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Background: Vasoconstriction occurs after percutaneous transluminal coronary angioplasty (PTCA) along the dilated vessel. The vasomotor changes, initiated by the mechanical stretch of the stenotic region, are thought to be due to various mechanisms but whether the sympathetic nervous system plays a role in this phenomenon remains unknown., Methods and Results: Quantitative angiography (ARTREK) was performed in 45 patients undergoing an epicardial vessel PTCA for a stenosis of 76 +/- 1% (1) in basal conditions, (2) after PTCA, and (3) 30 minutes after PTCA (vasoconstriction). In 14 control patients, the same measurements were obtained up to 60 minutes after PTCA. Coronary diameters were measured along the PTCA vessel at the narrowest stenosis level and at a level peripheral to stenosis. In 36 patients two diameters were also measured at a proximal segment and at a distal segment along a nonmanipulated vessel. Thirty minutes after PTCA the dilated segment underwent a -31 +/- 2% (mean +/- SEM, ANOVA, P < .05) reduction in diameter when compared with PTCA values, and the segment peripheral to stenosis showed a reduction of -17 +/- 2% (P < .05). In all patients a significant vasoconstriction also was observed along the control vessel (proximal segment, -14 +/- 3%; P < .05 versus basal; and distal segment, -17 +/- 2%). At the time of maximal vasoconstriction (30 minutes after PTCA), the patients (treatment groups) received (1) 18 micrograms/kg IC phentolamine (Phe, n = 7), (2) 14 micrograms/kg IC yohimbine (YO, n = 7), (3) 16 micrograms/kg IC propranolol (Pro) followed by 18 micrograms/kg IC phentolamine (Pro+Phe, n = 7), and (4) 0.2 mg/kg IC bretylium (Bre, n = 10). In 14 patients (control groups) an intracoronary injection of warm saline was given. After drug injections, angiograms were repeated at 5-minute intervals for 20 minutes and ended after a 300-micrograms intracoronary trinitroglycerin injection. At stenosis level, Phe and Bre counteracted vasoconstriction, inducing a dilatation of +19 +/- 3% and +22 +/- 6%, respectively, while Pro+Phe caused a dilatation of +16 +/- 9% above the PTCA values (P < .05 versus PTCA). YO only partially reversed vasoconstriction (from -33 +/- 4% to -12 +/- 4%, P = NS versus PTCA). At peripheral-to-stenosis level, vasoconstriction was abolished by Phe (+26 +/- 7%, P < .05 versus basal), while it was still present after Pro+Phe (-23 +/- 2%) and Bre (-18 +/- 4%). In addition, Phe and Bre dilated the control vessel at the proximal segment (+17 +/- 6% and +8 +/- 4%, respectively, P < .05 versus basal), while YO and Pro+Phe only counteracted vasoconstriction (from -15 +/- 3% to +7.6 +/- 1% and from -16 +/- 3% to +4 +/- 5%, respectively, P = NS versus basal). At the distal segment only Phe produced a vasodilatation of +23 +/- 1%; YO counteracted constriction (from -16 +/- 2% to +9 +/- 6%, P < .05 versus basal), whereas after Pro+Phe and Bre, the vasoconstriction persisted., Conclusions: The mechanical stretch and ischemia caused by balloon inflation induced vasoconstriction mediated by alpha-adrenergic receptors (mainly alpha 1), overcoming a beta-mediated dilatation. The use of different antiadrenergic drugs showed that Phe counteracts post-PTCA vasoconstriction, and the simultaneous use of alpha- and beta-receptor blocking agents (Pro+Phe and Bre) reveals the presence of a peripheral, predominant beta-mediated dilatation. The presence of vasoconstriction also along the control vessels not branching from the stretched ramus provides evidence for the existence of neural sympathetic vasoconstrictor reflexes.

