Adrenergic Neurone Blockade Research Articles

A comparison of aralkylamines and aralkylguanidines as antagonists of adrenergic neurone blockade.

Abstract Structure-activity relationships have been studied for aralkylamines and aralkylguanidines which restore the responses of the nictitating membranes to nerve stimulation in anaesthetised cats given sympathetic blocking drugs. This reversing action was largely specific for adrenergic neurone blockade; blockade of sympathetic ganglia or of α-adrenergic receptors was unaffected. (+)-Amphetamine was the most active amine and N-benzyl-N-methylguanidine was the most active guanidine. In mice, ptosis resulting from adrenergic neurone blockade was much more readily prevented or abolished by the aralkylamines and aralkylguanidines than was ptosis caused by other types of sympathetic blocking agent. The most potent antagonist of ptosis was N-(2-phenylcyclopropyl)guanidine which was about ten times as active as amphetamine. The relative antagonistic potencies of 2 amines and 8 guanidines were virtually identical for all types of adrenergic neurone blocking drug, regardless of whether or not they cause noradrenaline depletion. The prevention of guanethidine-induced ptosis was always accompanied by some reduction in the extent of heart-noradrenaline depletion, but the minimum dose of antagonist required to prevent ptosis completely was always lower than that required to eliminate depletion.

Actions of the muscle relaxant chandonium iodide on guinea-pig ileum and vas deferens preparations.

The effects of the newly synthesized neuromuscular blocking agent, chandonium iodide (17a-methyl-3beta-pyrrolidino-17a-aza-D-homo-5-androstene dimethiodide) have been investigated on guinea-pig isolated ileum and vas deferens preparations. On the ileum, chandonium (0-1-10-0 mug ml(-1); 1-6 X 10(-7) M-1-6 X 10(-5) M) had weak muscarinic receptor blocking action (pA2 is 5-7), but no antihistamine properties at the concentration tested. No evidence for anticholinesterase actions was found. On the vas deferens, chandonium (10-50 mug ml(-1); 1-6-8-1 X 10(-5) M) potentiated responses to exogenous noradrenaline; responses to electrical stimulation were potentiated only in the presence of 50 mug ml(-1) chandonium. No adrenoceptor or adrenergic neuron blockade was found. The results provide evidence that chandonium acts selectively at acetylcholine receptors and that it is more active as a nicotinic receptor antagonist than as a muscarinic receptor antagonist.

Dual actions of some N-(1-phenylethyl)guanidines on the nictitating membrane of conscious cats

Abstract After 6 hr, high doses (10 or 20 mg/kg) of some adrenergic neuron blocking drugs derived from N-(1-phenylethyl)guanidine produce relaxation of the nictitating membranes of conscious cats which is less than that produced by small doses (2.5 or 5 mg/kg). After 24 hr, there were marked responses to some drugs that had produced little effect after 6 hr. High doses of the drugs contract the nictitating membranes of cats treated with pempidine or (—)-N-(1-phenylethyl)guanidine; low doses do not. This contraction opposes the relaxation evoked by the adrenergic neuron blockade and could account for the anomalous dose-response relationships. The contraction may result from localized release of noradrenaline from the nictitating membrane.

The effects of calcium on adrenergic neuron blockade.

Abstract The effects of increasing extracellular calcium were investigated on the responses to sympathetic nerve stimulation of three isolated organs; rabbit ileum, guinea-pig vas deferens and rabbit ear artery. A rise in the calcium concentration increased the responses of the ileum to low frequency stimulation, the maximum increase being obtained at 8.8 mM calcium. After partial blockade by guanethidine of the responses of the ileum to high frequency stimulation, raised calcium concentrations again increased the responses. The increase was similar in guanethidine-treated and untreated preparations and the maximum increase in both was obtained using 8.8 mM calcium. In the vas deferens and rabbit ear artery preparations an increase in extracellular calcium did not antagonize the blocking action of guanethidine. These experiments do not therefore support the theory that guanethidine acts by preventing the entry of calcium into the sympathetic nerve endings.

