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Aim: To investigate the prevalence and geographical variation of high arterial stiffness in groups from the Amami islands (Amami) and Kagoshima mainland (mainland), Japan, using the cardio-ankle vascular index (CAVI) as a surrogate marker of arterial stiffness., Methods: We recruited 4,523 health checkup examinees from Amami and 440 examinees from the mainland, with an age range of 40-69 years. The frequency of high arterial stiffness (CAVI≥9.0) was geographically compared between the regions, and both mean CAVI values were compared with those of the healthy Japanese population with less risk factors for coronary artery disease. Clinical, lifestyle, and regional factors for increased CAVI values were estimated by the multiple linear regression model., Results: The frequency of high arterial stiffness on Amami was significantly lower than on the mainland. Mean CAVI values on Amami were similar in males and lower in females than in the healthy Japanese population, but those on the mainland were higher for both sexes. Age, systolic blood pressure, triglycerides, fasting blood glucose, and a history of hypertension and diabetes mellitus were positively related to increased CAVI values on Amami. The regional factor of Amami, compared with the mainland, was negatively related to increased CAVI values in both sexes after adjusting for traditional cardiovascular risk factors., Conclusion: CAVI values in Amami residents were significantly lower than in mainland residents, suggesting that environmental or genetic factors might have improved arterial stiffness in the Amami population.

Using isolated, blood-perfused canine atrial preparations, adenosine was continuously administered at various infusion rates into the cannulated sinus node artery. Adenosine induced negative chrono- and inotropic effects in an infusion-rate related manner. The inotropic responses to the adenosine infusion apparently faded but the chronotropic responses did not. Effects of a bolus injection of adenosine, acetylcholine (ACh), or norepinephrine and effects of intracardiac autonomic nerve stimulation (ICNS) were examined before and during the adenosine infusion. During the adenosine infusion, adenosine-induced effects were significantly reduced but ACh-induced ones were significantly potentiated, and the norepinephrine-induced effects were slightly depressed. ICNS readily induced negative and positive chrono- and inotropic responses which were blocked by atropine and propranolol. These negative responses were enhanced but positive ones were slightly but insignificantly depressed during the adenosine infusion. From these results, it is concluded that adenosine infusion (1) produces a stable continuous bradycardia but in the developed tension an initial decrease is followed by a gradual recovery response showing the fade phenomenon, (2) causes an acute desensitizing action on a subsequent bolus dose of adenosine, and (3) induces a weak antiadrenergic effect, while enhancing cholinergic effects in isolated canine atria.

There is no data about whether botulinum neurotoxin inhibits the parasympathetic ganglionic neurotransmission in the heart, although botulinum toxin as a clinical drug inhibits the release of acetylcholine at the neuromuscular junction. Therefore, we investigated whether botulinum toxin (type A) injected into the sinoatrial (SA) fat pad inhibits decreases in heart rate induced by stimulation of the preganglionic parasympathetic nerves in the heart of the anesthetized dog. Stimulation of the parasympathetic nerves in the SA fat pad (SAP stimulation) prolonged the atrial interval but not the atrioventricular (AV) interval, and cervical vagus nerve stimulation (CV stimulation) prolonged both atrial and AV intervals. After botulinum toxin (20 or 25 mouse units) was injected into the SA fat pad, it gradually inhibited the prolongation of the atrial interval evoked by SAP and CV stimulations but not the prolongation of the AV interval evoked by CV stimulation. Conditioning successive stimulation of the cervical vagus nerves accelerated the inhibition by botulinum toxin of the chronotropic response to CV stimulation. These results indicate that selective injection of botulinum toxin into the SA fat pad blocks bradycardia mediated by parasympathetic ganglionic activation in the dog heart.

