Cold-induced vasoconstriction at forearm and hand skin sites: the effect of age.

During mild cold exposure, elderly are at risk of hypothermia. In humans, glabrous skin at the hands is well adapted as a heat exchanger. Evidence exists that elderly show equal vasoconstriction due to local cooling at the ventral forearm, yet no age effects on vasoconstriction at hand skin have been studied. Here, we tested the hypotheses that at hand sites (a) elderly show equal vasoconstriction due to local cooling and (b) elderly show reduced response to noradrenergic stimuli. Skin perfusion and mean arterial pressure were measured in 16 young adults (Y: 18-28 years) and 16 elderly (E: 68-78 years). To study the effect of local vasoconstriction mechanisms local sympathetic nerve terminals were blocked by bretylium (BR). Baseline local skin temperature was clamped at 33 degrees C. Next, local temperature was reduced to 24 degrees C. After 15 min of local cooling, noradrenaline (NA) was administered to study the effect of neural vasoconstriction mechanisms. No significant age effect was observed in vasoconstriction due to local cooling at BR sites. After NA, vasoconstriction at the forearm showed a significant age effect; however, no significant age effect was found at the hand sites. [Change in CVC (% from baseline): Forearm Y: -76 +/- 3 vs. E: -60 +/- 5 (P < 0.01), dorsal hand Y: -74 +/- 4 vs. E: -72 +/- 4 (n.s.), ventral hand Y: -80 +/- 7 vs. E: -70 +/- 11 (n.s.)]. In conclusion, in contrast to results from the ventral forearm, elderly did not show a blunted response to local cooling and noradrenaline at hand skin sites. This indicates that at hand skin the noradrenergic mechanism of vasoconstriction is maintained with age.

Nervous and humoral catecholaminergic control of blood pressure and cardiac performance in the Antarctic fish Pagothenia borchgrevinki.

The role of circulating and neural catecholamines for cardiovascular control in the Antarctic fish Pagothenia borchgrevinki was studied in vivo using pharmacological tools and with immunohistochemistry on isolated tissues. Adrenergic nerve blockade with bretylium decreased dorsal aortic pressure (P(da)) and systemic vascular resistance (R(sys)), while cardiac output (Q) did not change. The blockade of alpha-adrenoceptors with phentolamine reduced P(da) and R(sys) further, revealing that vasomotor tone was influenced by circulating catecholamines in bretylium treated fish. The physiological evidence for an adrenergic nervous control of the vasculature was corroborated by the presence of tyrosine hydroxylase (TH)-immunoreactive fibres associated with blood vessels in spleen, gonads and gastrointestinal tract. TH-immunoreactive fibres were not observed in the atrium and ventricle, but a dense population of TH-immunoreactive fibres was apparent in the bulbus arteriosus. The present study suggests that an adrenergic nervous mechanism is responsible for maintaining vasomotor tone in P. borchgrevinki. While experiments failed to demonstrate a tonic adrenergic nervous influence affecting cardiac performance, an adrenergic nervous control of bulbar compliance may be essential for optimizing gill blood flow dynamics in this species, which has a high relative stroke volume and displays profound changes in stroke volume in vivo.

Bretylium, a Class III Antiarrhythmic, Returns to the Market.

Bretylium, with an extensive pharmacologic and medicinal history, was approved by the United States Food and Drug Administration in 1986 for "short-term prevention and treatment of ventricular fibrillation (VF) and treatment of life-threatening ventricular arrhythmias and ventricular tachycardia (VT) unresponsive to adequate doses of a first-line antiarrhythmic agent, such as lidocaine." The NDA sponsor withdrew bretylium from the market in 2011, largely due to unavailability of raw materials required for its production; prior to this, bretylium was removed from the 2000 ACLS Guidelines algorithm for VF/pulseless VT given the challenges obtaining raw materials for drug manufacture. Recently, bretylium has been reintroduced into the US market by a generic pharmaceutical company with the same indications as before. This article provides a history of the salient trials evaluating the efficacy and safety of bretylium and looks to the future as bretylium finds its place in the modern day management of ventricular arrhythmia.