The effect of propranolol on sympathetic nerve stimulation in isolated vasa deferentia.

(+/-)-Propranolol hydrochloride (0.5 mg kg(-1) twice daily, subcutaneously, for 3 days or approximately 2.4 mg kg(-1) daily, orally, for 21 days) failed to produce ptosis or to affect responses to transmural stimulation of isolated vasa deferentia removed from treated mice. In guinea-pig isolated vasa deferentia responses to transmural stimulation through parallel electrodes were reduced by propranolol (1 to 20 mug ml(-1); blockade was concentration dependent, fast to equilibrium (45 min), easily reversed by washing but not reversed by (+)-amphetamine sulphate (0.2 mug ml(-1). At lower concentrations (0.04 and 0.2 mug ml(-1), propranolol marginally potentiated responses to transmural stimulation. In contrast, guanethidine (0.2 mug ml(-1)) produced a slow onset blockade which was completely reversed by (+)-amphetamine. The response to electrical stimulation through concentric ring electrodes was reduced by low concentrations of propranolol but this effect is ascribed to the known local anaesthetic actions of propranolol and no evidence of true adrenergic neuron blockade was found.

Phosphocholine 2,6-xylyl ether bromide: proton-phosphorus coupling constants and preliminary pharmacological assessment.

Abstract Phosphocholine 2, 6-xylyl ether bromide [PPP-trimethyl-2-(2, 6-xylyloxy)ethylphosphonium bromide], has been synthesized by reacting 2-(2, 6-xylyloxy)ethyl bromide with a solution of trimethyl-phosphine in phenol, but ethylenebis(trimethylphosphonium bromide), 1, 2-di(2, 6-xylyloxy)ethane and 2, 6-xylenol were the only reaction products identified when ether was used as solvent. The 2JPH and 3JPH coupling constants for these phosphonium salts have been determined. Although the phosphocholine xylyl ether blocks the Finkleman preparation in concentrations of 2–3 × 10−5 g/ml, this blockade does not have all the characteristics of the adrenergic neuron blockade produced by xylocholine.

The preparation and properties of (+)- and (--)-guanoxan.

Abstract (±)-2-Aminomethyl-1, 4-benzodioxan has been resolved into its optically active isomers: (+)- and (-)-guanoxan have been synthesized from these. The pharmacological effects of racemic-guanoxan and of the two optical isomers have been compared on the isolated central ear artery of the rabbit, on the pithed rat in which pressor responses were evoked by stimulation of the thoraco-lumbar sympathetic outflow, and on the pre- and post-ganglionically stimulated nictitating membrane of the cat. The two isomers were equipotent in producing adrenergic neuron blockade. Initial catecholamine release was weak in the cat, but occurred more powerfully in the rabbit ear artery and in the rat. Ability to produce this effect resided mainly with the (+)-isomer. α-Adrenoreceptor blocking activity was detectable in the rat and was produced mainly by the (+)-isomer suggesting that its stereochemical configuration corresponds to that of D-(-)-noradrenaline. Ganglion blockade was an unimportant action of the compounds, but both isomers possessed weak atropine-like activity in the rat.

Involvement of peptide histidine isoleucine in non-adrenergic non-cholinergic relaxation of the rat gastric fundus induced by high-frequency neuronal firing.

