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Introduction: Parasympathetic activity predominates over sympathetic activity not only with respect to heart rate but also with respect to the pacemaker location in the dog heart. After we removed the parasympathetic neural elements in the sinoatrial (SA) fat pad in the right atrium, we observed that cervical vagus stimulation did not decrease the atrial rate, but it did suppress the increase in rate evoked by sympathetic stimulation. We determined whether the pacemaker rate and location were affected by presynaptic or postsynaptic mechanisms., Methods and Results: We determined the earliest activation site by means of isochronic activation mapping of the right atrium of open chest, anesthetized dog hearts. An electrode array, which consisted of 48 unipolar electrodes, was used to record atrial activation. This array covered the three main pacemaker regions, including the SA node region. After parasympathetic nerve fibers in the SA fat pad had been denervated, vagus stimulation at 10 and 30 Hz did not decrease the heart rate, but it attenuated the increase in heart rate evoked by sympathetic stimulation or isoproterenol. Vagus stimulation at 10 Hz during sympathetic stimulation did not shift the earliest activation site from the superior pacemaker region to the SA node region in 11 of 18 experiments. However, vagus stimulation at 10 Hz during isoproterenol infusion shifted the earliest activation site to the SA node region in 11 of 13 experiments. More intense vagus stimulation during combined sympathetic stimulation or isoproterenol infusion shifted the earliest activation site to the SA node or the inferior pacemaker region in 15 of 18 and in all experiments, respectively., Conclusion: The results suggest that activation of parasympathetic elements not located in the SA fat pad attenuates the increase in heart rate and the shift in pacemaker location evoked by sympathetic activation. The sympathetic and parasympathetic effects interact at presynaptic and postsynaptic sites in the dog heart.

1. The pacemaker site is known to shift away from the sinoatrial (SA) node in response to autonomic stimuli. 2. To test whether the shifting of the impulse-initiation site that occurs during autonomic nerve stimulation can be explained by the spatial distributions of beta-adrenoceptor and muscarinic receptors, we obtained densities (B(max)) and dissociation constants (K((d)) for these receptors in three regions along the sulcus terminalis (the SA node itself and regions superior and inferior to it) and a region of the right atrial appendage in the dog. 3. The Bmax values for [(125)I]-iodocyanopindolol binding to beta-adrenoceptors were not different among the four regions. The Bmax value for [(3)H]-quinuclidinyl benzilate binding to muscarinic receptors was significantly higher in the SA node area than in any other region (P < 0.01), although there was no difference among the other three regions. 4. For each receptor, K(d) values were similar among the four regions. 5. These results suggest that spatial variations in the densities of beta-adrenoceptors and muscarinic receptors are not important for shifting the impulse-initiation site and that other factors, such as non-uniform innervation by autonomic nerve fibres, may be mainly responsible for the pacemaker shift induced by autonomic nerve stimulation.

We investigated the effects of a continuous infusion of adenosine on responses of sinus rate and developed tension to bolus injections of adenosine and acetylcholine in isolated, blood-perfused canine right atria. Each drug was directly injected into the sinus node artery of the isolated atrium. During adenosine infusions, the negative chronotropic and inotropic responses to bolus injections of adenosine were significantly inhibited in a dose-related manner, while the negative responses to administered acetylcholine were consistently potentiated. These results indicate that adenosine infusion has an acute desensitizing action on subsequent bolus adenosine, although the cholinergic action is enhanced by a continuous infusion of adenosine.

