Spontaneous Sinus Rate Research Articles

P2565Decreased cardiac pacemaking and attenuated beta-adrenergic response in tric-a knock-out mice

Abstract Background Trimeric intracellular cation (TRIC) channels are expressed on the surface of the sarcoplasmic reticulum and compensate for calcium release from ryanodine receptors. Tric-a knock-out (KO) mice showed diminished calcium release from ryanodine receptors in vascular smooth muscle cells. The cardiac pacemaker is controlled by the surface membrane and intracellular calcium clocks. In spontaneously firing sinus node action potentials, the membrane and calcium clocks work together via numerous interactions modulated by membrane voltage, intracellular calcium release, and protein phosphorylation. Intracellular calcium changes modulate cardiac pacemaking in the sinus node, but the physiological importance of TRIC channels in cardiac rhythm formation is still obscure. Purpose In this study, we aimed to clarify the importance of TRIC channels on cardiac pacemaking using Tric-a KO mice. Methods The expression level of mRNA and proteins in the sinus node was examined by RT-PCR and immunoblotting. Systolic blood pressure was measured with tail-cuff method. Heart rate was measured by ECG, and heart rate variability was examined. The atrial contractile force from isolated hearts was measured with a force transducer. Cardiac action potential and spontaneous sinus rate from isolated hearts were measured with a microelectrode. Isoproterenol was used for sympathetic nerve manipulation. Results Tric-a KO heart showed increased adrenergic β1-receptor expression in immunoblotting. Although there was no significant difference in basal systolic blood pressure between Tric-a KO and wild type (WT) mice, basal heart rate in Tric-a KO mice was significantly lower than that in WT mice (660±10 and 698±10 bpm, n=15 and 19, Tric-a KO mice and WT mice, respectively, p=0.017). Tric-a KO mice showed limited heart rate changes to isoproterenol (24±6 and 99±15 bpm, n=9 and 10, Tric-a KO mice and WT mice, respectively, p<0.001). In the action potential recordings, Tric-a KO atria showed only limited sinus rate changes to isoproterenol (35±9 and 71±10 bpm, n=8 and 6, Tric-a KO mice and WT mice, respectively, p=0.038). WT mice and Tric-a KO mice atrial contractile force showed dose-dependent changes in response to isoproterenol (10–100 nM), but Tric-a KO mice atria showed limited contractile force changes to isoproterenol (116 and 169%, n=7 and 6, Tric-a KO mice and WT mice, respectively, p<0.01). In heart rate variability, Tric-a KO mice showed unstable RR intervals and longer standard deviation of RR intervals than WT mice. Conclusion Tric-a KO mice showed decreased cardiac pacemaking in the sinus node and attenuated responses to beta-adrenergic stimulus, which indicates the involvement of TRIC channels in cardiac rhythm formation and sympathetic nerve regulation.

Effects of Atrium on the Electrical Activity of Sino-Atrial Node

As the electrical source of hearts, sino-atrial node (SAN) plays a significant role in rhythmic firing. The aim of this study is to determine effects of atrium on the electrical activity of SAN. Based on a mathematical model considering central and peripheral SAN cells as well as an atrial model, one-dimensional fiber with a gradual heterogeneity of SANC was developed. The forth-order Runge-Kutta and three-point centered difference methods were used to integrate the conduction model. The results demonstrated that as a load of SAN, atrium decreased the spontaneous sinus rate casing a shift of leading pacemaker site from the periphery to the center. If the ectopic beat produced by a premature stimulation was late after the end of the atrial refractory, the pause following it was compensatory. Otherwise, the pause was non-compensatory. In this case, the peripheral SANC excited earlier than the central SANC. During multiple premature beats, at short intervals the propagation could block in SAN due to a long refractory period of the action potential close to the central SANC. Leading pacemaker site shift was observed during the following several spontaneous SANC excitation. Therefore, the existence of atrium is suggested affecting not only sinus rates, but also the mode of electrical propagation and the site of the earliest excitation.