The role of peptide histidine isoleucine (PHI) as a neurotransmitter of the inhibitory motor neurones, the physiological role of PHI and vasoactive intestinal polypeptide (VIP) in the non-adrenergic non-cholinergic (NANC) relaxation and the relative amounts of VIP- and PHI-like immunoreactivity (LI) co-released by neuronal activation were investigated in the rat gastric fundus. Longitudinal muscle strips from the rat gastric fundus precontracted by the thromboxane receptor agonist U46619 (0.1 micro M) were studied in organ baths under conditions of muscarinic receptor blockade by atropine (1 micro M) and adrenergic neurone blockade by guanethidine (5 micro M) ("NANC conditions"). Concentration-response curves were plotted for both amplitude and area under the curve (AUC) of the relaxant responses induced by VIP (0.3 nM-0.3 micro M), PHI (0.3 nM-1 micro M) and peptide histidine valine [PHV(1-42); 0.3 nM-1 micro M]. All three peptides were more potent in the curve based on amplitude than in that based on the AUC of relaxation. In addition, VIP was 5.3 and 7 times more potent than PHI and PHV(1-42), respectively, in producing relaxation expressed as amplitude, and 2.7 and 2.8 times, respectively, in producing relaxation expressed as AUC. PHI and PHV(1-42) behaved as partial agonists with respect to VIP in producing relaxation expressed as AUC. Electrical field stimulation (EFS; 120 mA, 1 ms, 4-32 Hz, pulse trains of 2 min) evoked frequency-dependent relaxant responses. Alpha-chymotrypsin (1 u/ml or 3 u/ml), an anti-VIP serum (1:100 or 1:50) and an anti-PHI serum (1:25), slightly reduced the amplitude, but greatly inhibited the AUC of the NANC relaxation induced by EFS (13 Hz) [approximately 72%, 47% and 28% less than that seen in time controls or with normal rabbit serum (1:100 or 1:25), respectively]. EFS (8-32 Hz) caused significant, frequency-dependent increases in the outflow of VIP- and PHI-LI from the strips. The EFS-induced release of VIP-LI was approximately 20% of the PHI-LI release. These findings indicate that PHI is involved in EFS-induced NANC relaxation of the rat gastric fundus, the major physiological role of VIP and PHI is the maintenance of smooth muscle relaxation and VIP is co-released in equimolar amounts mainly with PHI.

Biphasic inotropic effects of methamphetamine and methylphenidate on ferret papillary muscles.

Methamphetamine and methylphenidate are structurally related agents that have direct negative inotropic (NIEs) and indirect positive inotropic effects (PIEs) in cardiac tissues. This study was designed to determine and compare cellular mechanisms of the NIEs of methamphetamine and methylphenidate by using a mammalian animal model. Isometric tension was measured in ferret papillary muscles in physiologic salt solution. A subset of muscles was loaded with the bioluminescent calcium indicator, aequorin. Further, to investigate the NIE of methamphetamine, the dose-response relations to isoproterenol, histamine, and calcium were measured with or without methamphetamine (2 x 10(-4) M), after adrenergic neuronal blockade with reserpine. Both methamphetamine and methylphenidate had direct NIEs at higher doses (>10(-4) M). A shift in the slope of the isoproterenol dose-response curve suggested involvement of the beta-adrenoceptor pathways. The direct NIE of methylphenidate was more prominent. Our results suggest that the negative inotropic effects of methamphetamine and methylphenidate may be important with clinically used and abused concentrations of these drugs and may be difficult to reverse with beta-adrenergic inotropic agents in cases of toxicity.

The actions of bretylium: Adrenergic neurone blocking and other effects

The actions of bretylium: Adrenergic neurone blocking and other effects

INHIBITION OF SYMPATHETIC NORADRENERGIC TRANSMISSION BY GUANABENZ AND GUANETHIDINE IN RAT ISOLATED MESENTERIC ARTERY: INVOLVEMENT OF NEURONAL POTASSIUM CHANNELS

