Spontaneous Sinus Cycle Length Research Articles

The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity

The purpose of this study is to test the role that parasympathetic postganglionic neurons could play on the adaptive electrophysiological changes produced by physical training on intrinsic myocardial automatism, conduction and refractoriness. Trained rabbits were submitted to a physical training protocol on treadmill during 6 weeks. The electrophysiological study was performed in an isolated heart preparation. The investigated myocardial properties were: (a) sinus automatism, (b) atrioventricular and ventriculoatrial conduction, (c) atrial, conduction system and ventricular refractoriness. The parameters to study the refractoriness were obtained by means of extrastimulus test at four different pacing cycle lengths (10% shorter than spontaneous sinus cycle length, 250, 200 and 150 ms) and (d) mean dominant frequency (DF) of the induced ventricular fibrillation (VF), using a spectral method. The electrophysiological protocol was performed before and during continuous atropine administration (1 μM), in order to block cholinergic receptors. Cholinergic receptor blockade did not modify either the increase in sinus cycle length, atrioventricular conduction and refractoriness (left ventricular and atrioventricular conduction system functional refractory periods) or the decrease of DF of VF. These findings reveal that the myocardial electrophysiological modifications produced by physical training are not mediated by intrinsic cardiac parasympathetic activity.

Rate Control in Atrial Fibrillation by Cooling: Effect of Temperature on Dromotropy in Perfused Rabbit Hearts

Background. Cooling has emerged as a therapeutic option in critically ill patients (especially after cardiac resuscitation) and might also have a negative dromotropic effect in atrial fibrillation. We sought to determine the impact of cooling on electrophysiologic properties of Langendorff-perfused rabbit hearts. Methods and Results. In 20 isolated Langendorff-perfused rabbit hearts, the temperature of the tissue bath was changed between 17 and 42°C. With decreasing temperature, significant increases of the spontaneous sinus cycle length, decreases of the mean ventricular heart rate during atrial fibrillation, and relevant increases of atrial and ventricular refractory periods were observed (ANOVA P < .01). Conclusions. Cardiac hypothermia leads to a significant drop of mean ventricular heart rate during atrial fibrillation. Negative chronotropy and dromotropy induced by moderate cardiac hypothermia might be a feasible therapeutic approach in patients with hemodynamically relevant tachyarrhythmias in a CCU/ICU setting.

Relationship between right cervical vagus nerve stimulation and atrial fibrillation inducibility: Therapeutic intensities do not increase arrhythmogenesis

Strong vagus nerve stimulation (VNS) is routinely used to induce and maintain atrial fibrillation (AF) in acute animal studies. Taken as a surrogate of increased vagal tone, such observations suggest an arrhythmogenic role of VNS in AF. In contrast, VNS has been demonstrated to have profound therapeutic effects in heart failure and other ailments. The purpose of this study was to examine the relationship between right cervical VNS and AF, especially the potential arrhythmogenic effects of therapeutic VNS. The relationship between VNS intensities and AF inducibility was studied in eight acute dogs at baseline and four different levels of VNS, which were set to prolong spontaneous sinus cycle length (SCL) by 20%, 40%, 60%, or 100%. The effect of mild VNS treatment on AF induction was further investigated in six chronically instrumented conscious dogs. These dogs were implanted with right cervical VNS stimulators and specialized atrial pacemakers. VNS intensity was titrated to slow the sinus rate by 10%. In acute studies, it was found that mild to moderate VNS (i.e., producing < or =40% SCL prolongation) did not increase AF inducibility, while strong VNS (i.e., producing > or =60% SCL prolongation) did. In chronic studies, compared with controls, AF induction did not change during the 4-week VNS treatment. AF inducibility by right cervical VNS is intensity dependent: strong VNS (producing > or =60% SCL prolongation) facilitates AF, while moderate VNS (producing < or =40% SCL prolongation) appears not to affect AF. The nonarrhythmogenic effect of therapeutic chronic VNS was further verified in conscious animals. We conclude that VNS with moderate intensities can be used to deliver therapeutic benefits without arrhythmogenic risk.