Contributions of permanent cardiac pacing in the treatment of atrial fibrillation.

Newer indications for permanent cardiac stimulation include the prevention of paroxysmal atrial fibrillation (AF) and cardiac resynchronisation in patients suffering from advanced heart failure. Direct comparisons between VVI and DDD or AAI pacing showed an advantage conferred by physiological pacing on the risk of developing AF during long-term follow-up in patients with sinus node dysfunction, AV block, or both. Furthermore, in patients with conventional pacing indications and paroxysmal atrial tachyarrhythmias, a high percentage of atrial pacing was associated with a lighter AF burden. This article reviews several important issues involved in the optimisation of cardiac pacing with a view to prevent paroxysmal AF by new, dedicated pacing algorithms. The AF Suppression trade mark algorithm significantly reduced the rates of symptomatic paroxysmal AF. This algorithm, which confers its benefit by maintaining the atrial pacing rate slightly above the spontaneous sinus rate, should be activated in patients with a history of atrial tachyarrhythmia. Implanting the lead in the low atrial septum seems to reduce further the frequency of tachyarrhythmic events. Future indications for this mode of pacing may be extended to patients at high risk of new-onset or recurrent AF, such as candidates for cardiac resynchronisation therapy or implantable cardioverter/defibrillator recipients.

High incidence of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based pacing in the Mode Selection Trial (MOST)

ObjectivesWe evaluated the incidence, predictors, and treatment of pacemaker syndrome in patients with sinus node dysfunction treated with ventricular-based (VVIR) pacing in the Mode Selection Trial (MOST). BackgroundPacemaker syndrome, or intolerance to VVIR pacing, consists of cardiovascular signs and symptoms induced by VVIR pacing. MethodsThe definition of pacemaker syndrome required that a patient with single-chamber VVIR pacing develop either congestive signs and symptoms associated with retrograde conduction during VVIR pacing or a ≥20 mm Hg reduction of systolic blood pressure during VVIR pacing, associated with reproducible symptoms of weakness, lightheadedness, or syncope. ResultsOf 996 patients randomized to VVIR pacing, 182 (18.3%) met criteria for pacemaker syndrome in follow-up. Pacemaker syndrome occurred early in most patients (13.8% at 6 months, 16.0% at 1 year, increasing to 19.7% at 4 years). Baseline univariate predictors of pacemaker syndrome included a lower sinus rate and higher programmed pacemaker rate. Previous heart failure, ejection fraction, and drop in systolic blood pressure with VVIR pacing at implantation did not predict the development of pacemaker syndrome. Post-implantation predictors of pacemaker syndrome were a higher percentage of paced beats, higher programmed low rate, and slower underlying spontaneous sinus rate. Quality of life decreased at the time of diagnosis of pacemaker syndrome and improved with reprogramming to atrial-based pacing. ConclusionsSevere pacemaker syndrome developed in nearly 20% of VVIR-paced patients and improved with reprogramming to the dual-chamber pacing mode. Because prediction of pacemaker syndrome is difficult, the only way to prevent pacemaker syndrome is to implant atrial-based pacemakers in all patients.

Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes. The third fat pad.