Some parasympathetic ganglionic cells are located in the epicardial fat pad between the medial superior vena cava and the aortic root (SVC-Ao fat pad) of the dog. We investigated whether the ganglionic cells in the SVC-Ao fat pad control the right atrial contractile force, sinus cycle length (SCL), and atrioventricular (AV) conduction in the autonomically decentralized heart of the anesthetized dog. Stimulation of both sides of the cervical vagal complexes (CVS) decreased right atrial contractile force, increased SCL, and prolonged AV interval. Stimulation of the rate-related parasympathetic nerves to the sinoatrial (SA) node (SAPS) increased SCL and decreased atrial contractile force. Stimulation of the AV conduction-related parasympathetic nerves to the AV node prolonged AV interval. Trimethaphan, a ganglionic nicotinic receptor blocker, injected into the SVC-Ao fat pad attenuated the negative inotropic, chronotropic, and dromotropic responses to CVS by 33 approximately 37%. On the other hand, lidocaine, a sodium channel blocker, injected into the SVC-Ao fat pad almost totally inhibited the inotropic and chronotropic responses to CVS and partly inhibited the dromotropic one. Lidocaine or trimethaphan injected into the SAPS locus abolished the inotropic responses to SAPS, but it partly attenuated those to CVS, although these treatments abolished the chronotropic responses to SAPS or CVS. These results suggest that parasympathetic ganglionic cells in the SVC-Ao fat pad, differing from those in SA and AV fat pads, nonselectively control the atrial contractile force, SCL, and AV conduction partially in the dog heart.

1. Cardiac effects of lignocaine on sinoatrial nodal pacemaker activity and atrial contractility were investigated in five canine isolated, blood-perfused right atria that were perfused with heparinized blood from support dogs. The effects of lignocaine on responses to intracardiac nerve stimulation and administered acetylcholine and noradrenaline were also examined. 2. Lignocaine was injected into the support dog intravenously or administered selectively to the sinus node artery of the isolated atrium. At doses that did not produce significant depressor action (0.3, 1.0 and 3.0 mg/kg), lignocaine produced no significant changes in heart rate. A large dose of 10 mg/kg lignocaine caused significant depressor effects and slight bradycardia. Direct administration of lignocaine (0.3, 1.0, 3.0, 10.0 and 30.0 mumol) into the sinus node artery of the isolated atrium consistently caused slight negative chronotropic and rather marked negative inotropic effects. 3. After treatment with a relatively large dose of lignocaine, electrical stimulation-induced negative chronotropic and inotropic responses were significantly inhibited in a dose-related manner, but positive chronotropic and inotropic responses were slightly depressed only at an extremely high dose of lignocaine (10.0 mumol). 4. Noradrenaline-induced positive chronotropic and inotropic effects were not modified by any doses of lignocaine used (0.3, 1.0, 3.0 and 10.0 mumol). Acetylcholine-induced negative chronotropic and inotropic effects were slightly, but significantly, depressed by 10 mumol lignocaine. 5. These results suggest that a relatively large dose of lignocaine has a dominant presynaptic inhibitory action, particularly on the parasympathetic component.

To investigate whether slow inward Ca2+ current (ICa), hyperpolarization-activated inward current (If), and a rapid type of delayed rectifier K+ current (IKr) similarly act on the pacemaker location, sinoatrial node region, and subsidiary superior and inferior pacemaker regions, we studied the effects of verapamil, zatebradine, and E-4031 on the atrial rate and the 3-ms earliest activation region (EAR) determined from the isochronal activation sequence map in the autonomically decentralized heart of the anesthetized dog. Three blockers decreased atrial rate similarly. Verapamil shifted the EAR from the SA node region to the inferior pacemaker region. The EAR induced by zatebradine was variable, but the EAR induced by E-4031 tended to shift to the inferior pacemaker region. Sympathetic nerve stimulation increased atrial rate and shifted the EAR to the superior pacemaker region. Verapamil attenuated the increased atrial rate by 28%, and it shifted the EAR to the lower pacemaker regions consistently. Zatebradine also attenuated the increased rate by 53% and shifted the EAR from the anterior to the posterior-superior right atrium. On the other hand, E-4031 affected neither the rate nor the EAR in response to sympathetic stimulation. These results suggest that ICa, If, and IKr inhibitors differentially influence the pacemaker activity among three pacemaker regions when sympathetic tone is absent or present and that the role of ICa, If, and IKr of the pacemaker cells distributed in the atrial pacemaker complex is different in the dog heart in situ.

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.