Achieving regular slow rhythm during atrial fibrillation without atrioventricular nodal ablation: Selective vagal stimulation plus ventricular pacing

The aim of this study was to achieve regular slow ventricular rhythm during atrial fibrillation (AF) without destroying the AV node (AVN). Recent experimental and clinical studies have demonstrated that selective AVN vagal stimulation (AVN-VS) can be used to slow ventricular rate during AF; however, an irregular rhythm remains. Alternatively, ventricular on-demand (VVI) pacing achieves rate regularization but at rates faster than the already fast intrinsic rate during AF. We hypothesized that AVN-VS combined with VVI pacing would achieve slow, regular rhythm during AF without requiring AVN ablation. AF was induced in eight dogs. AVN-VS was applied to the epicardial fat pad that projects vagal nerve fibers to the AVN. A computer-controlled algorithm adjusted AVN-VS intensity to achieve three levels of mean ventricular RR interval: 75%, 100%, or 125% of the spontaneous sinus cycle length. At each of the three levels, concomitant VVI pacing was delivered at a constant cycle length equal to the corresponding target. Hemodynamic measurements were performed during the study to elucidate the advantages of the proposed method. AF resulted in rapid, irregular ventricular rates (RR = 287 +/- 36 ms, or 56% of sinus cycle length). AVN-VS achieved average ventricular rate slowing to the three target levels in all dogs (RR increased to 381 +/- 41, 508 +/- 54, and 632 +/- 68 ms, respectively). At each of the three target rate levels, AVN-VS combined with VVI pacing fully eliminated rate irregularities. The regular slow ventricular rhythms during AF were associated with significant hemodynamic improvement. A novel approach combining AVN-VS with VVI pacing results in a regular, slow ventricular rhythm during AF that does not necessitate AVN ablation. Rate regularization achieved by this approach was associated with pronounced hemodynamic benefits during AF.

Effects of halothane and enflurane on ventricular conduction, refractoriness, and wavelength: a concentration-response study in isolated hearts.

Effects of halothane and enflurane on ventricular conduction, anisotropy, duration and dispersion of refractory periods, and wavelengths were studied, and putative antiarrhythmic or arrhythmogenic properties on ventricles were discussed. High-resolution epicardial mapping system was used to study the effects of 1, 3, and 5 vol% halothane and enflurane in 30 isolated rabbit hearts. Ten hearts were kept intact to study the effects on spontaneous sinus cycle length (RR interval), perfusion pressure, and the occurrence of spontaneous dysrhythmias. In 20 other hearts, a thin epicardial layer was obtained (frozen hearts) to study ventricular conduction velocity, ventricular effective refractory period (VERP in four sites) and wavelengths. Halothane induced a concentration-dependent lengthening of RR interval, whereas enflurane did not. Both agents slowed longitudinal and transverse ventricular conduction velocity with no anisotropic change. Ventricular effective refractory period was prolonged at 1 vol% and was shortened at higher concentrations, with no significant increase in dispersion. Ventricular longitudinal and transverse wavelengths decreased in a concentration-dependent manner. Although changes in wavelengths could express proarrhythmic effects of volatile anesthetics, no arrhythmia occurred in spontaneously beating hearts or in frozen hearts. The ventricular electrophysiologic effects of halothane and enflurane were slight, suggesting that both agents are unable per se to induce functional conduction block and therefore reentrant ventricular arrhythmias.

Effects of ketamine on ventricular conduction, refractoriness, and wavelength: potential antiarrhythmic effects: a high-resolution epicardial mapping in rabbit hearts.

The aims of the study were to verify the effects of ketamine on ventricular conduction velocity and on the ventricular effective refractory period, to determine its effects on anisotropy and on homogeneity of refractoriness, and to use wavelength to determine whether ketamine has antiarrhythmic or arrhythmogenic properties. A high-resolution epicardial mapping system was used to study the effects of 50, 100, 150, and 200 microM racemic ketamine in 15 isolated, Langendorff-perfused rabbit hearts. Five hearts were kept intact to study the effects of ketamine on spontaneous sinus cycle length (RR) interval and its putative arrhythmogenic effects. In 10 other hearts, a thin epicardial layer was obtained by an endocardial cryoprocedure (frozen hearts) to study ventricular conduction velocity, ventricular effective refractory periods (five sites), and ventricular wavelength. Ketamine induced a concentration-dependent lengthening of the RR interval. Ketamine slowed longitudinal and transverse ventricular conduction velocity with no anisotropic change, and it prolonged the ventricular effective refractory period with no significant increase in dispersion. Ventricular longitudinal and transverse wavelengths tend to increase, but this was not statistically significant. Finally, no arrhythmia could be induced regardless of the ketamine concentration. Ketamine slowed ventricular conduction and prolonged refractoriness without changing anisotropy or increasing dispersion of refractoriness. Although these effects should result in significant antiarrhythmic effects of ketamine, this should not be construed to suggest a protective effect in ischemic or other abnormal myocardium.