Bretylium abolishes neurotransmitter release without necessarily abolishing the nerve terminal action potential in sympathetic terminals.

BACKGROUND AND PURPOSE: The antidysrhythmic bretylium is useful experimentally because it selectively abolishes neurotransmitter release from sympathetic peripheral nerve terminals. Its mechanism of action seemed settled, but recent results from optical monitoring of single terminals now suggests a new interpretation. EXPERIMENTAL APPROACH: Orthograde transport of a dextran-conjugated Ca(2+) indicator to monitor Ca(2+) in nerve terminals of mouse isolated vas deferens with a confocal microscope. In some experiments, local neurotransmitter release was detected by monitoring neuroeffector Ca(2+) transients (NCTs) in adjacent smooth muscles, a local measure of purinergic transmission. Sympathetic terminals were identified with catecholamine fluorescence (UV excitation) or post-experiment immunohistochemistry. KEY RESULTS: Bretylium (10 microM) abolished NCTs at 60/61 junctions over the course of 2 h, indicating effective abolition of neurotransmitter release. However, bretylium did not abolish the field stimulus-induced Ca(2+) transient in most nerve terminals, but did increase both action potential delay (by 2+/-0.4 ms) and absolute refractory period (by 4+/-2 ms). Immunohistochemistry demonstrated that 85-96% of terminals orthogradely filled with a dextran-conjugated fluorescent probe contained Neuropeptide Y (NPY). A formaldehyde-glutaraldehyde-induced catecholamine fluorescence (FAGLU) technique was modified to allow sympathetic terminals to be identified with a Ca(2+) indicator present. Most terminals contained catecholamines (based on FAGLU) or secrete ATP (as NCTs in adjacent smooth muscle cells are abolished). CONCLUSIONS AND IMPLICATIONS: Bretylium can inhibit neurotransmitter release downstream of Ca(2+) influx without abolishing the nerve terminal action potential. Bretylium-induced increases in the absolute refractory period permit living sympathetic terminals to be identified.

Mechanisms regulating the cardiac output response to cyanide infusion, a model of hypoxia.

When tissue metabolic changes like those of hypoxia were induced by intra-aortic infusion of cyanide in dogs, cardiac output began to increase after 3 to 5 min, reached a peak (220% of the control value) at 15 min, and returned to control in 40 min. This pattern of cardiac output rise was not altered by vagotomy with or without atropine pretreatment. However, this cardiac output response could be differentiated into three phases by pretreating the animals with agents that block specific activities of the sympatho-adrenal system. First, ganglionic blockade produced by mecamylamine or sympathetic nerve blockade by bretylium abolished the middle phase of the cardiac output seen in the untreated animal, but early and late phases still could be discerned. Second, beta-adrenergic receptor blockade produced by propranolol shortened the total duration of the cardiac output rise by abolishing the late phase. Third, when given together, propranolol and mecamylamine (or bretylium) prevented most of the cardiac output rise that follows the early phase. When cyanide was given to splenectomized dogs, the duration of the cardiac output response was not shortened, but the response became biphasic, resembling that seen after chemical sympathectomy. A similar biphasic response of the cardiac output also resulted from splenic denervation; sham operation or nephrectomy had no effect on the monophasic pattern of the normal response. Splenic venous blood obtained from cyanide-treated dogs, when infused intraportally, caused an increase in cardiac output in recipient dogs; similar infusion of arterial blood had no effects. THESE RESULTS SUGGEST THAT THE CARDIAC OUTPUT RESPONSE TO CYANIDE INFUSION CONSISTS OF THREE COMPONENTS: an early phase, related neither to the autonomic nervous system nor to circulating catecholamines; a middle phase, caused by a nonadrenergic humoral substance released from the spleen by sympathetic stimulation; and a late phase, dependent upon adrenergic receptors but not upon sympathetic transmission.

Cerebroventricular calcitonin gene-related peptide inhibits rat duodenal bicarbonate secretion by release of norepinephrine and vasopressin.

