Cardiac Sympathetic Neural Discharge Research Articles

The effects of intrinsic nitric oxide on cardiac neural regulation in cats.

In this study, we aimed to elucidate the effects of intrinsic nitric oxide (NO) on cardiac neural regulation. Twenty-two cats were anesthetized with 1.5% isoflurane and allocated to Group I (intact; n = 7), Group D (denervated baroreceptors and vagi; n = 8), or Group B (autonomic blockade with i.v. hexamethonium, propranolol, and atropine; n = 7). Cardiac sympathetic nerve activity (CSNA), mean arterial pressure (MAP), sinus heart rate (HR), and A-H and H-V intervals during pacing (150 bpm) were measured before and after i.v. administration of a NO synthase inhibitor, NG-nitro-L-arginine (L-NNA, 30 mg/kg) and after reversal with an excessive dose of L-arginine (300 mg/kg), before and during intermittent electrical stimulation of the posterior hypothalamus. L-NNA significantly increased MAP in Groups I and B, but not in Group D. L-NNA significantly decreased HR and lengthened A-H in Group I, but not in other groups. L-arginine further decreased HR and lengthened A-H unexpectedly. The reasons for these findings could not be determined in this study. L-NNA did not change CSNA. Hypothalamic stimulation did not potentiate L-NNA-induced changes in CSNA, hemodynamic variables, and atrioventricular conduction. In conclusion, intrinsic NO may modulate atrioventricular conduction and sinus rate through a vagal cholinergic, rather than a nonautonomic mechanism. Elucidating the roles of intrinsic nitric oxide (NO) on cardiac neural regulation is important. In intact, vagotomized, and baroreceptor-denervated or pharmacologically autonomic blockaded cats, an NO synthesis inhibitor was administered, and atrioventricular conduction and cardiac sympathetic neural discharge were measured. The results suggest a vagal cholinergic mechanism of intrinsic NO.

The Effects of Intrinsic Nitric Oxide on Cardiac Neural Regulation in Cats

In this study, we aimed to elucidate the effects of intrinsic nitric oxide (NO) on cardiac neural regulation.Twenty-two cats were anesthetized with 1.5% isoflurane and allocated to Group I (intact; n = 7), Group D (denervated baroreceptors and vagi; n = 8), or Group B (autonomic blockade with IV hexamethonium, propranolol, and atropine; n = 7). Cardiac sympathetic nerve activity (CSNA), mean arterial pressure (MAP), sinus heart rate (HR), and A-H and H-V intervals during pacing (150 bpm) were measured before and after IV administration of a NO synthase inhibitor, NG-nitro-L-arginine (L-NNA, 30 mg/kg) and after reversal with an excessive dose of L-arginine (300 mg/kg), before and during intermittent electrical stimulation of the posterior hypothalamus. L-NNA significantly increased MAP in Groups I and B, but not in Group D. L-NNA significantly decreased HR and lengthened A-H in Group I, but not in other groups. L-arginine further decreased HR and lengthened A-H unexpectedly. The reasons for these findings could not be determined in this study. L-NNA did not change CSNA. Hypothalamic stimulation did not potentiate L-NNA-induced changes in CSNA, hemodynamic variables, and atrioventricular conduction. In conclusion, intrinsic NO may modulate atrioventricular conduction and sinus rate through a vagal cholinergic, rather than a nonautonomic mechanism. Implications: Elucidating the roles of intrinsic nitric oxide (NO) on cardiac neural regulation is important. In intact, vagotomized, and baroreceptor-denervated or pharmacologically autonomic blockaded cats, an NO synthesis inhibitor was administered, and atrioventricular conduction and cardiac sympathetic neural discharge were measured. The results suggest a vagal cholinergic mechanism of intrinsic NO. (Anesth Analg 1998;86:1194-1200)

The Effect of Dilevalol on Cardiac Autonomic Neural Discharge, Plasma Catecholamines, and Myocardial Beta Receptor Density Associated with Coronary Occlusion