NO modulates autonomic effects on sinus discharge rate and AV nodal conduction in open-chest dogs.

The purpose of this study was to investigate the role of nitric oxide (NO) in mediating vagal and sympathetic modulation of spontaneous sinus cycle length (SCL) and atrioventricular (AV) nodal conduction time (A-H interval) in 62 open-chest mongrel dogs anesthetized with alpha-chloralose. Infusion of an NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA, 4 mg/ ml), into the sinus and AV nodal arteries attenuated significantly (P < 0.01) the negative chronotropic and dromotropic responses to vagal nerve stimulation (VS) and VS during ansae subclaviae stimulation (SS) or isoproterenol (Iso) infusion. Intravenous administration of L-arginine (100 mg/kg) reversed these responses toward control values, whereas D-arginine did not have a significant effect. L-NMMA significantly (P < 0.01) enhanced the effects of SS and Iso on SCL and A-H interval; L-arginine reversed these changes toward baseline. L-NMMA increased the minimum concentration of ACh needed to induce 50 or 100% prolongation of SCL or second-degree or complete AV block during concomitant Iso infusion. L-Arginine reversed these effects. NOS inhibition did not affect the direct cholinergic actions of ACh on SCL and A-H interval but enhanced adrenergic positive chronotropic and dromotropic effects. We conclude that NO plays a stimulatory role in mediating vagal neurotransmission and vagal modulation of sympathetic effects and an inhibitory role in mediating sympathetic neurotransmission.

Electrophysiologic effects of oral diltiazem before and after beta blockade

We conducted electrophysiologic (EP) studies and estimated the sinus node function and atrioventricular (AV) conduction in 10 patients with suspected coronary arterial disease (age range 35-55 years) before and during diltiazem therapy (60 mg thrice daily for 5-7 days). The effect of beta blockade (0.1 mg/kg of intravenous propranolol) was evaluated in both EP studies. The mean spontaneous sinus cycle length (SCL) and the AV nodal Wenckebach cycle lengths (AVWB) were significantly higher (p less than 0.05) after propranolol alone (913 +/- 131 and 504 +/- 197 ms, respectively) compared with baseline values (SCL: 827 +/- 149 ms, AVWB: 439 +/- 173 ms). Diltiazem alone failed to influence the SCL and AVWB significantly. Following the combination (diltiazem + propranolol), SCL (945 +/- 147 ms) and AVWB (533 +/- 148 ms) were significantly higher (p less than 0.05) than baseline and post diltiazem values (SCL: 840 +/- 150 ms; AVWB 457 +/- 103 ms). None of the other parameters (sinoatrial conduction time, corrected sinus node recovery time, AH and HV intervals, AV nodal and atrial effective refractory periods) were significantly influenced by propranolol, diltiazem, or the combination. No patient developed AV block, sinus arrest/sinoatrial exit block, or symptomatic sinus bradycardia following beta blockade after diltiazem administration. Oral diltiazem therapy alone and after beta blockade does not appear to adversely influence the sinus node function and AV conduction in patients below the age of 55 years. The combination of diltiazem and beta blocker thus appears safe in selected patients with coronary arterial disease.

Effects of propafenone on sinus node function in the rabbit heart

Propafenone is a type 1C antiarrhythmic drug with efficacy for both ventricular and supraventricular arrhythmias. We investigated the effects of propafenone on properties of sinus node function in an in vitro preparation of rabbit sinus node and surrounding atrium. Spontaneous sinus cycle length (SCL), atriosinus conduction time (ASCT), and sinus node effective refractory period (SNERP) at multiple pacing cycle lengths were measured in the control state and during superfusion with propafenone (2.3 microM). SNERP prolonged from 175 +/- 25 ms in the control state to 220 +/- 45 ms (p less than 0.001) with propafenone. ASCT also prolonged significantly (p less than 0.01) from 50 +/- 20 to 65 +/- 20 ms whereas SCL did not change. In four experiments, multiple concentrations of propafenone were utilized and there appeared to a dose-dependent prolongation of SNERP. Thus, propafenone has a significant effect on SNERP and ASCT in an isolated rabbit sinus node preparation.