Proximal duodenal bicarbonate secretion is an important factor in humans and animals protecting the mucosa against acid-peptic damage. This study examined the mechanisms responsible for the central nervous system regulation of duodenal bicarbonate secretion by calcitonin gene-related peptide (CGRP) in unrestrained rats. Cerebroventricular administration of rat CGRP significantly inhibited basal duodenal bicarbonate secretion as well as the stimulatory effects of vasoactive intestinal peptide, neurotensin, a luminal PGE1 analogue, misoprostol, and hydrochloric acid. The inhibitory effects of cerebroventricular CGRP were abolished by ganglionic blockade with chlorisondamine, significantly attenuated by noradrenergic blockade with bretylium, and enhanced by vagotomy. Inhibition of duodenal bicarbonate secretion induced by CGRP coincided with significant increases in plasma norepinephrine (NE) and vasopressin concentrations. The alpha adrenergic receptor antagonist, phentolamine, and the vasopressin V1 receptor antagonist, (1-deaminopenicillamine, 2-[O-methyl]Tyr, 8-Arg)-vasopressin, given intravenously reversed the central inhibitory effect of CGRP by approximately 50% each. Pretreatment of the animals with both phentolamine and the vasopressin antagonist completely abolished the central inhibitory effect of CGRP. Peripheral vasopressin and NE significantly decreased duodenal bicarbonate secretion, and their inhibitory effects were additive and prevented by phentolamine and the vasopressin antagonist, respectively. We conclude that cerebroventricular CGRP inhibits rat duodenal bicarbonate secretion by activation of sympathetic efferents and subsequent release of NE and vasopressin that act on alpha adrenergic and vasopressin receptors, respectively.

Cholinergic innervation of the guinea-pig isolated vas deferens.

Recently, a cholinergic neurogenic component of contraction has been characterised in the aganglionic mouse vas deferens. In this paper, a cholinergic component of contraction in the guinea-pig vas deferens is characterised pharmacologically. A residual, tetrodotoxin-sensitive (TTX, 0.3 microM), neurogenic contraction was revealed after prolonged exposure (5 h) to the adrenergic neurone blocker bretylium (20 microM) or in the presence of prazosin (100 nM) and alpha,beta-methylene ATP (1 microM), a purinergic agonist which desensitizes P2X receptors. The bretylium-resistant component was potentiated by the acetylcholinesterase (AChE) inhibitor neostigmine (10 microM) and inhibited by the muscarinic-receptor (mAChR) antagonist cyclopentolate (1 microM). Nicotine (30 microM) enhanced the bretylium-resistant component. Neostigmine increased the second component of contraction in the presence of prazosin and alpha,beta-methylene ATP, whilst yohimbine (1 microM), an alpha(2) adrenergic receptor antagonist, enhanced both the first and second components of the electrically evoked contraction. These enhanced contractions were blocked by cyclopentolate in both cases. Nicotine enhanced the cholinergic component of contraction revealed by neostigmine but failed to have any detectable effects in the presence of cyclopentolate. Neostigmine alone increased the slow component of contraction which was reversed by cyclopentolate to control levels. The M(3) receptor-antagonist 4-DAMP (10 nM) markedly inhibited the cholinergic component of contraction to a level comparable with cyclopentolate. Laser microscopy has shown that neostigmine also increased the frequency of spontaneous Ca(2+) transients remaining in smooth muscle cells after perfusion with prazosin and alpha,beta-methylene ATP, an effect blocked by 4-DAMP. These experimental data show that there is a functional cholinergic innervation in the guinea-pig vas deferens whose action is limited by acetylcholinesterase, blocked by cyclopentolate and mediated through M3 receptors. Moreover, by blocking the cholinesterase, the increased amount of ACh generates spontaneous Ca(2+) transients in smooth muscle cells.

The effect of the sympathetic and sensory nervous system on active eustachian tube function in the rat.