Cats anesthetized with alpha chloralose received saline or dilevalol (1 mg/kg, IV) during a 10-minute infusion. Fifteen minutes later, the left anterior descending coronary artery was subjected to coronary occlusion 2 mm below its origin. Regional differences in the beta receptor densities were found for the atria and ventricles and for the areas within the left ventricle in cats with no coronary occlusion and dilevalol or saline. The variation in beta receptor density distribution may be related to functional differences. Coronary occlusion and saline or dilevalol did not modify the myocardial beta receptor density regional distribution. Mean times to arrhythmia and death in five saline cats were 5.8 +/- 3.6 (N = 3) and 5.4 (N = 2) minutes; three cats were killed 6 hours after coronary occlusion. In five dilevalol cats the times to arrhythmia and death were 2.2 +/- 0.8 (N = 5) and 75.9 +/- 70.7 (N = 4); 1 cat was killed. Dilevalol induced a significant decrease in blood pressure and heart rate prior to coronary occlusion. Coronary occlusion decreased blood pressure and heart rate in both groups. Twenty-five minutes after dilevalol but prior to coronary occlusion, postganglionic cardiac sympathetic neural discharge decreased to 81%. In the minutes prior to arrhythmia, postganglionic cardiac sympathetic neural discharge was 95% and was significantly increased to 121% 3 minutes after coronary occlusion. The postganglionic cardiac sympathetic neural discharge values after coronary occlusion were similar to those in the saline cats. Dilevalol depressed postganglionic cardiac sympathetic neural discharge prior to coronary occlusion but did not prevent the nonuniform (i.e., increases, decreases, or no change) discharge in the postganglionic cardiac sympathetic neural discharge associated with coronary occlusion-induced arrhythmia. Norepinephrine and epinephrine values in saline cats increased the first 5 minutes after coronary occlusion; this increase was associated with arrhythmia. Norepinephrine and epinephrine values from minute 15 to minute 360 did not differ from control. Dilevalol prevented the increase in norepinephrine and epinephrine levels associated with arrhythmia and death.

The effect of chronic timolol in an animal model for myocardial infarction.

The effect of no drug or timolol (5 mg/kg, PO, for 1, 2, or 8 weeks on postganglionic cardiac sympathetic neural discharge, blood pressure, heart rate and beta-receptor density after acute coronary occlusion of the left anterior descending artery was compared. Beta-receptor density, determined by binding of 3H-dihydroalprenolol, was examined in the myocardium (LA = left atrium, RA = right atrium, LV1 = proximal and LV2 = distal left anterior descending artery distribution, LV3 = posterior left ventricle, S = septum, and RV = right ventricle). In control cats (no coronary occlusion or timolol) beta-receptor density of LV2 and LV3 was greater (P less than .05) than LA, RA, LV1, and RV. LV3 was greater (P less than .05) than S and RA, and LA was less than S. Longer treatment with timolol increased beta-receptor density. When compared with no timolol, beta-receptor density was greater in RA after 8 weeks and in LV1 after 2 weeks and not different in LV2 and S. Beta-receptor density and LV3 and RV were greater after 8 weeks than after 1 week or no timolol. Spearman rank correlation coefficients between dose and beta-receptor density revealed an increase (P less than .05) for all heart areas. Heart rate did not vary before timolol and was decreased after all doses of timolol. Timolol increased the mean times to coronary occlusion-induced death although the increase was not statistically significant. Timolol did not prevent postganglionic cardiac sympathetic neural discharge associated with arrhythmia. Timolol may increase beta-receptor density and decrease synaptic norepinephrine, causing a decreased release per cardiac sympathetic nerve impulse. Alternatively, molecules of timolol may accumulate in nerve endings and be released in greater concentrations at the receptors. This could explain the protection against coronary occlusion-induced arrhythmia and death.

Digitalis glycosides: a discussion of the similarities and differences in actions and existing controversies.