The purpose of this study was to investigate the functional pathways of efferent vagal innervation to the atrial myocardium and sinus and atrioventricular (AV) nodes. Using vagally induced atrial effective refractory period shortening, slowing of spontaneous sinus rate, and prolongation of AV nodal conduction time as end points of vagal effects, we determined the actions of phenol and epicardial radiofrequency catheter ablation (RFCA) applied to different sites at or near the atrial myocardium to inhibit these responses. We found that efferent vagal fibers to the atria are located both subepicardially and intramurally or subendocardially. Most efferent vagal fibers to the atria appear to travel through a newly described fat pad located between the medial superior vena cava and aortic root (SVC-Ao fat pad), superior to the right pulmonary artery, and then project onto two previously noted fat pads at the inferior vena cava-left atrial junction (IVC-LA fat pad) and the right pulmonary vein-atrial junction (RPV fat pad) and to both atria. A few vagal fibers may bypass the SVC-Ao fat pad and go directly to the IVC-LA or RPV fat pad and then innervate the atrial myocardium. Vagal fibers to the sinus and AV nodes also converge at the SVC-Ao fat pad (a few fibers to the sinus node go directly to the RPV fat pad) before projecting to the RPV and IVC-LA fat pads. Long-term vagal denervation of the atria and sinus and AV nodes can be produced by RFCA of these fat pads and results in vagal denervation supersensitivity. Vagal denervation prevents induction of atrial fibrillation in this model. The newly described SVC-Ao fat pad receives most of the vagal fibers to the atria and sinus and AV nodes. Elimination of the fat pads with RFCA selectively vagally denervated the atria and sinus and AV nodes.

Direct cadiac electorphysiologic effects of sufentanil and vecuronium in isolated guinea‐pig hearts

Sufentanil and vecuronium are commonly used simultaneously in anaesthesia. Bradycardia and asystole have been described immediately after the administration of these two compounds. Therefore, the purpose of the present study was to evaluate the direct cardiac effects of sufentanil and vecuronium in all parts of the cardiac pacemaker and conduction system. The electrophysiological effects of sufentanil and vecuronium were studied in isolated spontaneously beating guinea-pig hearts perfused by the method of Langendorff. At a concentration of 0.1 mumol/l sufentanil a significant reduction of the spontaneous sinus rate, prolongation of atrioventricular, intraventricular and His' bundle conduction could be observed. The highest concentration of 10 mumol/l of sufentanil led to an overall slowing of conduction velocity and to an profound showing of spontaneous sinus rate. AV nodal as well as atrial and ventricular refractoriness were markedly prolonged at this high concentration of sufentanil. In contrast, during perfusion with vecuronium at a concentration of 0.1 mumol/l up to 10 mumol/l no significant effects on cardiac conduction and pacemaker activity could be observed. In conclusion, the electrophysiological effects of sufentanil are comparable to that of unspecific calcium antagonists. Therefore, especially in patients with a preexisting damage of the cardiac conduction system, the indirect effect of the combination of sufentanil and vecuronium which is predominantly responsible for bradycardia and asystole may be worsened by the direct effects of sufentanil.

Diurnal fluctuations in human ventricular and atrial refractoriness.

The relative significance of the direct and indirect effects of autonomic tone on diurnal fluctuations in human ventricular and atrial refractoriness are not well known. In this study, the circadian rhythms of ventricular and atrial effective refractory periods (ERPs) were measured by noninvasive programmed stimulation in ten patients (mean age 62 +/- 10 years) who had a permanent dual chamber pacemaker for complete atrioventricular (AV) block. The ERP was measured at 4-hour intervals during spontaneous sinus rhythm with ventricular pacing (day 1) and during constant-rate dual chamber pacing (day 2). Cosinor analysis showed the ventricular ERP to have a significant diurnal rhythm in sinus rhythm (amplitude, 12 msec; 95% confidence intervals 1-24 msec) but not during constant-rate pacing (amplitude, 4 msec; 95% confidence intervals -3-12 msec). The atrial ERP had a significant rhythm at times of both spontaneous sinus rate (amplitude, 19 msec; confidence intervals 13-24 msec) and constant heart rate (amplitude, 11 msec; confidence intervals 1-21 msec) with acrophase during the sleeping hours. The increase in heart rate during dual chamber pacing resulted in a more marked decrease in the average 24-hour ERP in the ventricle than in the atrium (46 +/- 9 msec vs 12 +/- 6 msec, P < 0.01). Thus, refractoriness is more rate dependent in the ventricle than in the atrium, and autonomic influences on ventricular refractoriness are mainly indirect, via fluctuations in the sinus rate, but atrial refractoriness is also affected by direct neural influences and/or other rate independent factors.