Introduction: The site of impulse origin in the right atrium generally is considered to be a single static locus within the sinoatrial (SA) node. Previous investigators showed that the pacemaker site may shift due to changes in sympathetic or parasympathetic neural activity. We investigated the interactions between sympathetic and parasympathetic influences on the site of impulse initiation in the right atrium in anesthetized dogs., Methods and Results: We determined the site of impulse initiation and the spread of excitation over the anterior and posterior regions of the right atrium by a matrix of 48 unipolar recording electrodes. We assessed the spread of excitation at 3-msec intervals by constructing isochronal activation sequence maps. Sympathetic stimulation increased the frequency of atrial excitation (i.e., the heart rate), but also shifted the earliest activation region (EAR) from a locus in the SA node to a locus in the superior vena cava (the superior pacemaker site). Vagus stimulation decreased the heart rate and shifted the EAR to a lower site in the SA node or a site in the inferior right atrium along the sulcus terminalis (the inferior pacemaker site). A short period of vagus stimulation during a more prolonged sympathetic stimulation elicited a larger decrease in rate than did vagus stimulation alone and shifted the EAR from the superior site to the SA node or to the inferior site. After atropine, combined stimulation shifted the EAR to the superior site, but propranolol did not change EAR location., Conclusion: Our results suggest that parasympathetic activity predominates over sympathetic activity not only on heart rate, but also on the location of the EAR in the anesthetized dog.

To investigate the role on the right ventricular function of the parasympathetic nerves in discrete cardiac regions, we studied the effects of stimulation of the intracardiac parasympathetic nerves to the atrioventricular (AV) nodal area (AVPS) or sinoatrial (SA) nodal area (SAPS), and stimulation of the cervical vagus nerves (CVS) on the right atrial and ventricular function in the autonomically decentralized heart of the anesthetized dog. AVPS prolonged AV conduction time (AVCT) and decreased the ventricular rate without changes in atrial rate, right atrial 'a' wave pressure (RAP), its first derivative (RAd P/dt), right ventricular pressure (RVP) and its first derivative (RVd P/dt) in the spontaneously beating heart. On the other hand, AVPS prolonged the AVCT in the atrium paced electrically and further decreased the ventricular rate with decreases in ventricular pressure responses but not atrial responses. SAPS decreased atrial and ventricular rates without AVCT changes and attenuated the right atrial and ventricular pressure responses. In the atrial paced heart, SAPS decreased the ventricular responses less than those responses in the spontaneously beating heart with similar decreases in the atrial pressure responses, but it changed neither the AVCT nor ventricular rate. On the other hand, CVS decreased the atrial and ventricular rate or pressure responses, and increased the AVCT. CVS in the paced heart also decreased the atrial and ventricular pressure responses with the prolongation of AVCT. The cardiac responses to parasympathetic stimulations were abolished by atropine. These results suggest that AVPS decreases ventricular rate without direct right ventricular pressure effects but the negative chronotropic effects of AVPS and SAPS decrease the ventricular pressure responses rate-dependently in the dog heart.

Prolongation of the functional recovery of the sinoatrial (SA) nodal pacemaker activity after overdrive, "overdrive suppression," is determined by intrinsic pacemaker activity, pacemaker site, and SA conduction. We investigated the effects of E-4031, a blocker of a rapid type of the delayed rectifier K+ current (Ikr) and stimulation of the intracardiac parasympathetic nerves to the SA nodal region (SAP) on the prolongation of the first returning cycle length (1st RCL) after overdrive in autonomically decentralized hearts of open-chest anesthetized dogs. Second and third RCLs also were measured. We determined SA node recovery time (SNRT) and corrected SNRT (CSNRT) after atrial pacing at rates of 120, 150, and 200% of the control rate for 1 min and also determined SA conduction time (SACT) by the constant-atrial-pacing method. E-4031 (0.1-3 micromol/kg i.v.) increased the sinus cycle length (SCL) and SNRT dose dependently. However, E-4031 decreased CSNRT when the pacing rate was low or the number of pacing stimuli was small, although the agent did not induce a significant change in CSNRT when sufficient pacing stimuli were applied. E-4031 decreased SACT dose dependently. After E-4031 treatment. we observed changes in atrial electrical configurations, suggesting the possibility of pacemaker shift. When SAP stimulation increased SCL, SNRT, CSNRT, and SACT, E-4031 selectively inhibited the prolongation of SCL by SAP stimulation but did not affect the prolongation of CSNRT or SACT. These results suggest that functional recovery of the SA nodal pacemaker activity after overdrive is regulated by Ikr at least in part and that Ikr inhibition attenuates prolongation of the SCL but not the 1st RCL induced by parasympathetic nerve activation in the heart in situ.