Cardiac electrophysiological actions of captopril: lack of direct antiarrhythmic effects.

1. Standard microelectrode techniques were used to study the effects of captopril (1, 10 and 100 microM) on action potentials recorded from guinea-pig ventricular cells and sinoatrial node cells. 2. Captopril had no effect on the maximum rate of depolarization (Vmax) of ventricular action potentials in cells exposed to either normal Locke solution or 'simulated ischaemic' solution (K1 11.2 mM; pH-6.4; PO2 less than 80 mmHg), nor was there any augmentation of the normal small decline in Vmax with increasing stimulation rate (range of interstimulus intervals = 2400 ms to 300 ms). 3. Captopril had no effect on the duration of ventricular action potentials, nor did it alter the shortening seen on exposure to simulated ischaemia. 4. Captopril did not alter spontaneous sinus cycle length or any recorded parameter of sinus node action potentials. 5. It is concluded that any antiarrhythmic effects observed during clinical use of captopril are most unlikely to be due to direct actions of the drug on cardiac cell membrane properties.

Electrophysiological Properties of Isradipine (PN200–110) in Humans

Isradipine (PN 200-110) is a new dihydropyridine calcium-entry blocker with powerful vasodilating properties. Therapeutic concentrations do not affect myocardial contractility. However, in vitro studies have demonstrated at higher concentrations negative chronotropic action with only minor dromotropic influence. For this reason we studied the effect of intravenous isradipine (0.3 microgram/kg/min during 30 min) on sinus node and atrioventricular (AV) nodal function in 25 patients. Nine of these patients had normal sinus node function (group I), nine patients were treated with a beta blocker (group II), and seven patients had a sick sinus syndrome (group III). Mean supine arterial blood pressure decreased in all groups; however, in group I not significantly. Spontaneous sinus cycle length decreased significantly in all groups. In none of the patients effective refractory periods of atrium or ventricle were depressed. QRS duration was not significantly affected in any of the groups. There was only a slight, but significant, prolongation of the QTc of maximal 4% (except in group III). We concluded that isradipine has no depressant effect on sinus and AV nodal function in humans, not even in the presence of beta blockade or impaired sinus node function.

Cardiac electrophysiologic properties of intravenous isradipine in patients with sick sinus syndrome

Isradipine is a new dihydropyridine calcium antagonist with powerful vasodilating properties. Although therapeutic concentrations do not affect myocardial contractility in vivo, in vitro studies have demonstrated a negative chronotropic action with only minor dromotropic influence. In humans with normal sinus and atrioventricular node function, even in the presence of beta-blockade, such a negative chronotropic effect could not be proved. No data are available on the effects of isradipine on a compromised sinus node. Therefore, the effect of intravenous isradipine at 0.3 μg/kg/minute for 30 minutes was studied in seven patients with the clinical signs of a sick sinus syndrome. Mean arterial blood pressure decreased from 126 ± 21 to 113 ± 15 mm Hg (p <0.05). Spontaneous sinus cycle length decreased from 969 ± 22 to 843 ± 161 msec (p <0.05). Changes in sinoatrial conduction time, sinus node recovery time, and corrected sinus node recovery time were not significant. Changes in atrioventricular node functional refractory period, the atrial-His interval, the His-ventricle interval, and Wenckebach point were not significant. Also, effective. Also, effective refractory periods of atrium and ventricle, and QRS duration changed but not significantly. The QT interval decreased (419 ± 45 to 405 ± 44 msec; p <0.05), and there was a slight (not significant) increase of QTc interval (429 ± 41 to 443 ± 37 msec; not significant). It is concluded that isradipine in hemodynamically effective doses has no depressant effect on sinus and atrioventricular node function in patients with sick sinus syndrome.