The antifibrillatory effects of flecainide 1 mg/kg + 0.05 mg/kg/min intravenously (i.v.), bretylium 6 mg/kg i.v., D-sotalol 2 mg/kg + 0.1 mg/kg/min i.v., and E-4031, a new class III drug, 50 micrograms/kg + 5 micrograms/kg/min i.v. were compared with three different methods of determining ventricular fibrillation threshold (VFT) in anesthetized open-chest dogs. In protocol 1, VFT was determined with 2-S, 50-Hz continuous pulses. Flecainide (n = 7) prolonged intraventricular conduction time (CT) and ventricular effective refractory period (ERP) and increased VFT significantly. Bretylium (n = 6) prolonged ERP slightly, but did not increase VFT significantly. Both D-sotalol (n = 6) and E-4031 (n = 6) prolonged ERP and increased VFT. In protocol 2, VFT was determined with the extrastimulus technique in dogs, with localized ventricular necrosis produced with protease. Flecainide (n = 10), D-sotalol (n = 8), and E-4031 (n = 8) restored VFT, which had been decreased by protease injection, to the baseline level, whereas bretylium (n = 8) did not. In protocol 3, the train pulse method with 100-Hz train pulses covering the vulnerable period was used in the same dogs used for protocol 2. Flecainide, bretylium, and D-sotalol increased VFT, but E-4031 did not. The antifibrillatory effects of class III drugs differ depending on the method of VFT determination. The present data suggest that the antifibrillatory effects of antiarrhythmic drugs should be assessed by different methods of VFT determination.

The purpose of the present study was to determine whether sympathetic coronary vasoconstrictor responses are altered after brief ischemia and reperfusion. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, left ventricular pressure, left ventricular dP/dt, anterior myocardial wall thickening, and left circumflex coronary artery (LCX) and left anterior descending coronary artery (LAD) blood flow velocities. Changes in coronary vascular resistance were recorded during intravenous bolus doses of norepinephrine and bilateral electrical stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, electrical stimulation of the stellate ganglia increased coronary vascular resistance in the LAD and LCX beds by 38 +/- 5% and 39 +/- 5%, respectively. After a 15-minute LAD occlusion, repeat electrical stimulation produced increases in coronary resistance of 16 +/- 3% and 45 +/- 8%, respectively (p less than 0.05 for the LAD before versus after the occlusion). The peak increase in coronary vascular resistance to two doses of norepinephrine was unchanged. After a shorter period of myocardial ischemia (7 minutes), similar increase in coronary resistance to stellate stimulation were observed before (27 +/- 4%) and after (26 +/- 6%) myocardial ischemia. The mechanism of this impaired sympathetic coronary vasoconstriction was further tested by examining the responses to bretylium and tyramine. Brief ischemia did not alter the coronary constrictor responses to either bretylium or tyramine, suggesting that mechanisms governing prejunctional release of norepinephrine are intact in the postischemic coronary arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of MDL 11,939 hydrochloride [alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol HCl], a novel antiarrhythmic agent, was studied using microelectrode recording techniques. MDL 11,939 (10(-7) - 10(-6) M increased the action potential (AP) duration in both guinea pig papillary muscle and dog Purkinje fiber with a maximum effective concentration of 10(-6) to 3 x 10(-6) M. MDL 11,939 up to and including 10(-6) M did not alter upstroke velocity (Vmax) of the AP in either tissue but 10(-5) M decreased the Vmax in Purkinje fibers. Compared to the other class III antiarrhythmic agents (bretylium, clofilium, and d-sotalol), MDL 11,939 was among the most potent in increasing AP duration in the papillary muscle, while being relatively less effective in increasing AP duration in Purkinje fiber. Bretylium did not increase the AP duration in papillary muscle unless it was reserpinized. MDL 11,939, clofilium, and d-sotalol all produced negative inotropic effects in papillary muscle, whereas bretylium produced a positive inotropic effect. The positive inotropic effect of bretylium was abolished by reserpinization. In papillary muscle preparations depolarized with 22 mM K+, MDL 11,939 at concentrations greater than or equal to 10(-5) M depressed Vmax of the slow AP, suggesting that it inhibited the inward Ca2+ current, and such an effect may contribute to the negative inotropic effect of this agent. In the depolarized preparations, the slow AP duration was still increased by concentrations of MDL 11,939 greater than or equal to 10(-6) M. In conclusion, MDL 11,939 has cellular electrophysiological properties that suggest a class III antiarrhythmic activity.