We investigated the sympathetic-parasympathetic interactions involved in SA nodal pacemaker activity and AV conductivity in the anesthetized dog heart. Stimulation of the intracardiac parasympathetic nerves to the SA nodal region (SAPS) and stimulation of the intracardiac parasympathetic nerves to the AV nodal region (AVPS) induced negative chronotropic and dromotropic responses, respectively. Cardiac sympathetic stimulation, aminophylline, 3-isobutyl-1-methylxanthine (IBMX, a relatively pure nonselective phosphodiesterase inhibitor) and methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-p iridine-5-carboxylate (Bay k 8644, a Ca2+ channel agonist) increased sinus rate and decreased AV conduction time. Sympathetic stimulation augmented the negative chronotropic response to SAPS but not the negative dromotropic response to AVPS, IBMX augmented both responses, Bay k 8644 augmented the chronotropic response and attenuated the dromotropic response, and aminophylline did not affect the chronotropic response to SAPS and inhibited the dromotropic response to AVPS. Additionally, when Bay k 8644 directly given via the AV node artery decreased AV conduction time, it attenuated the negative dromotropic response to AVPS and carbachol injected into the AV node artery. These results suggest that the differential sympathetic-parasympathetic interactions on sinus rate and AV conduction are at least partly induced by an interaction between changes in slow inward Ca2+ current or intracellular Ca2+ and the cardiac effects of acetylcholine in the heart in situ.

Pituitary adenylate cyclase-activating polypeptide (PACAP) receptors exist, but the physiologic role of PACAP is unclear in the heart in situ. We investigated effects of PACAP-38 on sinus rate and on the negative chronotropic response to acetylcholine (ACh) or stimulation of the intracardiac parasympathetic nerve fibers to the sinoatrial nodal region in the automatically decentralized heart of the open chest, anesthetized dog. PACAP-38 (0.1-1 nmol) injected directly into the sinus node artery caused transient positive followed by negative chronotropic responses. Both pretreatment with atropine and tetrodotoxin inhibited the negative chronotropic responses to PACAP-38. However, hexamethonium did not block the negative responses to PACAP-38. After treatment with PACAP-38 (0.1-1 nmol), ACh induced atrial fibrillation significantly (p < 0.01). On the other hand, the negative chronotropic responses to intracardiac parasympathetic stimulation were not changed. These results suggest that (a) PACAP-38 induces negative chronotropic responses and liberates ACh from intracardiac postganglionic parasympathetic nerves, and that (b) PACAP-38 reduces ACh-induced atrial fibrillation threshold in the dog heart in situ.

The SA nodal pacemaker activity is regulated dominantly by autonomic nervous elements, i.e., sympathetic and parasympathetic nervous factors. In addition, circulatory bioactive substances and physicochemical factors also modify changes in sinus rate. Exogenously applied substances exert their actions on sinus rate directly and/or indirectly. The mechanisms of bradycardia and tachycardia induced by electrical nerve stimulation or exogenous substances are reviewed mostly by describing the results from experiments in isolated canine SA node preparations which were perfused with blood. In this review, newly developed bradycardic agents are introduced in addition to descriptions of numerous active substances developed in the past.

Stimulation of discrete intracardiac sympathetic nerves to the SA (SAS stimulation) or AV nodal region (AVS stimulation) increased the heart rate or decreased AV conduction time and caused an AV junctional rhythm, respectively, in anesthetized dogs treated with atropine. Topical application of tetrodotoxin (TTX) at the SAS or AVS stimulation locus totally inhibited the response to each stimulation, whereas each TTX treatment slightly attenuated the chronotropic response to the right ansa stimulation by 23 +/- 7.7% and the dromotropic response to the left ansa stimulation by 7 +/- 7.5%. TTX abolished AVS stimulation-induced one. Before atropine, topical application of hexamethonium at the locus for stimulation of intracardiac parasympathetic nerves to the SA (SAP stimulation) or AV nodal region (AVP stimulation) abolished almost totally negative chronotropic responses to SAP and cervical vagus stimulation or negative dromotropic responses to AVP and cervical vagus stimulation, respectively. These results demonstrate that activation of a very small population of intracardiac sympathetic nerves to target cells is enough to induced positive chronotropic and dromotropic responses in the heart in situ, and that SA and AV nodal pacemaker activity and AV conductivity are controlled multi-directionally by intracardiac sympathetic nerves in contrast with parasympathetic ones.