CONCLUSION: We propose that simultaneous activation of the sensory and sympathetic nervous system may adversely affect eustachian tube function, which may have a role in the genesis of Ménière's disease. OBJECTIVE: We have determined the distribution of sympathetic and nociceptive sensory axons in the mucosa of the rat eustachian tube and investigated whether sympathetic or nociceptive neurons influence the function of the eustachian tube. MATERIALS AND METHODS: We tested whether the ability of a rat to equalize air pressure in the middle ear during evoked swallowing was altered by activation or blockade of the local sympathetic nervous system, or by stimulation of nociceptive neurons with capsaicin. RESULTS: Sympathetic axons were sparse, but CGRP-immunoreactive, nociceptive axons formed a dense subepithelial plexus beneath the eustachian tube epithelium. Neither the adrenergic blocking drug, bretylium, nor electrical stimulation of the superior cervical ganglion significantly altered eustachian tube function. Capsaicin alone did not affect eustachian tube function but capsaicin applied with an alpha adrenoceptor agonist impaired the function of the eustachian tube. Capsaicin applied to the bulla also increased spontaneous swallowing in anaesthetized rats and this effect was enhanced by addition of an alpha adrenoceptor agonist and by stimulation of the superior cervical ganglion.

Inactivation of acetylcholinesterase with a bretylium tosylate photoaffinity probe.

Azidobretylium tosylate (ABT), the p-azido analogue of bretylium tosylate, has been synthesized to serve as a photoaffinity probe for bretylium binding sites. Bretylium tosylate has antiarrhythmic action and also interacts with amiloride-sensitive sodium ion transport sites. Acetylcholinesterase was used as a model protein, and both bretylium and ABT are reversible inhibitors of this enzyme. The kinetic inhibition constants (Ki) were determined to be 40 microM for bretylium tosylate and 6 microM for ABT. The azido compound is photochemically labile and apparently irreversibly inactivates the enzyme. The rate was retarded by the addition of bretylium tosylate or 4-oxo-N,N,N-trimethylpentanaminium iodide (OTI). Sephadex G-25 chromatography further demonstrated the irreversible nature of the photoinactivation. Since ABT binds at or near the acetylcholinesterase active site, it may be a useful probe for the characterization of the enzyme active site.

Bretylium-induced voltage-gated sodium current in human lymphocytes.

Using the whole-cell variation of the patch-clamp technique it has been determined that 0.25-3 mM bretylium tosylate (BT) exerts a repolarizing effect on partially depolarized human lymphocytes. The repolarizing effect was ouabain (40 microM)-sensitive, and was inhibited by the removal of external Na+ or by the Na(+)-channel-blocker amiloride (10-44 microM), but K(+)-channel-blockers 4-aminopyridine (0.1-5 mM) and quinine (100 microM) had no effect. The drug induced a sodium dependent, amiloride-sensitive transient inward current reaching its maximum value approx. 20-30 s after the administration of BT and lasting for 6-10 min. This current was activated by depolarization within 25 ms at around -42 mV, its inactivation took about 2 s and its reversal potential was +24 +/- 5 mV. An increase in the intracellular sodium concentration (1.8-3.2 mM) has been observed upon the addition of BT by monitoring the SBFI fluorescence of the dye-loaded cells. It has been shown that whole-cell K+ currents are significantly decreased by BT. The existence of voltage and ligand (BT)-gated sodium channels has been postulated in human lymphocytes. These channels are thought to participate in the initiation of membrane repolarization in human lymphocytes, and thereby influence mitogenic or antigen-induced cell-activation processes.

Bretylium opens mucosal amiloride-sensitive sodium channels.

Addition of the quanternary ammonium compound, bretylium, to the outer surface of a frog skin leads to an increase in the potential difference and in the short circuit current across the skin. Bretylium does not have any effect when applied to the inside face of the frog skin. The effect of bretylium is dependent upon the presence of sodium ions in the outer medium; it is depressed when sodium is replaced by choline or potassium but not when lithium substitutes for sodium. The bretylium effect is blocked by the specific sodium channel blocker, amiloride. It is proposed that bretylium opens mucosal, amiloride-sensitive sodium channels.