The present study investigated the effects of the α 2-adrenoceptor agonist guanabenz and the adrenergic neurone blocking drug guanethidine on the resting and stimulation-induced (S-I) effluxes of radioactivity from rat isolated mesenteric artery preparations in which the noradrenergic transmitter stores had been radiolabelled with [ 3H]-noradrenaline. The efflux of radioactivity evoked by electrical field stimulation of periarterial sympathetic nerves (60s trains of 1ms pulses, 2Hz, 12V) was taken as an index of transmitter noradrenaline release. Guanabenz (0.1–10μ M) decreased, in a concentration-dependent manner, both the resting and S-I effluxes of radioactivity. Guanethidine (0.1 and 1μ M) also decreased S-I efflux but increased resting efflux, both effects being concentration dependent. The inhibitory effects of guanabenz on both resting and S-I effluxes were reduced by blockade of the neuronal amine carrier with desipramine (1μ M). The inhibitory effect of guanabenz on resting efflux was prevented by inhibition of monoamine oxidase with pargyline (100μ M). The inhibitory effect of guanabenz on S-I efflux was not due to activation of prejunctional α 2-adrenoceptors since the inhibition was not blocked by the selective α 2-adrenoceptor antagonist idazoxan (0.1μ M). However, the inhibitory effect of guanabenz and guanethidine on S-I efflux was reduced by the inhibitor of Ca 2+-activated potassium channels apamin (0.1μ M). The findings suggest that guanabenz, like guanethidine, enters noradrenergic nerve terminals by the neuronal amine carrier. The inhibition of resting efflux produced by guanabenz may be due to inhibition of neuronal monoamine oxidase. The enhancement of resting efflux produced by guanethidine is attributable to its indirect sympathomimetic action. Finally, guanabenz and guanethidine may inhibit transmitter noradrenaline release by activating potassium channels on sympathetic noradrenergic nerve terminals. These findings may be relevant to the mechanism of adrenergic neurone blockade.

Antiarrhythmic effects of prostaglandins E 2 and I 2 on ouabain-induced cardiac arrhythmias in cats: Effect of vagotomy and adrenergic neuron blockade

The effects of i.v. prostaglandins (PGs) E 2 and I 2 on ouabain-induced cardiac arrhythmias were investigated in chloralose-anaesthetized cats. Bilateral vagotomy and guanethidine-pretreatment interventions were employed to elucidate the involvement of vagal and sympathetic neural influences in these effects. PGE 2 (1 μg/kg/min i.v. infusion for 5 min) and PGI 2 (4–16μg/kg i.v. bolus injections) effectively suppressed the ouabain-induced arrhythmias in a control group of cats. The bilateral vagotomy or guanethidine-pretreatment interventions did not significantly alter the antiarrhythmic effects of PGE 2 and PGI 2. It is concluded that the presence of functionally intact sympathetic and vagal nerve supply to the heart is not a prerequisite for the antiarrhythmic effects of i.v. administered PGE 2 and PGI 2. The possible role of direct action of these PGs on the myocardium is discussed.

Possible involvement of calcitonin gene-related peptide (CGRP) in non-cholinergic non-adrenergic relaxation induced by mesenteric nerve stimulation in guinea pig ileum

Mesenteric nerve (MN) stimulation produced a biphasic response, i.e., a contraction followed by a prolonged relaxation in the isolated guinea pig ileum after complete adrenergic neuron blockade with guanethidine. This biphasic response mimicked the effect of capsaicin by itself. The latter relaxation response to MN stimulation was unaffected by hexamethonium, but was abolished by capsaicin in an irreversible fashion. Calcitonin gene-related peptide desensitization (CGRP-D) reduced the relaxation response to about 20% of the control. After pretreatment with atropine and guanethidine, MN stimulation provoked a pure relaxation, which was significantly reduced to about 20% of the control by CGRP-D. Therefore, it seems likely that the non-adrenergic non-cholinergic relaxation response to MN stimulation is partly mediated via a release of CGRP from sensory nerve endings.

Protection of CGS 10078B against ouabain-induced arrhythmia in the cat.