The writing of this review was initiated to answer the question of whether differences in the actions of the various digitalis glycosides exist and to discuss current controversies in the research area of the digitalis glycosides. Data obtained in our laboratory indicated that the effect of digoxin on postganglionic cardiac sympathetic neural discharge in the minute prior to the occurrence of arrhythmia differed from that of ouabain. This raised the question of whether data published in other laboratories would support the contention that differences in glycosides do exist. To answer this question, a review of the literature was begun. Our survey of these studies are cited in the tables of this review. These tables summarize the actions of glycosides in vivo and in vitro in different animal models. The reader should bear in mind that the data included within the tables do not represent an inclusive summary of all studies in the literature. For detailed review articles, the reader is referred to the following references: Gillis et al; Gillis and Quest; Roberts et al; Lathers and Roberts; Farah and Alousi; Benthe; Levitt et al; Smith and Haber; Somberg; Lee and Klaus; Mason; Schwartz. Furthermore the summary of the results for each particular study cited in the table may not, in all cases, include each finding of the published data. Nevertheless, the tables do provide a summary of data obtained in various species with different glycosides in several different areas of research, and as such, represent an abridged compendium for the research working in the field of digitalis glycosides. This review has been organized firstly to consider glycoside-induced alterations in the autonomic nervous system and, secondly, to examine their direct actions on the heart.

Synchronization of cardiac autonomic neural discharge with epileptogenic activity: the lockstep phenomenon

Autonomic dysfunction has been implicated in the sudden, unexplained deaths which account for 5–17% of mortality in persons with epilepsy. This study was designed to determine if epileptogenic activity is associated with changes in the pattern of autonomic cardiac neural discharge and the development of arrhythmias. Nine cats, anesthetized with alpha-chloralose, received pentylenetetrazol (PTZ) 10, 20, 50, 100, 200 and 2000 mg/kg, i.v. at 10 min intervals. Cardiac postganglionic sympathetic and vagal nerve discharges were correlated with the interictal spikes, brief ictal discharges (bilateral polyspikes < 10 sec duration), and prolonged ictal discharges (polyspikes lasting > 10 sec). Cardiac sympathetic and vagal neural discharges were intermittently synchronized 1 : 1 with all 3 types of epileptogenic discharge, i.e., the lockstep phenomenon (LSP); at other times the relationship was almost 1 : 1. LSP was not present during control and did not always persist for the entire interval after each PTZ dose. Five of 8 cats showed LSP in the cardiac sympathetic neural discharge associated with the interictal spikes induced by 10 mg/kg PTZ; 3 others exhibited LSP with interictal spikes seen subsequent to ictal discharges. The incidence of LSP was less often associated with cardiac vagal neural discharge (2 of 7 cats). Premature ventricular contractions were sometimes associated with LSP. Abnormal cardiac sympathetic and vagal neural discharge and cardiac arrhythmias were thus associated with subconvulsant (interictal) activity. Therefore, the LSP may be a factor in the mechanism of unexplained death in persons with epilepsy who exhibited no overt seizure activity at the time of demise.

The effect of beta blockers on cardiac neural discharge associated with coronary occlusion in the cat.

The effect of timolol on postganglionic cardiac sympathetic neural discharge, blood pressure, heart rate, and rhythm changes associated with acute coronary occlusion of the left anterior descending artery was examined and compared with the effects of the beta blockers practolol and metoprolol. Timolol (5 mg/kg, IV) was infused 15 minutes prior to coronary occlusion in cats anesthetized with alpha-chloralose. Control heart rate fell from 129 +/- 10 to 106 +/- 2 one minute prior to coronary occlusion and remained at 106 +/- 2 beats/minute in the minute prior to arrhythmia. Control blood pressure fell from 126 +/- 20 to 91 +/- 19 and stabilized at 99 +/- 19 mm Hg one minute prior to coronary occlusion. Mean time to arrhythmia and death was 4.7 +/- 2.3 and 68.0 +/- 51.0 minutes (P greater than .05 vs no drug), respectively. Three cats died and two were sacrificed six hours after coronary occlusion. Blood pressure fell to 86 +/- 20 mm Hg two minutes after coronary occlusion, rose to 95 +/- 23 mm Hg at ten minutes, and remained there for ten minutes. Timolol did not alter postganglionic cardiac sympathetic neural discharge prior to coronary occlusion. Two minutes after coronary occlusion, mean postganglionic cardiac sympathetic neural discharge was 128 +/- 27 and increased to 139 +/- 36 impulses/second (% control) 4 minutes after coronary occlusion. A similar trend was found for the data recorded in 15 nerves (eight cats) in which coronary occlusion was initiated without timolol. The data suggest that a difference exists among beta blockers because prior to coronary occlusion, the cardioselective drugs metoprolol (1, 5, and 10 mg/kg, IV) and practolol (8 mg/kg, IV) depressed postganglionic cardiac sympathetic neural discharge whereas noncardioselective timolol did not. Because all three beta blockers increased the times to arrhythmia and death (although the increase was significant only after metoprolol and practolol), the acute protective mechanism does not appear to be due primarily to a depression of spontaneous sympathetic neural discharge.