The effects of adenosine and adenosine triphosphate (ATP) on sinus cycle length (SCL) and sinoatrial conduction time (SACT) estimated by constant atrial pacing were studied in isolated, blood-perfused canine right atria. Adenosine and ATP were infused into the sinus node artery at a rate of 1, 2 and 4 micrograms/min. Both adenosine and ATP caused an increase in SCL and SACT in a dose-dependent manner and decreased atrial developed tension. There was no significant difference between the effect of adenosine and that of ATP on SCL and SACT. The prolongation of SACT induced by 4 micrograms/min of adenosine and ATP was significantly inhibited by a single injection of 1 to 3 mg of aminophylline, although this dose level of aminophylline did not significantly suppress the prolongation of SCL produced by adenosine and ATP. From these results it is concluded that both adenosine and ATP lengthen SCL and SACT in a dose-related manner, and that aminophylline blocks the increase in SACT much more easily than that in SCL.

Dopamine, administered at a constant infusion rate of 1-2 micrograms/min into the cannulated sinus node artery of the isolated dog atrium, decreased sinus cycle length (SCL) from 630 +/- 19 to 501 +/- 22 msec (mean +/- SEM, 38 trials in 12 atria). However, on sinoatrial conduction time (SACT) estimated by a constant atrial pacing method, dopamine produced 2 types of response (shortening and lengthening) with sinus tachycardia. In 24 trials in 11 atria, the drug decreased SACT from 86 +/- 8 to 56 +/- 4 msec, and in 14 trials in 6 atria it increased SACT from 67 +/- 7 to 101 +/- 9 msec. In general, the effects of dopamine on SACT were dependent on the control levels of SCL: dopamine caused a reduction of SACT at small levels of SCL and a prolongation at large levels. At a control sinus rate of 120 beats/min, dopamine usually shortened SACT. Dopamine-induced shortening of SACT was blocked by a beta-adrenoceptor blocker, propranolol, and an uptake blocker, imipramine, but not by a dopaminergic inhibitor, sulpiride. Furthermore, dopamine-induced lengthening of SACT tended to be suppressed by propranolol, but not by sulpiride. It is concluded that the dopamine-induced changes in SACT are mediated via beta-adrenergic mechanism and partially due to a tyramine-like action.

Using isolated, blood-perfused atrium preparation of the dogs, the effect of stretch on sinus rate was studied in 11 preparations. Stretching usually produced sinus acceleration in all 11 spontaneously beating atria. Within a range of 0--30 Gm, greater degrees of stretch produced greater degrees of sinus acceleration. During maintained stretch sinus rate slightly reduced but not to the control rate. On release from stretch sinus rate immediately returned to the control rate, and there was occasionally a slowing to rates lower than control in verapamil treated preparations. Atropine, adrenergic beta-receptor blocking agents, propranolol and carteolol, verapamil, and tetrodotoxin did not greatly modify responses to stretching.

1. The effects of five antiarrhythmic drugs (quinidine, procainamide, lignocaine, phenytoin and propranolol) were studied on pacemaker activity in the sinoatrial node and on contractility in twenty-three isolated, blood-perfused atrium preparations of dogs. Each drug was administered directly into the cannulated sinus node artery of an isolated atrium over a period of 4 s. 2. Quinidine produced negative chronotropic and inotropic effects. Occasionally, higher doses induced a biphasic inotropic effect, an initial negative phase being followed by an increase in contractility. 3. Three response patterns to procainamide were observed: negative chronotropic and inotropic effects; biphasic effects, initially negative chronotropic and inotropic effects being followed by positive effects; a biphasic inotropic effect and a negative chronotropic effect. The third pattern was most frequently produced by relatively high doses. 4. Lignocaine, phenytoin and propranolol induced dose-related negative chronotropic and inotropic effects. 5. All five of the antiarrhythmic drugs used caused sinus arrest in high doses. 6. Procainamide-induced positive chronotropic and inotropic effects were significantly inhibited by treatment with alprenolol or nadolol, but not by tetrodotoxin or desipramine. 7. These results indicate that procainamide-induced positive chronotropic and inotropic effects may involve an adrenergic mechanism.