The electrophysiologic effects of enoximone in patients with preexisting ventricular tachyarrhythmias

Electrophysiologic and hemodynamic effects of intravenous enoximone were studied in 15 male patients, mean age 62.2 years, with New York Heart Association classes II to IV congestive heart fallure (coronary artery disease in 10 and idlopathic dllated cardiomyopathy in five patients; mean ejection fraction, 0.19). All patients had spontaneous ventricular tachyarrhythmias: eight had sustained ventricular tachycardia (VT), one had ventricular fibrillation, and six had nonsustained VT. Hemodynamic and electrophysiologic parameters including VT induction were determined before and during an intravenous infusion of enoximone. The cardiac index increased (2.49 ± 0.89 to 2.96 ± 0.78), and the pulmonary capillary wedge pressure decreased (22.4 ± 13.2 to 10.0 ± 9.0) after enoximone per predefined protocol endpoints. There was a significant decrease in spontaneous sinus cycle length, corrected sinus nodal recovery time, AH interval during atrial pacing, shortest cycle length at which 1:1 atrioventricular nodal conduction occurred, and refractory periods of the atrium, ventricle, and atrioventricular node. Enoximone did not alter the cycle length of induced VT, and there was no consistent change in the number of extrastimuli required for VT induction. A baseline 24-hour ECG recording was obtained on 14 patients (while recelving a long-term antiarrhythmic drug regimen, if needed) and repeated after 1 week and 1 month of oral enoximone therapy. There was no significant increase in the number of premature ventricular complexes per hour or VT episodes per 24 hours after 1 week or 1 month of therapy with enoximone. However, if four patients who received amiodarone and may not yet have reached steady state were excluded from analysis, there was a significant increase in the frequency of premature ventricular complexes per hour 1 month after initiation of enoximone. We conclude that intravenous enoximone reduces pulmonary capillary wedge pressure and increases cardiac output in most patients. Intravenous enoximone in doses sufficlent to have hemodynamic effects shortens atrial, ventricular, and atrioventricular nodal refractoriness and decreases AV nodal conduction time but has no consistent effect on VT induction or VT cycle length. The frequency of spontaneous ventricular ectopy may increase in some patients after oral enoximone, but its clinical significance is undefined. Enoximone may be administered cautiously to patients with congestive heart fallure and preexisting ventricular tachyarrhythmias.

Electrophysiologic Effects of Enoximone in Patients with

The electrophysiologic effects of enoximone were evaluated in 12 patients with idiopathic dilated cardiomyopathy undergoing routine programmed electrical stimulation (PES). Enoximone (1.5 mg/kg for 20 min followed by 0.75 mg/kg for 20 min) significantly shortened the spontaneous sinus cycle length as well as the atrial and ventricular refractory period. Neither during control PES nor during enoximone infusion were sustained ventricular arrhythmias provoked. However, in 5 of 12 patients, there was an increase in the number of repetitive ventricular responses induced by PES during enoximone administration. The observed electrophysiologic changes may be indicators for increased electrical instability of the myocardium in selected patients.

Electrophysiologic Effects of Enoximone in Patients with

The electrophysiologic effects of enoximone were evaluated in 12 patients with idiopathic dilated car-diomyopathy undergoing routine programmed electrical stimulation (PES). Enoximone (1.5 mg/kg for 20 min followed by 0.75 mg/kg for 20 min) significantly shortened the spontaneous sinus cycle length as well as the atrial and ventricular refractory period. Neither during control PES nor during enoximone infusion were sustained ventricular arrhythmias provoked. However, in 5 of 12 patients, there was an increase in the number of repetitive ventricular responses induced by PES during enoximone administration. The observed electrophysiologic changes may be indicators for increased electrical instability of the myocardium in selected patients

Surgery for Wolff-Parkinson-White syndrome interrupts efferent vagal innervation to the left ventricle and to the atrioventricular node in the canine heart.