CGS 10078B (CGS; 1-[2,3-dihydro-1,4-(2S)-benzodioxin-2-yl]-5-[2,3-dihydro-1,4-(2R)- benzodioxin-2-yl]-3-(1R,5S)-aza-1,5-pentanediol methane sulfonate) is an agent with alpha- and beta-receptor and calcium channel blocking actions. To study its antiarrhythmic activity, cats were anesthetized with alpha-chloralose, ventilated, and given atropine and gallamine. CGS (10 or 20 mg/kg, i.v.) was infused 15 min prior to ouabain. Bolus injections of ouabain (25 micrograms/kg, i.v.) were given every 15 min until death (D). Some cats were pretreated with reserpine (R; 5 mg/kg, i.p.) 24 h prior to the experiment. In other cats 6-hydroxydopamine (6-OHDA; 20 mg/kg, i.v.) was administered 3 days prior to CGS 20 mg/kg and ouabain. Data were compared with those of Lathers [Eur. J. Pharmacol. 64: 95, 1980], i.e., with 12 cats who received only ouabain and with 11 pretreated with timolol (T; 5 mg/kg, i.v.) prior to ouabain. After CGS (10 or 20 mg/kg, i.v.), but just prior to the first dose of ouabain, the blood pressure (BP) was decreased (p less than 0.05) from control (165 +/- 6 vs. 96 +/- 7, and 136 +/- 5 vs. 90 +/- 10 mm Hg, respectively). Comparable heart rate (HR) values were also decreased (p less than 0.05) from 225 +/- 17 to 166 +/- 14 and from 193 +/- 8 to 152 +/- 6 beats/min. 11 min after T, BP and HR had decreased (p less than 0.05) from 133 +/- 6 to 103 +/- 7 mm Hg and from 134 +/- 4 to 104 +/- 6 beats/min, respectively. Ouabain did not influence these decreases in BP and HR. CGS (10 or 20 mg/kg, i.v.) increased (p less than 0.05) the time to ouabain-induced arrhythmia (AR) and D. The magnitude of the protection appeared to be similar to that afforded by T. R given prior to CGS (20 mg/kg, i.v.) also increased the time to ouabain-induced AR and D while 6-OHDA increased the time to AR. The CGS protection against ouabain-induced AR was still present in animals pretreated with R or 6-OHDA. This indicates that the antiarrhythmic affect is not dependent upon adrenergic neuronal blockade.

Antifibrillatory action of bretylium: role of the sympathetic nervous system.

This study was performed to assess the role of cardiac sympathetic nerves in the in vivo antifibrillatory action of bretylium using the technique of electrically induced ventricular fibrillation. An initial study determined that 3 mg/kg of nortriptyline, an adrenergic amine uptake inhibitor, was sufficient to prevent the adrenergic neuron blockade produced by 5 mg/kg of bretylium in pentobarbital anesthetized dogs. Electrical ventricular fibrillation threshold (VFT) was then determined in two groups of pentobarbital anesthetized dogs using gated trains of increasing current applied to the epicardial surface of the right ventricle during atrial pacing. After determination of an initial VFT in both groups, one group of dogs (n = 8) received 3 mg/kg nortriptyline, the other group received saline (n = 9). The VFT was redetermined in both groups, after which all dogs received 5 mg/kg of bretylium, intravenously, and VFT was then measured at 15 and 90 min after bretylium. In saline-treated dogs, bretylium produced a significant increase in VFT from a control value of 6.9 +/- 1.6 mA (mean +/- SEM) to 31.0 +/- 0.5 mA at 15 min (p less than 0.05) and 45.1 +/- 4.8 mA at 90 min (p less than 0.05). In nortriptyline-treated dogs, however, nortriptyline itself produced an increase in VFT which was reversed by bretylium, and VFT after bretylium was not significantly elevated until 90 min to a value of 25.2 +/- 9.6 mA (control: 5.2 +/- 0.9 mA). These data demonstrate that pretreatment with nortriptyline attenuates and delays the onset of the acute antifibrillatory effect of bretylium and suggests a role for the cardiac adrenergic neuron as a potential target for part of the beneficial effects to be derived from antifibrillatory drugs.