No data are available for the direct effect of C-type natriuretic peptide (CNP) on atrioventricular (AV) conduction in mammalian hearts. Thus we studied the dromotropic effects of CNP-22 injected into the AV node artery in autonomically decentralized hearts in open-chest, anesthetized dogs. CNP decreased AV interval (AV conduction time) in a dose-dependent manner with increase in coronary artery blood flow rate in six anesthetized dogs. Isosorbide dinitrate did not affect AV interval, but it increased coronary artery blood flow rate. A guanylyl cyclase-linked natriuretic peptide receptor antagonist, HS-142-1, inhibited the decreases in AV interval and the increases in coronary blood flow rate in response to CNP, whereas propranolol did not affect the positive dromotropic response to CNP. These results demonstrate that CNP decreases AV interval and increases coronary artery blood flow rate mediated by a guanylyl cyclase-linked natriuretic peptide receptor, but not beta-adrenoceptor, in the dog heart.

Recent observations indicate that several neuropeptides may be involved in the regulation of cardiac function, but the effects of these peptides on the atrium are not always the same as those on the ventricle. To compare the effect of pituitary adenylate cyclase-activating polypeptide (PACAP)-27 on the atrium with that on the ventricle, we investigated the effects of PACAP-27 on the sinus rate and atrial and ventricular contractility in isolated, blood-perfused dog heart preparations. PACAP-27 (0.01-0.3 nmol) caused transient positive followed by negative chronotropic and inotropic responses in a dose-dependent manner in the isolated right atrium, whereas it caused only a dose-dependent positive inotropic response in the left ventricle. After atropine treatment, PACAP-27 caused only positive cardiac responses in isolated atria. The order of the increase in response to PACAP-27 was atrial contractile force > sinus rate > or = ventricular contractile force. Tetrodotoxin blocked the negative chronotropic and inotropic responses to PACAP-27 in isolated atria. Propranolol did not affect the positive response. PACAP-(6-27), a type I PACAP receptor antagonist, attenuated the positive responses similarly in the atropine-treated right atrium and the left ventricle. Thus, we demonstrated that (1) PACAP-27 caused negative cardiac effects in the atrium and sinoatrial node by activation of intracardiac parasympathetic nerves, but had no negative effect on the ventricle; (2) PACAP-27 had positive effects in the atrium, sinoatrial node and ventricle mediated by type I PACAP receptors, but PACAP-27 was more effective in the atrium and sinoatrial node than in the ventricle of 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 whether the intracardiac parasympathetic ganglia for sinoatrial (SA) nodal pacemaker cells control the right atrial contractility selectively and totally in the autonomically decentralized heart of the open-chest anesthetized dog. Stimulation of the intracardiac parasympathetic nerves to the SA nodal area (SAP Stim) decreased the right atrial pressure (a wave pressure) and its first pressure derivative (dP/dt) as well as the atrial rate but did not change the atrioventricular (AV) conduction time. Stimulation of right and left cervical vagosympathetic complexes (CV Stim) decreased the a wave pressure, dP/dt, and atrial rate and prolonged the AV conduction time. When SAP and CV Stim decreased the atrial rate similarly, the decreases in a wave pressure and dP/dt in response to SAP Stim were less than those to CV Stim in unpaced and paced hearts. When treatment with hexamethonium bromide or tetrodotoxin into the SAP Stim locus abolished the decreases in atrial rate evoked by SAP and CV Stim, each treatment abolished the decrease in a wave pressure response to SAP Stim but only slightly attenuated the pressure response to CV Stim. These results demonstrate that right atrial pressure is modified by efferent parasympathetic neurons, which are located in a region that differs from that of efferent parasympathetic neurons controlling heart rate.