The effect of acute and chronic administration of timolol on cardiac sympathetic neural discharge, arrhythmia, and beta adrenergic receptor density associated with coronary occlusion in the cat

The effect of timolol (5 mg/kg, p.o., b.i.d. 7 or 14 days) on cardiac beta adrenergic receptor density, the times to arrhythmia (AR) and death (D), heart rate, mean arterial blood pressure, and postganglionic cardiac sympathetic neural discharge after acute coronary occlusion in cats was examined. In the control animals, receptor densities in the left and right atria did not differ, but were lower than the right ventricle. Left ventricle and septum receptor densities were higher, with the left ventricle the highest. The importance of the gradation of beta receptors with increasing density from base to apex appears to be its relation to cardiac contractile function. Occlusion in cats not treated with timolol did not alter the cardiac beta receptor densities. After timolol for 7 or 14 days, no occlusion, receptor density increased in left ventricle and septum although the increase was only significant after 14 days. A comparison of the beta adrenergic receptor densities in cats pretreated with timolol for 7 or 14 days with or without occlusion revealed that, in general, a decrease (p>0.05) occurred for the occlusion group. Timolol decreased heart rate and blood pressure prior to occlusion. The mean times to AR and D were not significantly increased by either dosing regimen of timolol, although the trend was for an increase in the time to D after 7 days of timolol and an increase in the time to AR and D after 14 days of timolol. When compared with data obtained in saline cats, chronic timolol produced minimal changes in postganglionic cardiac sympathetic neural discharge. Timolol given chronically (p.o.) or acutely (5 mg/kg, i.v. given 15 min prior to occlusion) also did not prevent the cardiac sympathetic discharge associated with the development of AR. The time to AR and D in the acutely treated cats was increased but not significantly. Since cardiac sympathetic neural discharge increased as blood pressure fell in the control period but did not increase after occlusion in the timolol treated animals, the combination of timolol and occlusion may have modified neural discharge via an action on the baro-receptor mechanism. That chronic administration of timolol produces an effect not present in cats in which only occlusion was done is supported by the observation that chronic treatment produced an occlusion-induced decrease in beta adrenergic receptor density. Since pretreatment with timolol for 7 or 14 days did not increase the time to occlusion-induced AR and D, the data suggest that the clinical protective effect reported for timolol after myocardial infarction seems to be due to a factor or factors other than an action on the autonomic cardiac sympathetic neural discharge or on cardiac beta receptor density.

Are the sympathetic neural effects of digoxin and quinidine involved in their action on cardiac rhythm?