Using an isolated, blood-perfused atrium preparation, the effects of temperature on SA nodal pacemaker activity were investigated in 9 preparations. The PP interval decreased as temperature was raised. Regular sinus rhythm and atrial contraction were maintained above approximately 26 degrees C. Below 26 degrees C, sinus depolarization still showed a regular rate, although atrial contractions had ceased. At about 24 degrees C, atrial rhythm became irregular. Below 20 degrees C, atrial depolarization disappeared. Chronotropic responses to norepinephrine were suppressed at decreased temperatures, not only with respect to maximum PP shortening but also to the threshold dose for inducing sinus acceleration. Overdrive suppression was not influenced significantly by decreasing temperature. These results indicate that a temperature decrease causes suppression of SA nodal pacemaker activity, although the SA node continues to function regularly until about 25 degrees C.

Injection of a single bolus of acetylcholine into the sinus node artery of the isolated atrium of the dog produces a triphasic response similar to that previously observed after a single stimulus to the vagus nerves. There is an initial, brief but pronounced, cardiac deceleration followed by a brief, slight acceleration, which is then followed by a more prolonged deceleration which is of lesser magnitude than the initial deceleration. The most likely cause of the intermediate phase of cardiac acceleration is a direct effect of acetylcholine on the pacemaker cells, as it is also with the primary and tertiary phases of cardiac deceleration.

A constant pressure perfusion of the sinus node artery was performed in 10 in situ and in 3 isolated SA node preparations. The selective administration of apomorphine caused a negative chronotropic effect which was not blocked by treatment with atropine. The sinus deceleration was usually produced by apomorphine, 10-300 mug, while sinus irregularity and finally atrioventricular nodal rhythm in the in situ preparation or sinus arrest in the isolated one resulted from doses above 1 mg. In the in situ preparation at a higher dose from 300 mug to 1 mg, a slight sinus acceleration was occasionally induced following sinus deceleration; In this time, a fall in blood pressure was usually observed; This acceleration response to apomorphine was inhibited by propranolol. From these results, it is concluded that apomorphine induces direct depressive action on the SA node and, in extremely high doses, a slight sinus acceleration may be induced by reflex mechanism.

The isolated blood-perfused preparations of canine atrium were suspended in a bath and perfused with arterial blood led from the carotid artery of the heparinized donor dog. Disopyramide caused dose-related negative chronotropic and inotropic effects in a dose range of 30-1000 microgram when injected directly into the cannulated sinus node artery of the isolated atrium. The order of potencies for inducing the negative chronotropic effect in isolated atrium preparations was verapamil greater than propranolol greater than lidocaine = quinidine greater than phenytoin greater than or equal to disopyramide greater than procainamide. On the other hand, the order of potencies for inducing the negative inotropic effect was verapamil = propranolol greater than lidocaine greater than or equal to phenytoin greater than disopyramide greater than procainamide greater than or equal to quinidine. When disopyramide (1 mg/kg or 3 mg/kg) was administered i.v. into the jugular vein of the donor dog, the systemic blood pressure of the donor dog was markedly decreased. However, the tension developed and sinus rate of the isolated atrium were only slightly decreased. Disopyramide produced greater suppression at higher frequencies and slightly depressed the calcium chloride-induced positive inotropic effects.