In Vivo and In Vitro Electrophysiologic Effects of Terodiline on Dog Myocardium

Terodiline hydrochloride, widely prescribed for urinary incontinence, has been reported to cause bradycardia and torsades de pointes. In this study, we characterized the electrophysiologic effects of terodiline in dog cardiac tissues in vivo and in isolated canine cardiac Purkinje fibers. Terodiline (1 to 10 microM) resulted in dose-dependent reduction of action potential amplitude and maximal upstroke velocity (Vmax). The threshold for these effects was approximately 2 microM (0.6 mg/L), and the changes were cycle-length dependent. Terodiline (> or = 2 microM) also depressed the action potential plateau but did not significantly alter action potential duration at concentrations < or = 10 microM. In vivo studies demonstrated that high doses of terodiline (3 mg/kg) lengthened AH and HV intervals, slowed spontaneous sinus rate, prolonged ventricular refractoriness, and inhibited vagally induced slowing of the sinus node. Sympathetic effects on spontaneous sinus rate were unchanged. In both isolated canine Purkinje fibers and anesthetized dogs, terodiline did not evoke afterdepolarizations, repetitive firing, or ventricular tachyarrhythmias under normal or hypokalemic conditions. Our findings suggest that terodiline (> or = 1 to 2 microM) leads to blockade of sodium and calcium channels as well as muscarinic receptors in canine cardiac tissues.

Zatebradine attenuates cyclic AMP-related positive chronotropic but not inotropic responses in isolated, perfused right atria of the dog.

1. Inhibition of I(f) or ICa by zatebradine has been reported in mammalian SA nodal cells. We thus investigated whether zatebradine differentially attenuates the positive chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator), 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 (a calcium channel agonist) in the isolated, blood-perfused dog atrium. 2. When zatebradine (0.03-1 mumol) decreased sinus rate from 104 +/- 4.5 to 73 +/- 4.9 beats/min dose-dependently, it selectively attenuated the positive chronotropic but not inotropic responses to norepinephrine in a dose-related manner. Zatebradine decreased the norepinephrine-induced tachycardia (by approximately 80% from the control) more effectively than the spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive chronotropic but not inotropic responses to isoproterenol, NKH 477 and IBMX. Fifty per cent inhibition doses of zatebradine (0.10-0.18 mumol) for the chronotropic responses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive chronotropic nor inotropic responses to Bay k 8644. 5. We therefore suggest that zatebradine selectively attenuates the positive chronotropic but not inotropic responses to cyclic AMP-related substances due to inhibition of I(f) but not ICa in the dog heart.

A comparison of the effects of adenosine and verapamil on the conduction and pacemaker system of isolated guinea pig hearts

Adenosine and verapamil are effective in the treatment of supraventricular arrhythmias. Also, both substances can provoke sinus node arrest or a third-degree atrioventricular (AV) block with a ventricular escape rhythm. The aim of this study was to compare the effects of adenosine and verapamil on sinus rate and on the rate of the ventricular escape rhythm while a third-degree AV block was induced by both drugs. Experiments were performed on isolated spontaneously beating guinea pig hearts perfused by the method of Langendorff. A third-degree AV block was induced by adenosine at a concentration of 30 microns and by verapamil at a concentration of 1 micron. Adenosine (30 microns) reduced sinus rate only moderately whereas it nearly halved the rate of the ventricular escape rhythm compared with that produced by cutting the AV node. In contrast, verapamil left the rate of the ventricular escape rhythm unchanged but nearly halved the spontaneous sinus rate compared with control conditions. In conclusion, adenosine and verapamil given at dosages with comparable effect on the AV node have markedly different effects on different pacemakers in the same heart. In the treatment of supraventricular arrhythmias, adenosine probably should be used with great caution since it can cause a very slow ventricular escape rhythm.