Cutaneous arterioles are controlled by vasoconstrictor and active vasodilator sympathetic nerves. To find out whether the active vasodilator system is under baroreceptor control, laser-Doppler velocimetry and the local iontophoresis of bretylium were combined to allow selective study of the active vasodilator system. Each of six subjects had two forearm sites (0.64 cm2) treated with bretylium to abolish adrenergic vasoconstrictor control. Laser-Doppler velocimetry was monitored at those sites and at two adjacent untreated sites. Subjects underwent 3 minutes of lower-body negative pressure (LBNP) and 3 minutes of cold stress to verify blockade of vasoconstrictor nerves. They were then subjected to whole-body heat stress (water-perfused suits), and the 3 minutes of LBNP was repeated. Finally, subjects were returned to normothermia, and LBNP and cold stress were repeated to verify the persistence of blockade. During the application of LBNP in normothermia, cutaneous vascular conductance (CVC) fell at untreated sites by 22.7 +/- 4.7% (p less than 0.01) but was unaffected at bretylium-treated sites (p greater than 0.20). During cold stress, CVC at untreated sites fell by 30.2 +/- 1.7% (p less than 0.01) and at treated sites rose by 0.7 +/- 4.6% (p greater than 0.10). Both control and bretylium-treated sites reflexly vasodilated in response to hyperthermia. With LBNP during hyperthermia, CVC at untreated sites fell by 23.3 +/- 7.1% (p less than 0.05) and at treated sites 17.9 +/- 9.2% (p less than 0.05) with no significant difference between sites (p greater than 0.10). After return to normothermia, neither LBNP application nor cold stress caused CVC to fall at treated sites (p greater than 0.10). Thus, the vasoconstrictor system was blocked by bretylium treatment throughtout the study, whereas the active vasodilator response to heat stress was intact. Because LBNP in hyperthermia induced similar falls in CVC at both sites, we conclude that baroreceptor unloading elicits a withdrawal of active vasodilator tone and that the baroreflex has control of the active vasodilator system.

Bretylium tosylate and bethanidine sulfate were studied in two models of experimental myocardial ischemia. In anesthetized dogs, left anterior descending coronary artery occlusion during rapid atrial pacing (180-200 min-1) produced ventricular tachycardia and fibrillation within 5 min in 9 of 11 dogs studied. In all cases, arrhythmias were preceded by and appeared to be temporally related to progressive fractionation and delay of electrograms recorded from the ischemic zone. In four dogs, bretylium (10 mg/kg) did not alter the time course of electrogram changes nor the time to onset of arrhythmia. However, in five dogs bethanidine (10 mg/kg) markedly exacerbated conduction changes in the ischemic zone and decreased the time to onset of ventricular arrhythmias (173 +/- 35 vs. 262 +/- 34 s control, mean +/- SEM, p less than 0.05). Bethanidine administration also facilitated ischemia-induced ventricular tachycardia and fibrillation in two dogs that did not exhibit ischemia-induced arrhythmias before receiving the drug. In isolated perfused rabbit hearts, global ischemia produced conduction slowing, depolarization of resting membrane potential, and decreases in amplitude and Vmax that were reproducible in serial 10 min ischemic episodes. Bretylium (10 mg/L) did not affect these parameters under either perfused or ischemic conditions. Although bethanidine (10 mg/L) also did not affect these parameters during perfusion, conduction slowing and depression of Vmax during ischemia were accelerated without affecting the time course of change in resting membrane potential. Both bretylium and bethanidine prolonged action potential duration under perfused conditions, but after 10 min of ischemia this effect was no longer evident. The results demonstrate that differences in the electrophysiologic effects of bretylium and bethanidine are markedly accentuated in the setting of acute ischemia. Although both these agents have been demonstrated to have antifibrillatory effects in other experimental settings, under the conditions of this study, bretylium failed to protect against ischemia-induced arrhythmias and acute bethanidine administration produced a proarrhythmic effect in association with an exacerbation of ischemia-induced conduction changes.