We studied the effects of five beta-adrenoceptor blocking agents (propranolol, atenolol, sotalol, oxprenolol and carteolol) on sinus cycle length (SCL), sinoatrial conduction time (SACT) measured with a constant atrial pacing technique, and atrial developed tension (DT), using isolated blood-perfused canine atria. Except for carteolol, all tested beta-blockers were infused into the sinus node artery at a rate of 1-4 micrograms/min, and carteolol was given continuously at a rate of 0.1-0.4 micrograms/min. Atenolol and sotalol as well as propranolol prolonged SCL and SACT and reduced DT dose-dependently, although propranolol had more potent negative chrono-, dromo- and inotropisms than atenolol and sotalol. Oxprenolol did not change SCL significantly, but lengthened SACT at higher doses and decreased DT in a dose-related manner. Carteolol did not cause any significant changes in the three parameters. The relative potencies on deceleration of SA conduction on the basis of administration of doses which seems to be equipotent as to beta-blocking effect are as follows: propranolol greater than atenolol = sotalol greater than oxprenolol = carteolol. These results suggest that the membrane stabilizing action of beta-blockers may lengthen SACT but that the intrinsic sympathomimetic action of beta-blockers may resist such a prolongation of SACT.

The effects of a novel piperazine derivative (INO 2628) on sinus node pacemaker activity and atrial contractile force were investigated in isolated, blood-perfused dog atrium. Injections of INO 2628 (0.03-100 mumol) into the sinus node artery of the isolated atrium induced a dose-dependent decrease in sinus rate and an increase in contractile force. The positive inotropic effects at more than 10 mumol were accompanied by a transient negative inotropism. Propranolol did not affect the positive inotropic response to INO 2628, but it significantly suppressed positive chronotropic and inotropic responses to norepinephrine. Atropine at a dose which completely blocked negative chronotropic and inotropic responses to carbachol, produced a slight but significant depression of INO 2628-induced negative chronotropic responses; inotropic responses were unaffected. These results suggest that INO 2628 induces noncholinergic negative chronotropic and nonadrenergic positive inotropic responses in isolated dog atria.

Our previous study demonstrated that class I antiarrhythmics (fast sodium channel blockers) increased sinoatrial conduction time (SACT) in a dose-related fashion, indicating that a fast sodium current might play an important role in sinoatrial conduction. To assess a role of a slow calcium current in sinoatrial conduction, we examined effects of calcium channel blockers (diltiazem, verapamil, AQ-A 39, dilazep and bepridil) on SACT estimated by the constant atrial pacing in addition to on sinus cycle length (SCL) and on atrial developed tension (DT), using the isolated and blood-perfused dog right atrium. These calcium entry blockers except for bepridil were administered into the cannulated sinus node artery at an infusion rate of 0.2, 0.4 and 1.0 micrograms/min and bepridil at a rate of 0.6, 1.2 and 3.0 micrograms/min. The calcium antagonistic agents produced a dose-dependent decrease in DT and increase in SCL. The observed order of depression of inotropism was verapamil greater than diltiazem greater than bepridil = dilazep greater than AQ-A 39, while the order of negative chronotropism was diltiazem greater than verapamil greater than AQ-A 39 greater than dilazep greater than bepridil. However, as to dromotropism none of the five drugs exerted significant influences on SACT. From the previous and present results it is concluded that the fast sodium current may be predominantly important in sinoatrial conduction.

The magnitude of overdrive suppression of the SA nodal pacemaker activity was markedly influenced by its ischaemia which was produced by occlusion of the perfusion tubing close to the sinus node artery in the in-situ and isolated canine sino-atrial node preparations. In all isolated preparations, postdrive suppression was significantly augmented after occlusion of the perfusion system for at least 120 seconds. It is concluded that total ischaemia depresses sino-atrial node function in the atropinized canine heart and that postdrive suppression is a good index of such impaired function.