Right ventricular conductance to establish closed-loop pacing.

Innovations in pacing technology, which include the addition of rate-responsive features to programmable pacemakers, can improve the quality of life of patients suffering from sick sinus syndrome. Among the strategies providing rate-adaptive cardiac pacing, the most attractive is the physiological restoration of closed-loop chronotropic control. This paper describes how autonomic nervous system (ANS) control information is extracted from dynamic measures of myocardial contractile performance obtained from unipolar conductance measurements using the stimulation electrode in the right ventricular cavity. The pacemaker uses the ANS information to modulate pacing rate and restore normal physiological control of heart rate. A new algorithm, regional effective slope quantity (RQ), for isolating the ANS signal was developed. The resulting signal, ventricular inotropic parameter (VIP), is a normalized parameter proportional to the strength of the ANS inotropic signals to the myocardium. The efficacy of the ANS control concept was evaluated in multi-centre studies. Patients with AV block and VIP-controlled pulse generators performed defined exercise protocols. The ANS-controlled pacing rate and the spontaneous sinus rate were closely correlated. Blood pressure and subjective patient reports further indicated that good control of the cardiovascular circulation was achieved.

CP-96,345, a non-peptide antagonist of substance P. III. Cardiovascular effects in mammals unrelated to actions on substance P receptors.

The cardiovascular effects of CP-96,345, a non-peptide antagonist of substance P, were analyzed in vivo and in vitro. In the anaesthetized rat, the i.v. injection of 3 mumol kg-1 of CP-96,345 induced a fall in mean arterial blood pressure and a reduction in heart rate. Similar effects were obtained with the enantiomer CP-96,344 (2R,3R)-cis-isomer of CP-96,345) which does not interact with substance P receptors. Both enantiomers, at a concentration of 10 microM, decreased the beating frequency of the isolated atria and of the isolated perfused heart of the guinea-pig to a similar extent, and caused transient coronary dilatation. CP-96,345 (10 microM) decreased the spontaneous sinus rate, prolonged the atrioventricular-nodal conduction interval and the His-bundle conduction interval of the perfused guinea-pig heart. The intraventricular spread of conduction was markedly inhibited. During programmed stimulation 10 min after the beginning of the drug application, the effective refractory periods evaluated by stimulation with premature beats, as well as rate dependent effective refractory periods, of the atrioventricular node, of the atrial and of the ventricular myocardium, were prolonged. Sinus node recovery time was also prolonged. It was concluded that these cardiac effects of CP-96,345 were not caused by an action of the compound on substance P receptors.

The A‐R Interval as Exercise Indicator: A New Option for Rate Adaptation in Single and Dual Chamber Pacing

We investigated the possibility to use the interval from an atrial stimulus to the ventricular R wave (A-R interval) as an indicator of physical stress, in 16 patients with pacemakers implanted for severe atrial bradycardia but with intact AV conduction. The A-R interval was studied during incremental atrial pacing at rest and during exercise with a constant workload. In addition, the atrial pacing rate was kept constant just above spontaneous sinus rate and the dynamics of the A-R interval were studied during exercise with a low constant workload and during a maximal exercise test with increasing workload. Incremental atrial pacing prolonged the A-R interval and this response was blunted during exercise (P less than 0.003). Atrial pacing at a constant rate and during a constant workload resulted in an almost direct shortening of the A-R interval. When the workload was increased but the atrial rate kept constant, a pronounced shortening of the A-R interval was noted (P less than 0.0001). It is concluded that changes of the A-R interval during different kinds of exercise were prompt and predictable in patients with sinus node dysfunction but intact AV conduction. In these patients the shortening of the A-R interval during exercise may be a suitable indicator for rate adaptive atrial pacing.

