/kg), procainamide (30 mg/kg), and WY-48986 (10 mg/kg), a Class III antiarrhythmic, were evaluated in this dual test. Bethanidine and procainamide prolonged the cycle length of atrial reentry to a greater extent than WY-48986. The atrial arrhythmias were consistently terminated by procainamide and WY-48986 whereas bethanidine converted the tachycardias in one of the five dogs studied. All three agents elevated VFT with bethanidine producing higher values than procainamide and WY-48986. In conclusion, the dual electrophysiologic testing system offers both economic and scientific advantages for the study of modes of action of antiarrhythmic agents.

Animals↗
PubMed1979

A comparison and an investigation of a potential synergistic effect of labetalol and bethanidine in patients with mild hypertension.

1 The effects of labetalol, bethanidine and combined treatment with both drugs were compared in a within-patient randomized cross-over study in mild essential hypertension. Attention was directed to whether or not labetalol and bethanidine differed in their pattern of effect on arterial BP and whether evidence of synergism was apparent. 2 At the doses used labetalol significantly lowered systolic and diastolic BPs and heart rate lying, sitting, standing and after exercise. The dose of bethanidine used did not affect heart rate significantly while lowering systolic and diastolic BPs only after exercise and less clearly on standing. Combined treatment lowered BPs on standing and after exercise and heart rate after exercise. 3 The type and frequency of side-effects were similar with bethanidine and labetalol but were much less with combined treatment. 4 No evidence of synergism was observed.

Adult↗
PubMedDate not supplied

Bethanidine elimination from plasma.

Bethanidine was administered intravenously to six hypertensive patients with normal renal function and five hypertensive patients with renal impairment. After administration of 0.7 mumole/kg, blood was sampled at frequent intervals for measurement of plasma bethanidine. The plasma levels were analyzed on a three-compartment exponential open-model system. The second rapid elimination phase (beta) had a half-time of 3.4 hours in normal subjects and was insignificantly prolonged to 16.4 hours in renal impairment. There was an extended terminal elimination phase of 90 and 70 hours for normals and impaired, respectfully. The volume of distribution at pseudoequilibrium was 2.8 and 1.6 liters/kg, respectively, suggesting significant sequestration of the drug in body tissues. The pharmacokinetic constants of bethanidine in normal and impaired renal functions were similar.

Adult↗
PubMed1985

Electrophysiological effects of bethanidine sulfate on guinea-pig papillary muscle.

Bethanidine, a chemical analog of bretylium, increased the plateau phase of the action potential of guinea-pig papillary muscle in 2.7 mM K+ Tyrode solution without changing other electrophysiological parameters. In 25 mM K+ Tyrode solution, the amplitude, duration and Vmax of the Ca2+-dependent action potential were increased in a dose-dependent manner by bethanidine. It is speculated that the mechanism of antiarrhythmic effect of bethanidine might be due to the prolongation of action potential by an increase of the slow inward current.

Action Potentials↗
PubMedDate not supplied

Myocardial bethanidine kinetics after single-dose intravenous infusion: correlation with plasma kinetics in closed-chest dogs.

Myocardial and plasma bethanidine kinetics were determined in five dogs after an intravenous dose of 6 mg/kg/10 min. Serial myocardial drug concentrations were determined from endomyocardial samples obtained by transvenous biopsies between 15 min and 72 h. Tissue and plasma samples were assayed by gas-liquid chromatography. Bethanidine was rapidly concentrated in myocardium within 15 min. Tissue/plasma drug ratios averaged 131 +/- 35 between 15 min and 2 h and 53 +/- 10 between 6 and 48 h. Parallel biexponential decay then occurred for both tissue and plasma compartments; the terminal half-life approximated 16 h. Based on differences in rates of myocardial drug kinetics, the cardiac antifibrillatory effects of bethanidine may occur more rapidly than those of bretylium.

Animals↗
PubMed1964

THE EFFECTS OF BETHANIDINE ON THE PERIPHERAL CIRCULATION IN MAN.

Bethanidine has been administered intra-arterially and intravenously into normotensive subjects and its effects on the limb blood vessels, arterial blood pressure, vascular sensitivity to noradrenaline and the degree and time course of sympathetic nerve blockade have been studied. The drug caused an initial constriction of hand and forearm vessels which is attributed to release of catechol amines since it is abolished by the prior administration of phenoxybenzamine. The constriction was followed by a sustained vasodilatation lasting between 5 and 20 hr. Sympathetic blockade of hand vessels commenced immediately on infusion and was complete within 1 hr of administration. Recovery occurred in about 5 hr. Sensitivity to intra-arterial noradrenaline was increased within 10 to 15 min of infusion and before sympathetic blockade was complete. Intravenous administration caused a slight rise in blood pressure of supine subjects. Baroreceptor reflex responses of heart and of limb vessels elicited by tilting the subject feet downwards were abolished by bethanidine and postural hypotension occurred. Bethanidine is a potent sympathetic blocking agent in man with properties intermediate between those of bretylium and guanethidine.