This study was initiated to determine if ventricular arrhythmia induced by digoxin was associated with a nonuniform neural discharge in the cardiac sympathetic postganglionic fibers. In addition, splanchnic neural discharge was monitored to explore the role of adrenal medullary catecholamines in digoxin-induced arrhythmia. Experiments were performed to ascertain whether the antiarrhythmic effects of quinidine in digoxin-induced arrhythmias were related to an action on cardiac sympathetic neural discharge induced by digoxin. All cats were anesthetized with alpha-chloralose and given atropine; some were pretreated with quinidine (10 or 20 mg/kg i.v. 15 min before digoxin). Digoxin was given every 15 min until death; the first three doses were 50 micrograms/kg i.v., and all subsequent doses were 25 micrograms/kg. The mean +/- SE time to arrhythmia was 32 +/- 4 min (n = 16) and was significantly increased only after 20 mg/kg quinidine (64 +/- 7 min; p less than 0.001). Mean +/- SE time to death was also increased from 74 +/- 4 to 98 +/- 7 min (p less than 0.001). Postganglionic cardiac sympathetic neural discharge before digoxin-induced arrhythmia was depressed. Of the 28 nerves monitored in 16 animals receiving digoxin, in the minute before development of arrhythmia, 22 nerves were depressed, 3 were increased, and 3 showed no change when compared with the predigoxin control. Following this depression of neural discharge, arrhythmia developed, and the neural discharge began to rise, eventually increasing above control levels. During this time the variability of the neural discharge increased greatly, as evidenced by large SE values, so that the mean values were not significantly different from control levels. Splanchnic neural discharge (n = 9) progressively decreased, reaching 66% of control values after the third injection of digoxin; the discharge then began to increase gradually toward control levels in the next 10 min and arrhythmia developed. The data indicate that the arrhythmias caused by digoxin are not associated with the development of nonuniform discharge patterns in the cardiac sympathetic nerves. Furthermore, action on the splanchnic nerve discharge is not involved in the arrhythmogenic effects of digoxin. Pretreatment with quinidine, 20 mg/kg, decreased both splanchnic and post-ganglionic cardiac sympathetic neural discharge, arterial blood pressure, and heart rate. Although quinidine, 20 mg/kg, increased the time to arrhythmia induced by digoxin, the depression of postganglionic cardiac or splanchnic neural discharge did not seem to be a major component of the antiarrhythmic effect of quinidine.

Effect of phenobarbital pretreatment on cardiac neural discharge and pentylenetetrazol-induced epileptogenic activity in the cat.

The effect of phenobarbital on autonomic function associated with ictal discharges and interictal spikes (IS) was examined. Phenobarbital (20 mg/kg, i.v.) was infused over 10 min; 1 h later, pentylenetetrazol (PTZ) 10, 20, 50, 100, 200, and 2,000 mg/kg was given intravenously at 10-min intervals. 10 mg/kg PTZ produced IS in only 3 of 9 phenobarbital-pretreated cats; when used alone, 10 mg/kg of PTZ produced IS in 8 of 9 cats. Ictal discharges first appeared at 20 mg/kg PTZ in 6 of 9 phenobarbital-pretreated cats; all 9 cats receiving only PTZ exhibited ictal discharges after 20 mg/kg. Phenobarbital pretreatment depressed heart rate, blood pressure and postganglionic cardiac sympathetic neural discharge. Maximal ictal discharges in the cats pretreated with phenobarbital occurred with 100 mg/kg PTZ. This discharge was associated with a 10 mm Hg increase in blood pressure and a slight decrease in heart rate, followed by a subsequent return to baseline. The concurrent sympathetic neural discharge increased. When maximal ictal discharges occurred in the cats receiving PTZ alone, blood pressure, heart rate, and sympathetic neural discharge increased significantly. Cardiac vagal neural discharge was not altered after PTZ even in phenobarbital-pretreated cats. Although phenobarbital suppressed PTZ-induced epileptogenic activity and the associated changes in blood pressure and heart rate, a X2 test indicated no significant difference in the incidence of arrhythmias between the two groups. Since phenobarbital did not prevent the changes in cardiac neural discharge and the arrhythmias associated with epileptogenic activity, its effectiveness in decreasing autonomic dysfunction is questionable.

Neural mechanisms in cardiac arrhythmias associated with epileptogenic activity: The effect of phenobarbital in the cat

Sudden unexplained death accounts for 5–17% of mortality in epileptic persons; autonomic dysfunction is thought to be a contributing factor. This paper describes the effect of phenobarbital (PB) pretreatment (20 mg/kg, i.v.) one hour prior to pentylenetetrazol (PTZ) 10, 20, 50, 100, 200, and 2000 mg/kg, i.v. given at ten minute intervals on autonomic parameters in the cat. PB depressed heart rate, blood pressure, and postganglionic cardiac sympathetic neural discharge, but did not significantly alter vagal discharge. PB shifted the peak duration of interictal activity from a lower to a higher dose of PTZ without affecting the average duration across doses. PB also significantly diminished the increases in heart rate and blood pressure induced by PTZ but altered neither the occurrence of arrhytmias nor the changes in cardiac autonomic neural discharge. Thus, PB appears to prevent only some forms of autonomic dysfunction associated with epileptogenic activity in this model.