Comparison between bretylium and diphenylhydantoin interaction with mucosal sodium-channels.

The antifibrillatory drug bretylium and the antiepileptic drug diphenylhydantoin cause an increase in the potential different and in the short-circuit current (SCC) across frog skin when added to the outer surface. The effect of both drugs depends upon the presence of sodium ions in the outer medium and is blocked by the specific sodium channel blocker, amiloride. Quantitative analysis shows that amiloride binds to open as well as closed mucosal sodium channel with the same affinity. The effects of diphenylhydantoin and bretylium differ with respect to their dependence on external pH. The diphenylhydantoin or the bretylium stimulatory effects are additive to the effects of oxytocin. In most cases the diphenylhydantoin and bretylium effects are also additive. It is concluded that the external side of the mucosal Na+ channels contains sites which interact specifically with either bretylium or diphenylhydantoin and thus remove the sodium induced closure of the channels.

Peripheral mechanisms involved in gastric mucosal protection by intracerebroventricular and intraperitoneal nociceptin in rats.

Nociceptin (N/OFQ) exerts multiple effects in the gastrointestinal tract after central or peripheral administration. In the present study, we examined the possible peripheral mechanisms mediating gastric protection by N/OFQ in rats. Gastric mucosal lesions were induced by 50% ethanol (1 ml/rat intragastrically). N/OFQ, administered either intracerebroventricularly (3 microg/rat) or ip (10 microg/kg), significantly reduced macroscopic and histological damage. The protective effect of intracerebroventricular N/OFQ was blocked by atropine, subdiaphragmatic vagotomy, and bretylium. The effect of both central and peripheral N/OFQ was blocked by functional ablation of afferent nerves produced by capsaicin, by the antagonist of calcitonin gene-related peptide, CGRP(8-37), and by the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester. These results indicate that N/OFQ increases gastric mucosal resistance to ethanol by operating both in the central nervous system and in the periphery. Vagal cholinergic and sympathetic pathways mediate the central activity of N/OFQ, whereas vagal nonmuscarinic pathways mediate the peripheral activity of the peptide. The neuronal circuit involving extrinsic sensory neurons, calcitonin gene-related peptide, and nitric oxide is activated by central as well as peripheral N/OFQ. The study provides evidence that N/OFQ contributes to neurally mediated gastric mucosal protection.

Effect of lidocaine and bretylium on energy requirements for transthoracic defibrillation: experimental studies.

The purpose of this study was to determine the effect of the antiarrhythmic drugs lidocaine and bretylium on the minimal energy requirement for transthoracic defibrillation--the defibrillation threshold. Closed chest dogs were anesthetized with chloralose or pentobarbital; lidocaine was administered at varying rates for 2 hours and defibrillation threshold periodically redetermined. Similar protocols were followed for bretylium. Serum lidocaine levels from therapeutic to toxic ranges were obtained, and up to a 60% (p less than 0.05) increase in defibrillation threshold in the pentobarbital-anesthetized dogs was demonstrated. In chloralose-anesthetized dogs the lidocaine effect was modest, with only a 10 to 20% rise in defibrillation threshold (p = NS) despite similar increases in serum lidocaine levels. Thus, lidocaine increases the minimal energy requirements for transthoracic defibrillation, but this effect is in part anesthesia-related, indicating a lidocaine-pentobarbital interaction. When phentolamine was administered to chloralose-anesthetized dogs receiving lidocaine, defibrillation threshold rose 13% (p less than 0.05); this suggests that alpha-adrenergic receptor blockade is at least in part the mechanism of the pentobarbital-lidocaine interaction on defibrillation threshold. Bretylium with either anesthetic had no significant effect on defibrillation threshold.

Membrane action and catecholamine release action of bretylium tosylate in normoxic and hypoxic canine Purkinje fibers.