Antihypertensive Agents↗
PubMed1985

A comparison of the effects of bethanidine, meobentine and quinidine on the electrical activity of rat hearts in vivo and in vitro.

Glass microelectrodes were used to record transmembrane electrical activity from cells located just beneath the endocardial surface of segments of the right ventricular free wall of the rat heart during superfusion and electrical stimulation in vitro at 37 degrees C. The sulphates of bethanidine, meobentine or quinidine (4 to 20 microM) applied in vitro caused a prolongation of action potential duration and a delayed and slowed return of electrical excitability following an action potential. Intracardiac electrical stimulation of the urethane-anaesthetized rat heart in situ was used to measure ventricular refractory periods from the electrocardiogram. Intravenous administration of bethanidine, meobentine or quinidine (10 to 20 mg kg-1) caused a prolongation of ventricular refractory periods. Quinidine had a briefer duration of action than either of the other two drugs tested. Urethane-anaesthetized open-chested rats which were subjected to left coronary artery occlusion displayed ventricular tachyarrhythmias in their electrocardiogram. These arrhythmias occurred during the period of occlusion and even more prominently after release of the occlusion. Intravenous administration of bethanidine, meobentine or quinidine (1 to 20 mg kg-1) protected rats against these arrhythmias. The protective effect of quinidine was briefer than that of either of the other two drugs tested.

Action Potentials↗
PubMed1988

Bethanidine increases one type of potassium current and relaxes aortic muscle.

Using a whole-cell voltage-clamp technique, we identified two time- and voltage-dependent K+ currents: an early outward rectifier and a delayed outward rectifier in single vascular smooth muscle cells of rabbit aorta in culture. About 90% of the single cells tested showed a predominant delayed outward K+ current type. Both K+ currents were decreased by tetraethylammonium. In contrast, bethanidine sulphate (10(-4)M), a pharmacological analog of the cardiac antifibrillatory drug, bretylium tosylate, decreased the early outward K+ current, increased the delayed rectifier K+ current type, and hyperpolarized the resting membrane potential. Bethanidine was found to relax vascular smooth muscle. The vasodilatory effect of bethanidine is associated with the activation of a K+ current that is probably involved in keeping the membrane potential at the resting state, thereby depressing the excitability of the aortic vascular smooth muscle.

Animals↗
PubMed1988

Electrophysiologic and hemodynamic effects of bethanidine sulfate on the immature mammalian heart.

The cumulative electrophysiologic and hemodynamic effects of bethanidine sulfate (2.5, 5, 10 and 15 mg/kg i.v.) were studied in 9 canine neonates and 7 adult dogs. Increased heart rate, blood pressure and enhanced atrioventricular nodal function, observed in both groups, and decreased ventricular refractory periods and inducibility of ventricular arrhythmias seen in the adult, are probably related to a bethanidine-mediated release of catecholamines. However, in spite of the catecholamine release, bethanidine sulfate results in a significant prolongation of atrial refractoriness, this effect being quantitatively more important in the neonate than in the adult.

Aging↗
PubMed1976

Time-dependent change in renal clearance of bethanidine in humans.

Blood levels and urinary excretion rates of bethanidine were determined in three normal human subjects following oral administration of a single dose of the drug. The postabsorptive decline of blood concentration with time was noticeably slower than the corresponding decline in the urinary excretion rate. The discrepancy can be attributed to a continual decrease in the renal clearance of bethanidine throughout the study. Therefore, pharmacokinetic modeling of urinary excretion data alone would lead to erroneous conclusions concerning the persistence of drug in the blood.

Bethanidine↗
PubMed1976

A within-patient comparison of bethanidine, methyldopa and propranolol in the treatment of hypertension.

1. A within-patient comparison showed that bethanidine, methyldopa and propranolol produced similar control of the blood pressure. 2. Unlike bethanidine, propranolol did not produce postural and exercise hypotension; methyldopa was intermediate in effect. 3. Overall side effects were of a similar incidence though there were differences in incidence of particular side effects.

Bethanidine↗
PubMed1964

COMPARISON OF THE EFFECTS OF BRETYLIUM, GUANETHIDINE AND BETHANIDINE ON SMOOTH MUSCLE RESPONSES TO DIFFERENT RATES OF SYMPATHETIC NERVE STIMULATION.

The relative effects of bretylium, guanethidine and bethanidine on smooth muscle responses to different rates of sympathetic nerve stimulation have been compared. The responses studied were vasoconstriction in the femoral vascular bed and contraction of the spleen in anaesthetized cats, vasoconstriction in perfused ears of rabbits and inhibition of pendular movements in rabbit isolated ileum preparations. Except in the isolated ileum, the action of bretylium on curves relating the frequency of nerve stimulation and the effect on response was different from that of guanethidine. Whereas bretylium caused relatively greater inhibition of responses to high stimulus frequencies and depressed the slopes of the curves, guanethidine preferentially suppressed responses to low stimulus frequencies and caused roughly parallel shifts of the curves. In each situation tested bethanidine was the most potent of the three blocking agents and in general its effect on frequency/response curves was intermediate between those of bretylium and guanethidine.