Comparison of acute effects of anthracyclines on cardiac electrophysiological parameters of isolated guinea-pig hearts

This study was performed to evaluate the acute effects of two anthracycline derivatives, doxorubicin and 4'O-tetrahydropyranyl-doxorubicin [(THP)-doxorubicin], on the conduction intervals, heart rate and refractoriness of isolated spontaneously beating guinea-pig hearts using a high-resolution ECG recording technique (SST-ECG). Doxorubicin as well as (THP)-doxorubicin were added to the perfusate in increasing concentrations of 0.1, 1 and 10 microM. Doxorubicin did not significantly alter the heart rate or conduction intervals. Only the rate-dependent QT interval was significantly shortened under the influence of 10 microM doxorubicin. In contrast, 10 microM (THP)-doxorubicin led to a significant reduction in the heart rate (-13% +/- 3%; P less than 0.01, n = 7) and to a prolongation of atrioventricular conduction time (24% +/- 10%; P less than 0.05, n = 7). The rate-dependent repolarization period (QT interval) was only insignificantly shortened in the presence of 10 microM (THP)-doxorubicin. The maximal following frequencies of each part of the conduction system were not changed by 10 microM doxorubicin. In the presence of (THP)-doxorubicin, the maximal following frequency of the ventricular myocardium was increased by as much as 36% +/- 8% (P less than 0.01, n = 7), indicating a shortening of the effective refractory period of the ventricular myocardium (V-ERP). These results show that the activation of (THP)-doxorubicin resembles the effects of Ca-antagonistic compounds on the heart (i.e. decrease in the spontaneous sinus rate and prolongation of the AV-nodal conduction interval). Changes in the QT interval exerted by doxorubicin and the shortening of the ventricular effective refractory period by (THP)-doxorubicin may indicate an alteration of the K(+)-conductance of the membrane. As the acute electrophysiological effects of doxorubicin and (THP)-doxorubicin are modest and occur only at excessive concentrations (10 microM), a direct influence on the generation of arrhythmias in healthy hearts is unlikely.

The influence of elevated Mg2+ concentrations on cardiac electrophysiologic parameters

This study was performed to evaluate the direct effects of magnesium ions on cardiac conduction velocities and on refractoriness using a modified Langendorff perfusion system and a special ECG recording and stimulation technique. An increase of the MG2+ concentration to 2.3 mM had no detectable effects. Higher concentrations of up to 4.6 mM decreased the spontaneous sinus rate and the conduction velocity through the AV node and the His bundle in a concentration-dependent manner. During stimulation with premature beats, in the presence of 4.6 mM of Mg2+, the effective and relative refractory periods (ERP, RRP) of sinoatrial, AV nodal, and His bundle conduction and the ERP of the ventricular myocardium were significantly prolonged, whereas the ERP of the atrial myocardium remained unaffected. The refractoriness of sinoatrial, AV nodal, and His bundle conduction, and of the ventricular myocardium, were also prolonged during pacing with a stepwise increased pacing rate. These observations suggest a marked rate-dependent inhibitory effect of magnesium on the refractoriness of the His-bundle conduction and of the ventricular myocardium, which might be an important factor in the antiarrhythmic effectiveness of magnesium in ventricular tachyarrhythmias.

Effects of halothane with and without histamine and/or epinephrine on automaticity, intracardiac conduction times, and development of dysrhythmias in the isolated guinea pig heart.