Importance of Interaction with Adrenergic Neurons for Antifibrillatory Action of Bretylium in the Dog

The present study was designed to investigate whether or not interaction with the adrenergic neurons is important for the antifibrillatory effect of bretylium. The direct action of bretylium on cardiac electrophysiological properties, as indicated by effective refractory period prolongation, was also assessed. In pentobarbital-anesthetized, open-chest dogs, bretylium, 5 mg/kg i.v., increased ventricular fibrillation threshold rapidly and markedly. The effect peaked in 1 h and was sustained for at least 3 h. Complete adrenergic neuronal blockade also occurred within 30 min. Effective refractory period lengthening was minimal and variable. When bretylium's access to the adrenergic neurons was prevented either by antagonism of the presynaptic amine transport pump with desipramine or by chemical sympathectomy with 6-hydroxydopamine, the antifibrillatory effect was absent. Furthermore, when blockade of adrenergic neurotransmission by bretylium was reversed by the administration of d-amphetamine, ventricular fibrillation threshold also decreased. Data from all groups of experiments revealed that changes in effective refractory period did not correlate, in either magnitude or direction, with changes in ventricular fibrillation threshold. Thus, it can be concluded that interaction with adrenergic neurons is important for bretylium's antifibrillatory action and that absence of sympathetic neurotransmission contributes to the elevation of ventricular fibrillation threshold.

Hypotensive actions of ketanserin in dogs: Involvement of a centrally mediated inhibition of sympathetic vascular tone

The intravenous (i.v.) administration of ketanserin (0.1–0.4 mg/kg) produced immediate and sustained decreases in systemic blood pressure and heart rate in pentobarbitone-anaesthetized dogs. These doses of ketanserin did not inhibit common carotid vasoconstrictor responses to intraarterial (i.a.) noradrenaline, pre-ganglionic stimulation of the sectioned cervical sympathetic nerve, or i.v. nicotine, thus the effects of ketanserin are not due to blockade of vascular α-adrenoceptors, adrenergic neurone blockade, or ganglionic blockade. Systemic pressor responses to i.v. nicotine, which produces sympathetic activation by both central and ganglionic stimulating actions, and to common carotid artery occlusion, were inhibited by 0.1–0.4 mg/kg of ketanserin i.v. These results suggest that in the anaesthetized dog, the hypotensive action of ketanserin involves a centrally mediated inhibition of sympathetic tone. Peripheral vascular 5-HT 2 receptor blockade does not appear to be responsible for the hypotensive effect of ketanserin in this model, although this does not preclude the involvement of such a mechanism in its clinical antihypertensive action.

Mechanism of the effect of bretylium on the ventricular fibrillation threshold in dogs

Experiments were performed to determine the importance of sympathetic blockade vs a direct myocardial effect as a mechanism for the antifibrillatory action of bretylium. The ventricular fibrillation (VF) threshold was determined in open-chest, anesthetized dogs by scanning the vulnerable period with either a single electrical stimulus (10 ms) or a train of electrical stimuli (14 pulses, 4 ms, 100 Hz). Using the train-of-pulses technique, the VF threshold increased from 6.8 ± 0.6 mA to 29.7 ± 6.4 mA 15 minutes after a 10-mg/kg intravenous bolus of bretylium (p < 0.001, n = 8). There was no further significant change in the train-of-pulses VF threshold at 2 or 4 hours. Beta-adrenergic blockade with timolol (0.2 mg/kg) increased the train-of-pulses VF threshold from 6.7 ± 1.6 mA to 24.5 ± 5.2 mA (p >; 0.01 n = 8) and prevented any further significant change in response to bretylium. When single electrical pulses were used to scan the vulnerable period, bretylium at doses of 10 mg/kg (n = 8) and 100 mg/kg (n = 6) did not alter the VF threshold over a 4-hour observation period. The administration of timolol, alone or in combination with bretylium, did not significantly alter the single-pulse VF threshold. The failure of bretylium to alter the single-pulse VF threshold was not dependent on the site of stimulation. Stimulation of the right sympathetic cardiac nerves showed that 15 minutes of bretylium treatment was sufficient to completely inhibit adrenergic neuronal transmission to the myocardium. The data indicate that bretylium has little direct antifibrillatory action on the normal canine myocardium. The ability of bretylium to elevate the VF threshold determined with a train of stimuli appears to be primarily a result of adrenergic neuronal blockade.