Animals↗
PubMed1975

Systemic hemodynamic effects of bethanidine in essential hypertension.

Although available elsewhere, bethanidine remains under study in the U.S. and its hemodynamic effects are unreported. Therefore, 29 patients with moderately severe essential hypertension received one of four oral dose levels (0.10, 0.25, 0.35, or 0.50 mg/kg) of the postganglionic sympatholytic drug. Blood pressure was reduced only in the 14 patients receiving the highest dose. This was demonstrated within three hours, first by a significant postural hypotension (upright tilt: +14 before vs -19 mm Hg after, P less than 0.001). This orthostatic hypotension effect was associated with a greater fall in cardiac output (13 vs 22%, P less than 0.025) and a diminished reflective increase in total peripheral resistance (19 vs 6%, P less than 0.01); an attenuated Valsalva maneuver overshoot in the supine position was also observed (42 vs 10%, P less than 0.001). Eight of these 14 patients demonstrated supine hypotension associated with either reduced output and/or resistance. Hence, bethanidine is a rather rapidly acting oral sympatholytic agent which reduces blood pressure by producing: (1) decreasec venous return (especially in upright position), suggesting venodilation; (2) arteriolar dilation (supine and upright) reducing peripheral vascular resistance; and (3) attenuated cardiovascular sympathetic reflective adjustments.

Administration, Oral↗
PubMed1983

Determination of bethanidine in plasma by liquid-chromatography with a microbore reversed-phase column.

In this novel method for quantifying bethanidine in plasma, after a multi-step extraction of bethanidine and internal standard from 2.0 mL of plasma, the drugs are separated on a "microbore" C18 reversed-phase column and quantified by their ultraviolet absorbance at 210 nm. The isocratic chromatographic separation takes about 15 min with use of an ion-pairing regent in the mobile phase (acetate buffer/acetonitrile, 9/1 by vol) and a flow rate of 0.25 mL/min. Sensitivity is increased relative to conventional columns, and solvent consumption is reduced by 90%. The standard curve is linear to at least 5 mg/L, and the detection limit is 0.02 mg/L. The within-run precision of the method is excellent (CV 4%) at a midrange concentration of 1.25 mg/L.

Bethanidine↗
PubMed1970

Restoration of tyramine responses by bretylium, BW392C60, bethanidine and monoamine oxidase inhibitors in reserpine-treated rats.

1. Bretylium, BW392C60, bethanidine, nialamide and pheniprazine, but not guanethidine or ouabain, were all capable of restoring the cardiovascular response to tyramine in reserpine pretreated rats anaesthetized with sodium pentobarbitone.2. In parallel with their recorded in vitro activity as monoamine oxidase inhibitors, BW392C60 was found to be more potent at restoring the response to tyramine than bretylium or bethanidine.3. The restored responses to tyramine were completely blocked by desmethyl-imipramine or by a combination of phentolamine and propranolol.4. The effect of bretylium on the tyramine response was not influenced by bilateral adrenal demedullation, urethane anaesthesia, the dose or duration of the reserpine pretreatment and was not dependent upon the frequency of the tyramine injections.5. Bretylium, BW392C60 or bethanidine did not alter the pressor response to intravenous noradrenaline.6. Nialamide-induced restorations of the responses to tyramine were not further enhanced by the administration of bretylium, BW392C60 or bethanidine.7. In pithed reserpine-treated rats the ability of bretylium and BW392C60 to restore the response to tyramine was reduced.8. It is concluded that all the drugs which reversed the reserpine-induced subsensitivity to tyramine were acting as monoamine oxidase inhibitors, thus allowing the intra-neuronal accumulation of endogenously formed catecholamines. The presence of nerve impulses in the adrenergic fibres of reserpinized rats appears to be an important factor in mediating this effect.

Adrenalectomy↗
PubMedDate not supplied

Disposition of bethanidine, N-benzyl-N',N''-dimethylguanidine, in the rat, dog and man.

Bethanidine is metabolized in the rat and dog to a significant degree to N-benzyl-N'-methylguanidine, N-benzylguanidine, N-hydroxybenzyl-N'-methylguanidine, N-methylguanidine, N-hydroxybenzyl-N',N''-di-methylguanidine, and benzoic acid, whereas in man the drug is not metabolized. It is readily absorbed in all three species. The elimination kinetics in man show a difference between the urinary excretion rate and the rate of decline in the blood. Whole body autoradiograms showed a high concentration of drug in rat tissues rich in adrenergic nerve terminals, but insignificant penetration, if any, of the blood-brain barrier.

Adolescent↗