The hypothesis that cardiac surgery to interrupt accessory pathways also interrupts autonomic nerves to the canine ventricle and to the atrioventricular node was tested in four groups of dogs. Group 1 (n = 6) underwent dissection of the atrioventricular fat tissue and cryolesion created by application of a cryoprobe at -60 degrees C for 2 min along the lateral left atrioventricular groove, the same surgical procedure as carried out in patients with Wolff-Parkinson-White syndrome with accessory pathways located in the left ventricular free wall. Group 2 (n = 6) underwent dissection of the atrioventricular fat pad alone and group 3 (n = 6) dissection and cryolesion along the posterior left atrioventricular groove as performed in patients with Wolff-Parkinson-White syndrome with accessory pathways located in the posterior paraseptal area. Group 4 consisted of 11 non-operated control dogs. Four to 13 days after surgery the ventricular effective refractory period (ERP) was determined during bilateral ansae subclaviae stimulation (4 ms pulses, 2-3 Hz, and 2-3 mA), noradrenaline infusion (0.5 micrograms.kg-1.min-1), and bilateral vagal stimulation (4 ms pulses, 20 Hz, and current strength to induce asystole or complete atrioventricular block). Atrioventricular nodal conduction (AH interval) and spontaneous sinus cycle length were also determined in group 3 dogs. Ansae subclaviae stimulation and noradrenaline infusion shortened effective refractory period significantly at each left ventricular test site. The amount of effective refractory period shortening induced by ansae subclaviae stimulation did not differ among the test sites except for the posterior left ventricle in group 1 dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative quantitative electrophysiologic effects of adenosine triphosphate on the sinus node and atrioventricular node

A pharmacologic approach was used to characterize the sinus node (SN) and atrioventricular (AV) node responses to intravenous adenosine triphosphate (ATP) in 21 patients during electrophysiologic testing. ATP produced dose-dependent prolongation of spontaneous sinus cycle length. The mean maximal increase in sinus cycle length was 294 ± 60 ms (n = 10). The mean dose of ATP required to produce this maximal sinus cycle length prolongation was 3.5 ± 1.0 mg. The dose-response curve for sinus cycle length prolongation was sigmoid in shape with an EC 50 of 0.39 mg derived from a median effect plot. There was a negative correlation between the control sinus cycle length and the dose of ATP required to produce the maximal prolongation of cycle length (p < 0.05). In contrast, the mean dose of ATP producing AV block was 4.4 ±0.97 mg and the EC 50 was 2.98 mg. There was a positive correlation between the AV nodal functional refractory period and the prolongation of the AH interval with a 2 mg dose (p < 0.05). Consistent with the AV nodal dose-response curves, 8 mg ATP terminated paroxysmal reentrant supraventricular tachycardia at the AV node in 8 of 9 patients. Thus, SN and AV node responses to ATP have differences in their electrophysiologic correlates and EC 50. These findings suggest that ATP has potentially different mechanisms of action on SN automaticity and AV nodal conduction that requires further investigation.

Changes in atrial and ventricular refractoriness and in atrioventricular nodal conduction produced by combinations of vagal and sympathetic stimulation that result in a constant spontaneous sinus cycle length.

The vagal nerves modulate adrenergic effects on sinus cycle length, atrioventricular (AV) nodal conduction, and refractoriness of atria and ventricles. We tested whether varying levels of vagal-sympathetic input could yield the same spontaneous sinus cycle length but also alter effective refractory periods of the right atrium, right ventricle, and left ventricle and AV nodal conduction times. Dogs anesthetized by alpha-chloralose were studied in the open-chest, neurally decentralized state. In 10 dogs, sinus cycle length was maintained constant during 3 levels of bilateral ansae subclaviae stimulation (4 msec, 3 mA at 1, 2, and 4 Hz) by titrating simultaneous bilateral vagal stimulation (varying pulse width and frequency). Each combination of ansae subclaviae-vagal stimulation yielded the same sinus cycle length as the control value, but refractory periods of right atrium and right and left ventricles shortened progressively as the frequency of ansae subclaviae stimulation increased. Atrioventricular nodal conduction time (AH interval) shortened in 2 dogs and lengthened in 3 dogs. His-Purkinje conduction time (HV interval) was unchanged. In 9 dogs, the effect of simultaneous unilateral ansae subclaviae stimulation at 2 Hz and ipsilateral vagal stimulation that yielded the same sinus cycle length were determined. Right-sided ansae subclaviae-vagal stimulation shortened refractoriness of right atrium and anterior left ventricle significantly. The AH interval lengthened in 1 dog. Left ansae subclaviae-vagal stimulation shortened the refractory periods of anterior and posterior left ventricle significantly and reduced the AH interval in 3 dogs. In 8 dogs, the effects of bilateral ansae subclaviae stimulation alone at 2 Hz, vagal stimulation alone at an intensity required to keep the sinus cycle length constant during ansae subclaviae stimulation, and simultaneous bilateral ansae subclaviae and vagal stimulation were tested. The right atrial refractory period was shortened significantly by ansae subclaviae stimulation alone and by vagal stimulation alone and was shortened further by simultaneous stimulation of both autonomic limbs. The right and left ventricular refractory periods were shortened by ansae subclaviae stimulation alone and by simultaneous stimulation of both limbs but tended to be prolonged by vagal stimulation alone and when added to ansae subclaviae stimulation. In 7 dogs, the effects of simultaneous stimulation of bilateral ansae subclaviae at 2 Hz and vagi at intensities that maintained the AH interval constant at an atrial pacing cycle length of 300 msec were determined.(ABSTRACT TRUNCATED AT 400 WORDS)