The localization of vasoactive intestinal peptide-immunoreactive nerves innervating bovine lymphatic vessels was studied by an immunohistochemical technique. Nerve fibers containing vasoactive intestinal peptide immunoreactivity were present in the smooth muscle layers as well as in the adventitia of all mesenteric lymphatics that were examined. The effect of vasoactive intestinal peptide on isolated lymphatic vessels in vitro was studied. Vasoactive intestinal peptide caused a concentration-dependent relaxation of bradykinin-induced contractions of lymphatic vessels. The threshold and maximum relaxations were achieved with vasoactive intestinal peptide at concentrations less than 6 X 10(-9) M and 3 X 10(-7) M, respectively. The relaxant response to vasoactive intestinal peptide was not modified by atropine, propranolol, bretylium, or tetrodotoxin. These results suggest that vasoactive intestinal peptide may be a possible inhibitory neurotransmitter that causes relaxation of lymphatic vessels.

The antifibrillatory property of bretylium tosylate was first observed in experimental atrial fibrillation, yet the cellular basis for this phenomenon has not been explored. The purpose of this study was to determine the electrophysiologic properties of bretylium tosylate on guinea pig atrial myocardium in the presence and absence of cholinergic influence. Bretylium (10(-6) M - 10(-4) M) produced a concentration-dependent prolongation of atrial action potential duration with a threshold concentration of 10(-5) M. This direct effect of bretylium was unaltered by blockade of beta-adrenergic receptors with propranolol (10(-6) M) or blockade of alpha-adrenergic receptors with phentolamine (10(-6) M). In a second series of experiments the muscarinic receptor blocking properties of bretylium were determined. Acetylcholine produced a concentration-dependent shortening of action potential duration in paced (200 ms) left atrial muscle strips. This well-recognized muscarinic effect was unaltered in the presence of bretylium (10(-6) M - 10(-3) M). These data indicate that bretylium tosylate physiologically exerts direct effects on the atrial myocardium to prolong action potential duration. This compound does not appear to physiologically antagonize the effects of acetylcholine and therefore its reported atrial antiarrhythmic properties cannot be explained by muscarinic receptor blockade.

The serial electrophysiologic effects of bretylium were studied in 10 patients undergoing cardiac catheterization before giving the drug, at the end of bretylium tosylate-loading infusion (5 mg/kg/15 min), and after 1 h of intravenous drug maintenance (1.5 mg/min). Mean blood pressure increased during drug loading from 93.6 +/- 10.9 mm Hg to 121.1 +/- 16.2 mm Hg (p less than 0.01, t = 15 min) but returned toward control (100.9 +/- 18.7 mm Hg, p = NS) during drug maintenance (t = 75 min). Small changes in PR, QRS, QTc, AH, and HV intervals during spontaneous and paced rhythms were not significant. Comparison of the control electrophysiologic study with early and late postdrug studies showed no significant changes in corrected sinus node recovery times and in Wenckebach cycle lengths, but small decreases in refractory periods occurred. After drug loading, decreases in mean effective refractory periods of atrium, AV node, and right ventricle of 12, 2, and 16 ms, respectively, occurred (p = NS); during drug maintenance (t = 75 min), these refractory periods had decreased with respect to control by 21, 36, and 13 ms, respectively (p less than 0.05, 0.05, and 0.01). Functional refractory period of the AV node decreased at 75 min by 31 ms (p less than 0.01). The observed shortening of refractory periods contrasts with the direct effects of bretylium in isolated ventricular muscle and Purkinje fibers, which consist of prolongation of effective refractory periods and action potential duration. Thus, indirect (adrenergic) effects may be more important to overall clinical electrophysiologic actions not only acutely during loading but also during at least the first 60-90 min of maintenance therapy, which spans the expected time of initial clinical antifibrillatory response.

The antiarrhythmic drug bretylium tosylate competitively inhibits acetylcholinesterase activity. The Ki values for the inhibition of the purified enzyme (from electric eel), and acetylcholinesterase activity of crude rat ventricular and cortical homogenates were 6 X 10(-5), 3 X 10(-5), and 8 X 10(-5) M respectively. These values are close to the concentrations of the drug known to induce norepinephrine release from cardiac adrenergic presynaptic vesicles. It is suggested that inhibition of acetylcholinesterase activity by bretylium induces norepinephrine release through the effect of accumulated acetylcholine on nicotinic receptors in adrenergic nerve terminals.