Bretylium: Relations between plasma concentrations and pharmacologic actions in high-frequency ventricular arrhythmias

Although it is widely assumed that the early arrhythmogenic and pressor responses to bretylium are caused by catecholamine release from the adrenergic neuron, this assumption has not been systematically studied in humans. Pharmacologic responses to a placebo infusion and 3 separate bretylium infusions (2.5, 5.0, 10 mg/kg over 60 minutes) were assessed in 6 patients with recurrent, nonsustained ventricular tachycardia. Plasma bretylium concentration, blood pressure (BP), plasma norepinephrine (NE) concentration, arrhythmia frequency and adrenergic neuronal blockade (assessed by the presence or absence of reflex venoconstriction) were measured. Adrenergic blockade was seen with every bretylium infusion and at a time when relatively small amounts of bretylium had been administered (range 160 to 750 mg, median 252). Temporal relations (p < 0.03) were noted among the time of onset of adrenergic neuronal blockade, onset of the pressor response, increase in NE plasma concentration and increase in ventricular arrhythmia frequency. BP responses during the infusions were linearly related to change in plasma NE at the time of development of adrenergic neuronal blockade. Bretylium plasma concentrations higher than 3 μg/ml were frequently associated with a short-lived pressor response. There was a significant relation (p < 0.06) between the increase in plasma NE during the infusion and an increase in ventricular arrhythmia frequency. Reduction in arrhythmia frequency was seen in only 1 patient, beginning 6 hours after the development of adrenergic neuronal blockade. In conclusion, soon after bretylium administration to patients with ventricular arrhythmias, a dose-related increase in BP and arrhythmia frequency occurred that were temporally related to catecholamine release and adrenergic neuronal blockade. Lack of antiarrhythmic response in this highly selected population does not detract from the proved efficacy of bretylium in patients with recurrent sustained ventricular tachycardia and fibrillation.

The antiarrhythmic activity of meobentine sulfate in man.

Meobentine (sulfate) has antifibrillatory and antiarrhythmic activity in canine models. The antiarrhythmic, pharmacokinetic, and adrenergic neuronal blocking effects of meobentine were assessed in 15 patients with chronic, high-frequency ventricular ectopic depolarizations (VEDs). Eleven of the 15 patients had recurrent nonsustained ventricular tachycardia. The patients were given a series of gradually increasing single doses of meobentine; six received oral meobentine and nine had infusions. The antiarrhythmic efficacy of meobentine was assessed by a comparison of arrhythmia frequency during placebo given on days just prior to meobentine. Oral therapy with meobentine at dosages above 20 mg/kg caused diarrhea, and well-tolerated dosages achieved peak concentrations of 0.69 micrograms/ml (range 0.5-1.0 micrograms/ml). Antiarrhythmic activity was seen in only one patient with oral meobentine. In contrast, intravenous infusions (6.75-34.2 mg/kg) achieved concentrations ranging from 1.3-9.8 micrograms/ml. There was a linear relationship between pseudo-steady-state plasma concentrations and dosage, r = 0.82, p less than 0.01. Antiarrhythmic activity was seen in four of nine patients who received intravenous meobentine over a range of concentrations from 2.5-4.5 micrograms/ml. Four patients developed evidence of adrenergic neuronal blockage (loss of the venous reflex response); two at dosages of 16.2 mg/kg, one at 24.3 mg/kg, and one at 34.2 mg/kg. In one individual (24.3 mg/kg), the adrenergic neuronal blockade was associated with an acute episode of shortness of breath, orthopnea, and cough. With intravenous meobentine, there was a linear relationship between dosage and AUC, and the elimination half-life ranged from 11-27 h.(ABSTRACT TRUNCATED AT 250 WORDS)