CHARACTERIZATION OF SINUS NODE REFRACTORINESS AND SINOATRIAL CONDUCTION DURING ACUTE HYPOXIA

Since hypoxia inhibits conduction & automaticity predominantly in tissues dependent on the slow (Ca-channel) current, sinus node (SN) function should be selectively depressed. The effects of acute, severe hypoxia (H) on SN refractoriness and sinoatrial conduction time (SACT) were studied using rabbit SN-right atrial preparations and standard micro-electrode techniques. True SN pacemaker cells were identified by intracellular action potentials having low amplitude (65±7mV) and Vmax (3.3±1.0 V/s), and rapid rates of spontaneous diastolic depolarization (51±15 mV/s). Spontaneous sinus cycle length (CL) (control = 460±58ms) increased by 36% with H. Retrograde SACT, measured from the crista terminalis to a true SN pacemaker cell, was rate dependent; increasing at shorter paced CL. SACT increased at all paced CL with H. At a CL of 400ms, SACT increased from 41±12 to 101±19ms (+146%). The minimum paced CL with 1:1 atrio-SN conduction (CLm) increased from 203±34 to 308±41ms (+52%) with H. SACT at CLm increased from 65±19 to 134±30ms (+105%). SN effective refractory period (ERP)(at a paced CL of 400ms) increased from 158±37 to 261±45ms (+66%). All changes in SN function related to H were significant (at least p<0.05). SN pacing from the crista terminalis was never limited by atrial muscle conduction (fast, Na-channel dependent) or refractoriness. Atrial ERP changed from 86±14 to 96±20ms (NS) with H. In summary, acute H adversely affects SN automaticity, conduction and refractoriness; presumably related to alterations in the Ca current. These changes may be responsible for many of the bradyarrhythmias seen clinically during severe H.

Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics

Dl-sotalol is a specific beta-adrenergic blocking agent that markedly lengthens cardiac action potential duration. To determine whether d-sotalol, with little or no beta-blocking effect, also lengthens repolarization, standard microelectrode studies were used to determine the electrophysiologic properties of dl-sotalol and its stereoisomers in isolated rabbit and canine myocardial fibers. D- and l-sotalol produced concentration-dependent increases in action potential duration to 50% (APD50) and 90% (APD90) repolarization, respectively, and in the effective refractory period without changes in the maximal rate of rise of action potential. In rabbit sinoatrial node, d- and l-sotalol produced concentration-dependent increases in spontaneous sinus cycle length (29 and 35%, respectively) by lengthening the action potential duration (by 58 and 55%) without effect on phase 4 depolarization. At the highest concentration (27.2 micrograms/ml), d- and l-sotalol prolonged APD90 (by 38 and 54%, respectively, in Purkinje fibers and by 32 and 34% in ventricular muscle) and effective refractory period (by 49 and 49% in Purkinje fibers and 29 and 40% in ventricular muscle). The effects of the two isomers were not significantly different. At the middle concentration (2.7 micrograms/ml), d-sotalol, unlike l-sotalol, had no beta-adrenergic blocking effect, but the electrophysiologic effects of dl-, d- and l-sotalol were indistinguishable. The data indicate that d-sotalol is equipotent with l-sotalol in lengthening the action potential duration and effective refractory period in cardiac muscle, an action unrelated to adrenergic antagonism or pharmacokinetic differences between the stereoisomers.