Histamine is released during allergic reactions, and is known to produce cardiac dysrhythmias. The authors compared the cardiac effects of histamine and epinephrine during exposure to halothane in the isolated perfused guinea pig heart. Responses studied were spontaneous sinus rate, intra-atrial conduction time, atrial-septal conduction time (ASCT), intraventricular conduction time (IVCT), and left ventricular pressure (LVP). The incidence and type of dysrhythmias with histamine and halothane and with epinephrine and halothane were analyzed from electrograms. The authors found that halothane alone (0.7 to 2.1 vol%) causes dose-dependent depressions of sinus rate and LVP, prolongs ASCT and IVCT, and produces atrioventricular (AV) block with junctional bradycardia. Histamine alone (.01-10 microM) increases sinus rate and LVP but, like halothane, prolongs ASCT. Halothane antagonizes the inotropic and chronotropic effects of histamine, but enhances ASCT compared with histamine alone. Histamine with halothane greatly increases the incidence of junctional tachycardia with AV dissociation from 0% with histamine alone up to 48%. Epinephrine alone (0.1-5 microM), like histamine, increases sinus rate and LVP, but does not cause a relative increase in ASCT. Halothane antagonizes the inotropic and chronotropic effects of epinephrine, but increases the incidence of ventricular tachycardia from 6% to 28%, and the incidence of premature ventricular excitations from 0% to 40%, compared with epinephrine alone. The authors' in vitro findings show that histamine and halothane, like epinephrine and halothane, can cause dysrhythmias, but that the genesis and type of dysrhythmias induced by these agents are dissimilar. Consequently, the release of histamine with an anaphylactoid reaction during halothane anesthesia, and the treatment of the reaction with epinephrine, could result in dangerous ventricular tachydysrhythmias.

Specific bradycardic agents--a novel pharmacological class?

Data have been reviewed and presented which suggest that substances from two different chemical groups, congeners of alinidine and falipamil, respectively, can be described as representatives of a novel and distinct pharmacological class: specific bradycardic agents (SBAs). They are characterized by a slowing of the sinus rate within physiological limits as the prominent cardiovascular effect. Involvement of alpha-adrenoceptors, beta-adrenoceptors and cholinergic receptors as mediators of the bradycardic effects have been excluded. Experiments in isolated atrial preparations suggested that drugs of the same type as alinidine or as falipamil have a similar mode of rate lowering action which is different from that of Ca-channel blockers: low external Ca2+ increased and low Na+ as well as high K+ decreased the bradycardic effect of SBA; verapamil behaved in the opposite way. Combination of different SBAs did not result in excessive additive rate-lowering effects; in contrast, addition of verapamil to maximally acting concentrations of SBAs resulted in a further significant reduction in rate. SBAs were much more potent in reducing spontaneous sinus rate than in reducing BaCl2 induced automaticity, whereas Ca-channel blockers behaved in the opposite way. Differences in the cardiovascular profile against other drugs with rate lowering effects have been pointed out: beta-adrenoceptor blocking agents more markedly decrease contractility and Ca-channel blocking agents more markedly decrease contractility, slow down AV conduction and have vasorelaxing properties.(ABSTRACT TRUNCATED AT 250 WORDS)

DPI 201-106, a novel cardioactive agent. Combination of cAMP-independent positive inotropic, negative chronotropic, action potential prolonging and coronary dilatory properties.

The in vitro cardiac effects of DPI 201-106, a novel piperazinyl-indole, were investigated. DPI 201-106 produced concentration-dependent positive inotropic effects in guinea-pig and rat left atria, kitten, rabbit and guinea-pig papillary muscles and Langendorff perfused hearts of rabbits between 10(-7) and 3 X 10(-6) mol/l. During isometric twitches, contraction and relaxation phases were prolonged in guinea-pig left atria and right ventricular papillary muscles from kitten and guinea-pigs. Spontaneous sinus rate was decreased in right atria of guinea-pigs and rats. Coronary flow increased in rabbit isolated hearts. Functional refractory period was increased in left atria from guinea-pigs and rats with EC50 values of 1.7 and 0.24 mumol/l respectively. In electrophysiological measurements, DPI 201-106 prolonged the action potential duration (APD70) in guinea-pig papillary muscles up to 70% and in rabbit atria up to 120% at 3 mumol/l. Other action potential characteristics were not changed in guinea-pig papillary muscles but Vmax was decreased in rabbit left atria. The electrophysiological as well as the positive inotropic effects were stereoselective with the activity residing in the S-enantiomer. DPI 201-106 increased the Ca2+-sensitivity of skinned fibres from porcine trabecula septomarginalis with an EC50 of 0.2 nmol/l. DPI 201-106 dit not change cAMP levels in guinea-pig atria and rabbit papillary muscles. Slow action potentials were not induced by DPI 201-106 in partially depolarized guinea-pig papillary muscles. Phosphodiesterase activity of rat hearts was not inhibited by DPI 201-106 at pharmacologically relevant concentrations. The presence of propranolol did not influence the inotropic potency of DPI 201-106 in guinea-pig atria. In conclusion, DPI 201-106 represents a novel type of positive inotropic agents with a synergistic sarcolemmal and intracellular mechanism of action.