Relationship between sympathetic neural activity, coronary dynamics, and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion

The relationship between neural sympathetic discharge and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion was studied in 26 chloralose-anesthetized dogs. Preganglionic cardiac sympathetic impulse activity and ventricular fibrillation thresholds were separately determined before and during a 10-minute period of left anterior descending coronary artery occlusion and during release-reperfusion. Within 2 minutes of occlusion the ventricular fibrillation threshold was significantly decreased (from 25 ± 1.3 to 16 ± 2.3 mA, p < 0.05) corresponding with the period of maximal activation of cardiac sympathetic preganglionic fibers (from 4.4 ± 0.2 to 6.3 ± 0.5 impulses/sec). Coronary sinus blood flow and oxygen tension decreased significantly. All these changes persisted for 5 to 6 minutes, thereafter returning to control levels despite continued obstruction of the coronary artery. A transient but significant reduction in ventricular fibrillation threshold also occurred with release of the occlusion but was unaccompanied by increases in sympathetic neural discharge. Bilateral stellectomy completely prevented the ventricular fibrillation threshold changes observed during coronary artery occlusion. However, there was no change in coronary sinus oxygen tension or blood flow. During reperfusion, stellectomy increased rather than decreased vulnerability to ventricular fibrillation. Stellectomy augmented the reactive hyperemic response to release-reperfusion. These findings indicate that enhanced cardiac sympathetic neural activity contributes to ventricular vulnerability associated with coronary artery obstruction. An opposite action results during release-reperfusion. Cardiac sympathetic neural discharge, by reducing the magnitude of reactive hyperemic response through influence on coronary vascular tone, exerts an antifibrillatory effect.

Failure of methylprednisolone to prevent nonuniform cardiac accelerator nerve discharge associated with coronary occlusion-induced arrhythmia: Evidence against prostaglandin modulation of autonomic cardioaccelerator neural discharge in the anesthetized cat

Postganglionic cardiac sympathetic neural discharge in the minute prior to arrhythmia produced by acute occlusion of the left anterior descending coronary artery was nonuniform, i.e., both increases or decreases occurred. It is hypothesized that the nonuniform neural discharge is transmitted to the heart, causing nonuniform changes in excitability and conduction which produce ventricular arrhythmias. Prostaglandins have been shown to exhibit both arrhythmogenic as well as antiarrhythmic actions. Methylprednisolone (30 or 50 mg/kg, i.v., a known inhibitor of prostaglandin synthesis) was given 30 minutes prior to coronary occlusion of the left anterior descending artery. Both doses of methylprednisolone failed to: exert any effect on the mean postganglionic cardiac sympathetic nerve discharge prior to coronary occlusion; eliminate the nonuniform neural discharge associated with occlusion-induced arrhythmia; increase the time to arrhythmia or death; and decrease the number of cats dying after acute coronary occlusion. Thus, it is hypothesized that methylprednisolone failed to prevent the arrhythmogenic actions of prostaglandins. The failure of methylprednisolone to decrease the time to arrhythmia suggests that, in this study, an antiarrhythmic mechanism for prostaglandins does not exist. The failure of methylprednisolone to prevent the occlusion-induced nonuniform cardiac sympathetic discharge suggests that prostaglandin modulation of the autonomic balance on the heart is not due to a direct action on the postganglionic cardiac sympathetic nerve.