Local mechanisms that regulate transmitter release at autonomic neuroeffector junctions may be classified into four main types: (a) Automodulation, involving a feedback effect of the transmitter on receptors associated with the prejunctional terminals resulting in a restraint on the facilitation of release that occurs when a train of nerve impulses invades the terminals. Changes in the composition of the transmitter, such as the presence of adrenaline as a cotransmitter together with noradrenaline, can result in increased facilitation of transmission. (b) Transneuronal modulation involving an effect of the transmitter released from terminals of one type on adjacent terminals of another type; thus, noradrenaline release may be inhibited by acetylcholine released from cholinergic nerve terminals adjacent to the noradrenergic terminals. (c) Transjunctional modulation involving a feedback effect on the prejunctional nerve terminals of one or more factors released from effector cells. Such substances include adenyl compounds (adenosine and/or ATP) and metabolites of arachidonic acid. (d) Hormonal modulation involving the action of blood-borne hormones or locally generated hormone-like substances on prejunctional terminals. Some of the substances involved in modulation may act in more than one way; thus, opioids may function as cotransmitters or as hormones, and adenyl compounds may be cotransmitters or be released from effector cells. The effects of exogenous drugs on the substances involved in the modulation of transmission and on the prejunctional receptors for these substances account for many anomalous actions of drugs used or proposed for use in therapeutics.

The interaction of the antifibrillatory antiarrhythmic drug, bretylium tosylate, with the muscarinic receptor in tissue homogenates from regions of rat brain and heart was investigated. Competition-binding experiments were carried out with the highly specific tritiated antagonist N-methyl-4-piperidyl benzilate. Bretylium tosylate competitively displaced the labeled antagonist from the muscarinic receptor. The binding of the drug to the two brain preparations was found to be best fitted by a one-site model in each case. On the other hand, in the case of both heart preparations, a two-site model yielded a significantly better fit for the binding data than that given by a single-site model. The low affinity-binding constants in the atrium and the ventricle were similar (approximately 10 microM) to those in the brain regions examined, namely, the cortex and the medullapons. Sites with relatively higher affinity for the drug were detected in the heart only, with equilibrium-binding constants of 0.24 +/- 0.12 microM and 0.97 +/- 0.27 microM for the atrium and the ventricle, respectively. The drug also exerted anti-acetylcholine activity (K1 = 14 +/- 2 microM) measured physiologically in the guinea pig atrium, which correlated well with the concentration of the drug observed to be efficacious clinically (approximately 10 microM).

The electrophysiologic and antiarrhythmic actions of bretylium tosylate were studied after acute coronary artery occlusion and reperfusion in pentobarbital-anesthetized dogs. Three groups of animals were studied: Group I (n = 8) served as saline controls, Group II (n = 7) received bretylium tosylate (10 mg/kg i.v.) 60 min prior to coronary artery occlusion, and Group III (n = 5) received bretylium tosylate (30 mg/kg i.v.) in three divided doses over the 24 h prior to coronary artery occlusion. In Groups II and III the effective refractory period of the nonischemic myocardium was not altered by bretylium before or during the occlusion period, nor was it influenced by bretylium during the subsequent reperfusion period. In Group I the effective refractory period of the ischemic myocardium decreased 24 +/- 3.0% after coronary occlusion and increased 12 +/- 3% above the preocclusion level on reperfusion. In Group II the effective refractory period of the ischemic myocardium decreased 28 +/- 3.2% after coronary occlusion but did not overshoot preischemic levels on reperfusion. In Group III the effective refractory period decreased 15 +/- 3.8% following coronary occlusion and did not overshoot preocclusion levels during reperfusion. The ventricular activation times of the normal and ischemic myocardium were not affected by bretylium tosylate during occlusion or reperfusion in Group II or III. Significant reperfusion arrhythmias were observed only in Groups I and II. These data suggest that bretylium tosylate exerts its antiarrhythmic actions in ischemic myocardium by reducing the dispersion of cardiac refractoriness produced by coronary artery occlusion and, consequently, abolishing the abrupt change in cardiac refractoriness that follows coronary artery reperfusion. These antiarrhythmic actions of bretylium are pronounced in the chronically treated group, suggesting an electrophysiologic basis of the delayed antiarrhythmic actions of bretylium.