158 AMIODARONE (AM) ADVERSELY AFFECTS SINUS NODE (SN) FUNCTION IN VITRO

AM is being used more frequently to control “resistant” childhood arrhythmias. As a Class III agent, AM supposedly acts by uniformly prolonging action potential (AP) duration and refractoriness. Because sinus slowing is observed clinically, we evaluated the acute effects of 0.68-34μg/ml AM on SN pacemaker activity using rabbit SN preparations and standard microelectrode techniques. Data were collected only from true SN pacemaker cells impaled continuously throughout the study. AM produced significant (p<0.05) concentration dependent decreases in spontaneous sinus rate (-6% at 6.8μg/ml; -12% at 34μg/ml), AP amplitude (-15% at 34μg/ml) and rate of phase 4 diastolic depolarization (-14%, -18%, -27% at 0.68, 6.8 & 34μg/ml respectively). Maximum diastolic & threshold potentials and Vmax also decreased significantly. Since AP duration did not increase, the fall in spontaneous rate was related solely to AM induced decreases in automaticity. Corrected SNRT and SACT were increased markedly by AM. In 4 preparations, SN exit or entrance block developed on prolonged exposure. The AM induced changes could not be reversed despite superfusion in AM-free medium for up to 1.5 hrs. Rather, SN function deteriorated further. AMs Class III actions cannot explain its effects on the SN. Since the automaticity and upstroke of SN pacemaker activity are dependent upon the slow inward Ca++ current (isi), AM may also possess Class IV (verapamillike) actions or marked antiadrenergic activity in-vitro.

Negative chronotropic and parasympatholytic effects of alinidine on canine sinus node and AV junction.

The direct effects of alinidine (N-allyl-clonidine) on the sinus node and atrioventricular (AV) junction were studied in 18 anesthetized dogs. Stimulus frequency-response curves to right stellate ganglion and right cervical vagus stimulations as well as responses to norepinephrine or acetylcholine were determined before and after selective perfusion of alinidine into the sinus node artery. Alinidine (1 microgram/ml) had no effect on spontaneous sinus rate [148 +/- 5 (SE) beats/min]. However, alinidine concentrations of 5, 10, and 25 micrograms/ml produced significant (P less than 0.05) sinus slowing to 138, 127, and 121 beats/min, respectively. Recovery to control rate was dose dependent and took from 4 to 33 min. Sinus rate increases with right stellate stimulations were not affected by alinidine. However, sinus rate decreases with right vagal stimulations were significantly (P less than 0.01) attenuated by alinidine. The negative chronotropic effects of acetylcholine were not influenced by alinidine. Alinidine (1-100 micrograms/ml into AV node artery) had no effect on the A-H interval of the His bundle electrogram. However, alinidine (10 and 25 micrograms/ml) diminished the AV block produced by stimulation of the left vagus in electrically paced hearts but not the negative dromotropic actions of directly administered acetylcholine. Thus alinidine has direct negative chronotropic effects, no effect on sinus node responses to sympathetic stimulation, ability to diminish sinus node and AV junctional responses to vagal stimulations without interference at the cholinergic muscarinic receptor, and 4) no effect on AV nodal conduction.