Electrophysiologic effects of bretylium tosylate on transmembrane action potentials of canine Purkinje fibers were studied by microelectrode methods. Perfusion of this agent (20 mg/liter) prolonged the action potential duration and the effective refractory period, but did not alter the maximal diastolic potential, upstroke phase of the action potential and membrane responsiveness curve under normal oxygenation. With a hypoxic superfusion, the action potential amplitude, maximal diastolic potential, maximal rate of depolarization and action potential duration were all decreased. Subsequent addition of bretylium antagonized all these effects of hypoxia and restored the action potential variables to control values. However, similar effects of hypoxia observed in Purkinje fibers pretreated with reserpine were not reversed by bretylium except for a prolongation of repolarization. These results suggest that antiarrhythmic effects of bretylium in hypoxic or depressed myocardium are probably due to: 1) increased maximal rate of depolarization (and conduction velocity) caused by membrane hyperpolarization, and 2) prolongation of the effective refractory period. The first electrophysiologic action appears to depend on catecholamine release by bretylium, as hyperpolarization was not observed in reserpine-pretreated Purkinje fibers. The second effect may represent a direct membrane action.

Cholinergic innervation of the mouse isolated vas deferens.

Recently, a population of nerves has been described in the aganglionic mouse vas deferens, in which electrically evoked contractions were insensitive to high concentrations of the adrenergic neurone blocker, bretylium. In this paper, the pharmacology of this nerve-evoked contraction has been examined in more detail. Bretylium (20 microM) revealed, after 5 h exposure, a new residual neurogenic contraction (20 stimuli at 10 Hz) that was tetrodotoxin-sensitive. The muscarinic antagonist, cyclopentolate (0.1 and 1 microM), reduced this residual component and the inhibition was reversed by the acetylcholinesterase inhibitor, neostigmine (1 and 10 microM). Nicotine (30 microM) enhanced the residual component revealed by bretylium, suggesting that there are prejunctional nicotinic receptors (nAchRs) influencing acetylcholine (Ach) release. In the presence of prazosin (0.1 microM), a selective alpha(1)-adrenoceptor antagonist, and alpha,beta-methylene ATP (1 microM), a purinergic agonist that desensitise P2X receptors, neostigmine increased the hump component of contraction and yohimbine (0.3 microM), an alpha(2)-adrenoceptor antagonist, enhanced both components of the electrically evoked stimulation. The contraction was blocked by cyclopentolate (1 microM). In the absence of bretylium, neostigmine alone increased the hump component of contraction in a frequency-dependent manner. This increase was reversed by atropine (1 microM) and cyclopentolate (1 microM) to control levels. However, in control experiments, atropine or cyclopentolate did not detectably influence the delayed neurogenic contraction. Ach (10 microM) induced a contraction in the mouse vas deferens, either when applied alone or in the presence of neostigmine.Thus, it has been demonstrated unequivocally that the mouse vas deferens is innervated by functional cholinergic nerves, whose action is terminated by cholinesterase. Furthermore, Ach release can be enhanced by activation of prejunctional nAchRs presumably located on the cholinergic nerve terminals.

Active cutaneous vasodilation in resting humans during mild heat stress.

The role of skin temperature in reflex control of the active cutaneous vasodilator system was examined in six subjects during mild graded heat stress imposed by perfusing water at 34, 36, 38, and 40 degrees C through a tube-lined garment. Skin sympathetic nerve activity (SSNA) was recorded from the peroneal nerve with microneurography. While monitoring esophageal, mean skin, and local skin temperatures, we recorded skin blood flow at bretylium-treated and untreated skin sites by using laser-Doppler velocimetry and local sweat rate by using capacitance hygrometry on the dorsal foot. Cutaneous vascular conductance (CVC) was calculated by dividing skin blood flow by mean arterial pressure. Mild heat stress increased mean skin temperature by 0.2 or 0.3 degrees C every stage, but esophageal and local skin temperature did not change during the first three stages. CVC at the bretylium tosylate-treated site (CVC(BT)) and sweat expulsion number increased at 38 and 40 degrees C compared with 34 degrees C (P < 0.05); however, CVC at the untreated site did not change. SSNA increased at 40 degrees C (P < 0.05, different from 34 degrees C). However, SSNA burst amplitude increased (P < 0.05), whereas SSNA burst duration decreased (P < 0.05), at the same time as we observed the increase in CVC(BT) and sweat expulsion number. These data support the hypothesis that the active vasodilator system is activated by changes in mean skin temperature, even at normal core temperature, and illustrate the intricate competition between active vasodilator and the vasoconstrictor system for control of skin blood flow during mild heat stress.