The effects of selected drugs on the sustained atrial flutter induced in conscious dogs with surgically produced right atrial enlargement (TI dogs) were evaluated. This was done to better understand the electrophysiologic mechanism of the tachyarrhythmias. Agents known to cause a slowing of atrioventricular (AV) nodal conduction--verapamil, methacholine, and phenylephrine--did not significantly decrease the rate of the induced flutter, whereas beta-adrenergic stimulation with an infusion of isoproterenol increased the rate of the flutter in all trials. Propranolol and atropine had little effect on the atrial flutter rate. Agents known to increase atrial refractoriness, such as procainamide, n-acetylprocainamide, bretylium, and clofilium, all increased the cycle length of the induced flutter and, in some cases, terminated the arrhythmia. These results suggest then that the perpetuation of the sustained atrial flutter in the conscious TI dog is not due to a delayed afterdepolarization mechanism but is more likely due to reentrant excitation. Furthermore, it is unlikely that the flutter is due to reentry over a pathway involving the AV node; rather, the arrhythmia seems to be caused by reentrant excitation of the leading circle type.

The effect of bretylium on the response of an isolated muscle (guinea pig lumbrical) to direct and indirect stimulation was examined. An initial increase in twitch response to both indirect and direct stimulation was followed at higher concentrations of bretylium by block of the indirect response only. The ED50 for this latter effect was 106.9 +/- 9.25 microM. However, in the presence of subthreshold levels of d-tubocurarine the ED50 was markedly reduced to 1.31 +/- 1.11 microM, a concentration that could occur during clinical use of bretylium. Thus, the physician is cautioned to consider the possibility that neuromuscular block may be produced when bretylium is administered in close temporal proximity to neuromuscular blocking agents.

The MRL/1 and New Zealand black-New Zealand white cross (NZB x W) mice spontaneously develop a disease similar to systemic lupus erythematosus in man. The effect of antihypertensive treatment on MRL/1 and NZB x W mice was studied with respect to survival, blood pressure, proteinuria, haematuria and renal histopathology. The treatment consisted of angiotensin converting enzyme (ACE) inhibitors (captopril and enalapril) and bretylium, a sympathetic blocker. Tail systolic blood pressure was measured with a strain gauge technique. All antihypertensive drugs caused a reduction in blood pressure in both strains. In MRL/1 bretylium and both ACE inhibitors improved renal histopathology, but only captopril prolonged survival, and it decreased proteinuria and haematuria. In NZB x W captopril decreased proteinuria but did not influence survival or renal histopathology. Bretylium was without any effect on these parameters. At the doses used captopril improves survival in MRL/1 mice and decreases proteinuria and haematuria in both MRL/1 and NZB x W mice. Since bretylium and enalapril lack this property despite a similar blood pressure reduction, it seems to be a drug-specific action.