The effects of therapeutic doses of antiarrhythmic drugs (12 mg/Kg of procainamide, 2 mg/Kg of disopyramide and 0.2 mg/Kg of propranolol) on sinus cycle length (SCL), sinoatrial conduction time (SACT) estimated by a constant atrial pacing technique, and atrial developed tension (DT) were measured in isolated canine atria cross-perfused with heparinized arterial blood from donor dogs as well as on mean systemic blood pressure (SBP) and on heart rate (HR) in those dogs. Procainamide, which produced hypotension and bradycardia in the donor dog, did not change SACT significantly, although it increased SCL and decreased DT in the isolated atrium. However, disopyramide raising SBP slightly (but not significantly) and decreasing HR in the donor dog produced a significant prolongation of SACT and SCL and reduction of DT in the isolated atrium. Propranolol caused slight but insignificant hypotension and long-lasting bradycardia in the donor dog, accompanied by a significant increase in SCL and SACT, and decrease in DT in the isolated canine atrium. We concluded that SACT was significantly increased by a therapeutic dose of propranolol and disopyramide but was not altered by that of procainamide.

Direct perfusion of the sinus node artery at constant pressure of 100 mmHg was arranged in 6 canine hearts in situ. The injection of phentolamine into the sinus node artery usually induced dose-dependent positive chronotropic effect. However, at a larger dose of 300 mug, phentolamine frequently induced a biphasic chronotropic response, i.e., sinus deceleration followed by sinus acceleration. Phentolamine at a large dose of 1 mg usually induced a negative chronotropic effect. The threshold dose for inducing sinus acceleration was about 1 to 10 mug. The positive chronotropic response to phentolamine was blocked either by propranolol or by tetrodoxin. That to norepinephrine was blocked by propranolol but not suppressed by tetrodotoxin. These results suggest that the phentolamine-induced sinus acceleration is due to catecholamine which is released by excitation of local adrenergic fibers. The sinus deceleration to higher doses of phentolamine was not blocked either by atropine or by tetrodotoxin. It suggests that phentolamine has a direct depressive effect on the SA node at extremely high dose levels.

(1) Using isolated, blood-perfused atrium preparation of dogs, the effect of ischemia on sinus rate was studied in ten preparations. Cessation of atrial perfusion usually induced gradual deceleration of the sinus rate which was not blocked by atropine. Occasionally, brief and slight sinus acceleration was initially observed in three of ten atrium preparations. This positive chronotropic effect was not blocked by a beta-adrenoceptor blocking agent, propranolol. (2) In every preparation, just after release of occlusion, there was an initial profound sinus deceleration, occasionally followed by oscillatory changes in sinus rate. (3) The chronotropic response pattern induced by temporary occlusion and release of the sinus node artery was not influenced by propranolol, phenoxybenzamine or atropine treatment. (4) These results suggest that ischemia exerts its principal effect directly on the sino auricular node pacemaker cells, rather than on neighboring nerve endings.

We examined the effects of four antiarrhythmic drugs (quinidine, disopyramide, procainamide and propranolol) on sinus cycle length (SCL), sinoatrial conduction time (SACT) measured by a constant atrial pacing technique, and atrial developed tension (DT), using isolated blood-perfused dog atrial preparations. When an infusion rate of 10-40 micrograms/min of quinidine, disopyramide or procainamide was continuously given into the sinus node artery and propranolol at a rate of 1-4 micrograms/min, all the agents prolonged SCL and SACT, and reduced DT dose-dependently, but not in the same fashion. Propranolol caused almost a parallel action in prolongation of SCL and SACT, and reduction of DT in increasing doses. Quinidine, disopyramide and procainamide caused negative inotropic and chronotropic effects with only a small prolongation of SACT in a relatively small dose. At larger doses, quinidine and disopyramide produced a relatively more marked prolongation of SACT than procainamide. In the doses used, quinidine, disopyramide and procainamide caused relatively small depression of DT in contrast to propranolol. The order of potencies for inducing a prolongation of SACT was propranolol greater than quinidine = disopyramide greater than procainamide.

The effects of potassium chloride were studied on pacemaker activity in the sinoatrial (SA) node and on contractility in isolated, blood-perfused atrial and left ventricular preparations of dogs, which were suspended in the bath and perfused with arterial blood from the carotid artery of the heparinized support dog. Potassium chloride given directly into the sinus node artery in a dose range of 100 micrograms--1 mg produced a dose-related positive chronotropic and a negative inotropic effect in isolated atrium preparations. Potassium chloride into the cannulated anterior descending branch of the left coronary artery caused only a negative inotropic effect in isolated ventricular preparations. A larger dose of potassium chloride caused temporary atrial or ventricular arrest. These effects of potassium chloride were not modified by pretreatment with atropine or propranolol.