Bretylium causes a K(+)-Na+ pump activation that is independent of Na+/H+ exchange in depolarized rat, mouse and human lymphocytes.

We have studied a bretylium tosylate induced increase of the membrane potentials of partially depolarized rat, mouse and human lymphocytes, using the potential sensitive dye, bis [1,3, dibutylbarbituric acid-(5) trimethine oxonol]. The extent of this repolarization is dose-dependent and decreased in magnitude as the temp was reduced from 37 degrees C to room temp. The repolarizing effect is inhibited by K(+)-Na(+)-pump blockers or lack of extracellular Na+. Sodium ion channel blockers are effective in abolishing repolarization only if applied prior to, or simultaneously with, bretylium. Activation of Na+/H+ exchange is not involved in the mechanism of the phenomenon as the latter is completely eliminated in the presence of 10 microM amiloride (concn of the diuretics having no measurable inhibition on the action of the exchanger). These data suggest that bretylium opens ligand- and voltage-gated Na+ channels, and repolarization occurs due to higher activity of the K(+)-Na(+)-pump stimulated by the enhanced intracellular Na+ accumulation.

Effects of bretylium and lidocaine on ventricular fibrillation in the isolated rabbit heart.

We studied the effects of bretylium tosylate and lidocaine on ventricular fibrillation in the isolated, perfused rabbit heart induced by perfusion with potassium-deficient solutions and by premature stimuli. The purpose of the study was to determine if the reported antifibrillatory effects of the drugs could be reproduced in the absence of an intact sympathetic nervous system. Lidocaine in the concentration of 5 mug/ml. prevented ventricular fibrillation induced by both methods while bretylium, in concentrations of 25 to 50 mug/ml. prevented neither type of filbrillation. These results indicate that the antifibrillatory effects of lidocaine can be attributed to drug-induced alterations in cellular electrophysiology, whereas those of bretylium are independent of such changes. Our study suggests that the reported antifibrillatory capability of bretylium is related to the drug's effects at sympathetic nerve terminals and thus is dependent upon an intact sympathetic nervous system.

Effects of bretylium tosylate on inhomogeneity of refractoriness and ventricular fibrillation threshold in canine hearts with quinidine-induced long QT interval.

We studied effects of bretylium tosylate (6 mg X kg-1, injected intravenously over 60s) on ventricular refractoriness and its inhomogeneity, and ventricular fibrillation threshold (VFT) in canine hearts with quinidine-induced long QT interval. In 3 anaesthetised open chest dogs, 30 mg X kg-1 of quinidine sulphate was injected intravenously over 5 min to produce QT prolongation. Effective refractory period (ERP) was determined at 8 test points of the right ventricle using extrastimuli. Temporal dispersion as an expression of inhomogeneity of ventricular refractoriness was estimated as the difference between the longest and the shortest ERP. VFT was determined using a train of pulses, 4 ms in duration and at 10 ms intervals. Effects of bretylium were determined from 30 to 60 min after injection. Quinidine-induced long QT interval did not change after bretylium (358 +/- 37 vs 348 +/- 26 ms) when transiently elevated blood pressure returned to the pre-bretylium level. Bretylium shortened ERP slightly (278 +/- 16 vs 268 +/- 14 ms, p less than 0.02) but did not shorten ERP after premature depolarisation (209 +/- 14 vs 209 +/- 15). However, temporal dispersion was significantly decreased by bretylium. VFT, which was lowered by quinidine (14.5 +/- 5.0 vs 8.5 +/- 2.9 mA, p less than 0.01), was elevated significantly by bretylium (21.9 +/- 6.9, p less than 0.001). These effects of bretylium might be attributed to the combination of its direct electrophysiology and indirect adrenergic actions.