This study determined whether the protective action of bretylium against ouabain-induced ventricular arrhythmia in the cat is related to an action of bretylium on the adrenergic nerve terminal. Bretylium pretreatment (20 mg/kg, i.v.) administered 2 h prior to ouabain (2 micrograms/kg/min, i.v. until death) increased the dose of ouabain to produce premature ventricular contraction, ventricular tachycardia, and death from 77.2 +/- 5.2 to 107.7 +/- 6.7 micrograms/kg; from 84.9 +/- 5.2 to 113.9 +/- 7.1 micrograms/kg; and from 108.8 +/- 4.0 to 146.7 +/- 5.7 micrograms/kg, respectively (p less than 0.05). Surgical denervation 2 weeks prior to the experiment or 6-hydroxydopamine (6OH dopamine), 20 mg/kg, i.v., administered 3 or 14 days prior to the ouabain infusion did not protect against the arrhythmogenic effects of ouabain. When bretylium was administered to cats pretreated with 6OH dopamine 3 days prior to the ouabain infusion or to surgically denervated cats, the protective action against ouabain-induced arrhythmia did not develop. Since 6OH dopamine and surgical denervation prevented the action of bretylium on ouabain-induced ventricular arrhythmia, it appears that bretylium is acting on the adrenergic nerve terminal. Thus, agents like bretylium that act on the adrenergic nerve terminal, leaving it structurally intact but not functional, are effective against ouabain-induced ventricular arrhythmia while procedures which cause the degeneration of the adrenergic nerve terminal, such as 6OH dopamine and surgical denervation, are not. These observations indicate that for the protective effect of sympathectomy against ouabain-induced arrhythmia to develop, the adrenergic nerve terminal must be present, although not functional as far as adrenergic neurotransmission is concerned. Changes in the heart rate or blood pressure did not appear to be a factor in the protective effect of bretylium.

Contractile responses of rabbit aortic strips to transmural stimulation and to exogenously applied norepinephrine (NE), potassium chloride (KCl), and histamine were studied in the presence of lidocaine or its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). Lidocaine, 10(-4) and 5 x 10(-4) M, attenuated the contractile response to transmural stimulation, whereas MEGX, 2 x 10(-5) and 10(-4) M, potentiated, but 10(-4) M, potentiated the response to transmural stimulation. The suppression induced by lidocaine and MEGX was not reversed by excess calcium, 2.2 and 4.4 mM, but was partially reversed by cocaine, 3 x 10(-6) M. Lidoncaine, 5 x 10(-4) M, and MEGX, 2 x 10(-3) M, shifted the dose-response curve of NE to the right, whereas GX, 5 x 10(-4) M, shifted the curve to the left. The maximum tension developed by K+ was attenuated by lidocaine, 5 x 10(-4) M, MEGX, 5 x 10(-4) and 2 x 10(-3) M, and GX, 2 x 10(-3) M. It may be concluded that lidocaine attenuates the response to stimulation of sympathetic nerves innervating the arterial wall by interfering with the release of NE. In contrast, the metabolites, MEGX and GX, potentiate the response, possibly by increasing the release of NE. MEGX in high concentrations appears to have the same mechanism of inhibitory action as does lidocaine.

Sympathetic vasoconstriction not mediated by alpha-adrenoceptors has been identified in vitro and in animals but not in humans. We evaluated the effect of alpha-adrenoceptor blockade on either endogenous vascular sympathetic activation (obtained through the application of a nonhypotensive lower-body negative pressure, -10 mm Hg for 5 minutes) or selective postsynaptic alpha-adrenoceptor stimulation by exogenous norepinephrine (0.005 micrograms/100 ml forearm tissue/min for 3 minutes) in the presence of beta-blockade by propranolol (10 micrograms/100 ml forearm tissue/min for 15 minutes). Drugs were infused into the brachial artery at systemically ineffective rates while continuously monitoring forearm blood flow (by venous plethysmography), intra-arterial mean arterial pressure, and heart rate in patients with essential hypertension. The irreversible antagonist phenoxybenzamine was used at a rate of 20 micrograms/100 ml forearm tissue/min for 1 hour, which antagonized the local responses to norepinephrine in a range of 0.005-0.05 micrograms/100 ml forearm tissue/min. During saline administration, either lower-body negative pressure or exogenous norepinephrine decreased forearm blood flow comparably. However, after phenoxybenzamine administration, forearm vasoconstriction to norepinephrine was abolished while a residual response to lower-body negative pressure remained in each patient. To exclude insufficient alpha-adrenoceptor blockade, the same experimental protocol was repeated by doubling phenoxybenzamine concentrations. No difference from the data obtained with the lower level of antagonist was found. Further studies were performed to confirm the sympathetic origin of the residual vasoconstriction. Bretylium tosylate, a neurotransmitter blocker, infused into the brachial artery (50 micrograms/100 ml forearm tissue/min for 90 minutes) abolished the effect of endogenous sympathetic activation but did not alter the effect of exogenous norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)