Using 10 isolated, blood-perfused canine atrial, and ventricular preparations, the effects of d- and l-verapamil on SA nodal pacemaker activity and contractility were investigated. l-verapamil and d-verapamil produced dose-related negative chronotropic and inotropic effects in all experiments. l-verapamil was approximately 10 time more potent than d-verapamil both in inotropism and chronotropism. Negative inotropism of either d- or l-verapamil can be reversed by injection of calcium chloride. Not only d-verapamil but also l-verapamil produced a stronger suppression at higher frequencies in both atrial and ventricular muscles.

Effects of salmon calcitonin on SA node pacemaker activity and contractility were investigated in isolated atrium and papillary muscle preparations which were perfused with arterial blood led from a carotid artery of the support dog. Calcitonin at a dose range from 0.005 to 0.16 units was injected into the cannulated sinus node artery, which dose-relatedly caused a negative chronotropic and inotropic effect in atrium preparations. This negative effect was not modified by treatment with atropine. On the other hand, in the isolated paillary muscle preparations, an intraarterial calcitonin caused little negative inotropic effect even at higher dose level of 0.16 units. From these results, it is concluded that 1) in chronotropy, calcitonin causes a negative chronotropic effect, and 2) in inotropy calcitonin causes a negative inotropic effect on the atrium but not on the ventricle.

We studied the direct effects of digitalis on sinoatrial conduction time (SACT), atrial rate (AR) and developed tension (DT) in isolated atrial muscle, using an isolated dog atrial preparation perfused with heparinized blood from the carotid artery of an anesthetized donor dog. After digoxin or deslanoside (100 micrograms or 200 micrograms/Kg) was given intravenously to the donor dog, SACT, AR and DT of the isolated atrium were continuously measured. Following administration of 100 micrograms/Kg of digoxin, an immediate sinus bradycardia followed by various kinds of ventricular arrhythmias was observed in the donor dog, and the DT of the isolated atrium was augmented without any effects on the SACT and AR in all 3 experiments. With 200 micrograms/Kg of digoxin or deslanoside, ventricular fibrillation was induced in all 5 donor dogs within 75 min after digitalis administration. In these cases, the DT of the isolated atrium was immediately increased to over 200% of control DT, but SACT and AR were not affected until 20 min later, at which time increases in SACT and AR were finally induced. From these results, it is concluded that a large amount of digitalis has no distinct direct effect on SA nodal pacemaker activity and SA conductivity. Moreover, extremely large doses of digitalis which cause ventricular fibrillation might also induce a prolongation of SACT in addition to sinus tachycardia.

The right atrium isolated from the dog heart was perfused through the cannulated sinus node artery with heparinized arterial blood led from a support dog anesthesized with 30 mg/Kg of sodium pentobarbital. When adenosine was administered into the sinus node artery, negative chronotropic and inotropic effects were dose-relatedly induced. The threshold dose for inducing the negative ones was 0.3 mug. Even a large dose level of 100 mug of adenosine did not cause sinus arrest although a profound sinus deceleration was induced. Adenosine action was suppressed by treatment with caffeine both in chronotropism and in inotropism. On the other hand, ACh induced only negative inotropic effect at a dose range of 0.01-0.03 mug. At 0.1 mug, ACh produced a significantly negative chronotropic effect. A large amount of 3-10 mug of ACh usually caused sinus arrest. Atropine treatment inhibited a negative chronotropic effect much more readily than a negative inotropic one. Although ACh action was enhanced by physostigmine, the difference of threshold doses remained unchanged even after physostigmine treatment. From these results, either adenosine or ACh depresses both SA nodal pacemaker activity and atrial contractile force and there may be the difference of receptor density for ACh between the SA node and atrial tissue.