Autonomic Dysfunction in Epilepsy: Characterization of Autonomic Cardiac Neural Discharge Associated with Pentylenetetrazol‐Induced Epileptogenic Activity

The purpose of this study was to determine if epileptogenic activity is associated with changes in autonomic cardiac neural discharge and the development of arrhythmias. Nine cats, anesthetized with alpha-chloralose, received pentylenetetrazol (PTZ), 10, 20, 50, 100, 200, and 2,000 mg/kg, intravenously at 10 min intervals. The following were monitored: neural discharge from 1 to 3 postganglionic cardiac sympathetic branches (8 cats, 17 nerves) and the vagus (7 cats, 8 nerves); the electrocorticogram; blood pressure; heart rate; and lead II electrocardiogram. Autonomic dysfunction was manifested by: the observation that autonomic cardiac nerves did not always respond in a predictable manner to changes in blood pressure; the development of a marked increase in variability in mean autonomic cardiac sympathetic and parasympathetic neural discharge; and the fact that the very large increase in the variability of the discharge rate of parasympathetic nerves was seen after PTZ, 50 mg/kg, but did not develop until 100 mg/kg in sympathetic neural discharge. This autonomic imbalance was associated with both interictal and ictal epileptogenic activity. Almost invariably, interictal discharge occurred after PTZ, 10 mg/kg; with higher doses, the duration of ictal activity increased although interictal discharges were present. The altered cardiac autonomic neural discharge was associated with minimal epileptogenic activity in the form of interictal discharges and cardiac arrhythmias which may contribute to sudden unexplained death of the epileptic.

Effect of timolol on autonomic neural discharge associated with ouabain-induced arrhythmia

The purpose of this study was to determine the effect of the β-blocking agent timolol on postganglionic cardiac and preganglionic splanchnic sympathetic and vagal neural discharge, ouabain-induced arrhythmia, heart rate and mean arterial blood pressure. Cats were anesthetized with α-chloralose, given atropine, and pretreated with timolol (5 mg/kg, i.v. infused at a rate of 0.5 mg/kg/min for 10 min). Bolus injections of ouabain (25 μg/kg, i.v.) were given every 15 min until the animals died; the first injection was given 15 min after the end of the timolol infusion. When compared with cats (n = 13) receiving only ouabain, timolol (n = 11 cats) increased the time to ouabain-induced arrhythmia and death from 23 ± 3 to 48 ± 7 and 46 ± 3 to 76 ± 9 min, respectively (P < 0.05). Both heart rate and mean arterial blood pressure fell immediately after the onset of the timolol infusion. Eleven minutes later, the mean heart rate and blood pressure had decreased from 137 ± 3 to 104 ± 6 beats/min and 133 ± 6 to 103 ± 7 mm Hg, respectively (P < 0.05); ouabain did not reverse the decreases. Neural activity monitored from the vagus and from the postganglionic cardiac and preganglionic splanchnic sympathetic nerves was not significantly altered by the infusion of timolol. The administration of ouabain after timolol did not alter splanchnic nor vagal discharge. Most important was the observation that postganglionic cardiac sympathetic neural discharge exhibited both increases and decreases, i.e., a nonuniform neural discharge, at the time of ouabain-induced arrhythmia and that the ouabain-induced nonuniformity did not occur in the cats pretreated with timolol. Thus, the protective effect of timolol may be due, in part, to prevention of the nonuniform postganglionic cardiac sympathetic neural discharge and to the prevention of ouabain-induced increases in vagal discharge. The establishment of β-blockade and a direct negative inotropic action may also have contributed to the antiarrhythmic action of timolol.

Nonuniform cardiac sympathetic nerve discharge: mechanism for coronary occlusion and digitalis-induced arrhythmia.

This study examined nonuniform postganglionic cardiac sympathetic neural discharge as a possible mechanism involved in the production of coronary occlusion or ouabain-induced arrhythmias. After acute occlusion of the left anterior descending coronary artery in 12 cats, anesthetized with alpha-chloralose and pretreated with atropine, arrhythmia occurred within 3 min in eight animals; three of these died in ventricular fibrillation. In recordings from 15 nerves in the eight animals with arrhythmia, spontaneous discharge increased in nine nerves, decreased in five nerves, and showed no change in one nerve. This nonuniform neural discharge was associated with the development of arrhythmia after occlusion. In four of the cats, neural discharge did not change within the first 3 min after coronary artery occlusion and arrhythmia did not occur. Development of ouabain-induced arrhythmia was accompanied by a nonuniform pattern in the neural discharge (13 cats). This discharge may alter ventricular excitation and conduction to produce arrhythmia.