E4080, a novel bradycardic agent acts on various ionic currents including the hyperpolarization-activated inward current (I(f)), L-type Ca2+ current (ICa) and ATP-sensitive K+ (K+ATP) current in mammalian heart and vascular tissues. We thus investigated the chronotropic and inotropic effects of E4080 and its interaction with the positive cardiac responses to norepinephrine, 3-isobutyl-1-methyl-xanthine (IBMX) and Bay k 8644 in the isolated, blood-perfused dog right atria and left ventricles. E4080 (0.01-1 mumol) decreased the sinus rate and atrial and ventricular contractile forces in a dose-related manner. Glibenclamide (3 mumol) partly blocked the decrease in atrial force but not the decreases in sinus rate and ventricular force induced by E4080. Atropine (10 nmol) did not affect the negative cardiac responses to E4080. E4080 (0.01-1 mumol) inhibited the positive chronotropic responses to norepinephrine and IBMX dose dependently, but did not inhibit the positive inotropic ones in isolated atria. E4080 affected neither positive chronotropic nor inotropic responses to Bay k 8644. These results suggest that (1) the activation of K+ATP channels by E4080 is partly related to the decrease in atrial force but not the decreases in sinus rate and ventricular force, and (2) the selective inhibition of E4080 of the cyclic AMP-dependent positive chronotropic responses but not inotropic ones is probably due to the inhibition of I(f) rather than other properties, e.g., activation of K+ATP channels and inhibition of ICa in the dog heart.

1. We investigated the effects of omega-conotoxin GVIA (omega-CgTX), a blocker of N-type voltage-operated calcium channels, on the chronotropic response to stimulation of the intracardiac sympathetic and parasympathetic nerves in the isolated, blood-perfused right atrium of the dog. 2. omega-CgTX (0.3-3 nmol) itself did not affect the sinus rate significantly, but it inhibited the negative followed by positive chronotropic response to simultaneous stimulation of sympathetic and parasympathetic nerves in a dose-dependent manner. 3. omega-CgTX at higher doses (1-3 nmol) inhibited the positive response to sympathetic stimulation more strongly than the negative response to parasympathetic stimulation. omega-CgTX (3 nmol) abolished the positive chronotropic response to sympathetic nerve stimulation in the atrium treated with atropine, but did not abolish the negative response to selective parasympathetic stimulation. Neither the chronotropic response to noradrenaline nor the response to acetylcholine was affected by omega-CgTX. 4. These results indicate that omega-CgTX inhibits not only the response to sympathetic stimulation but also the response to parasympathetic stimulation in the dog heart and it inhibits the positive chronotropic response to sympathetic stimulation more strongly than the negative chronotropic response to parasympathetic stimulation.

We investigated the effects of V1 IOPC-21268, 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)-3,4-dihydro-2( 1H)- quinolinone) and V2 (OPC-31260, 5-dimethylamino-1[4-(2-methylbensoylamino)benzoyl]-2,3,4,5-tetrahy dro-1H- benzazepine) vasopressin receptor antagonists on the negative inotropic response to arginine vasopressin (AVP) in the isolated perfused heart preparations of the dog. AVP (7.5-750 pmol) decreased the atrial and ventricular contractile force when the preparation was perfused with constant pressure or constant flow. AVP induced a small increase in sinus rate. Desmopressin, a selective vasopressin V2 agonist, did not change the sinus rate and atrial or ventricular contractile force. OPC-21268 (0.01-3 mumol) and OPC-31260 (0.01-1 mumol) induced a small negative inotropic effect. Both OPC-21268 and OPC-31260 inhibited the negative inotropic response to AVP in a dose-dependent manner. The doses of 50% inhibition (ID50) for OPC-21268 and OPC-31260 on the inotropic effect were 0.30 +/- 0.16 mumol and 0.084 +/- 0.034 mumol, respectively. Neither OPC-21268 nor OPC-31260 affected the acetylcholine-, adenosine- or norepinephrine-induced inotropic and chronotropic effects. It has been reported that the concentration of OPC-21268 that displaced 50% of specific AVP binding is 0.4 microM for V1 receptors and > 100 microM for V2 receptors and the concentration of OPC-31260 is 0.01 microM for V2 receptors and 1 microM for V1 receptors. We, therefore, suggest that AVP directly causes negative inotropic effects mediated at least in part by V1 receptors in the dog heart.

We investigated the beta 2-adrenoceptor-mediated effects of atrial and ventricular effective refractory period (ERP), SA node pacemaker activity, and AV conductivity induced by sympathetic nerve stimulation or epinephrine infusion in anesthetized dogs. A beta 2-adrenoceptor antagonist, ICI 118,551 up to 100 micrograms/kg, i.v., inhibited the positive chronotropic and dromotropic responses to sympathetic stimulation but did not shorten the atrial or ventricular ERP, ICI 118,551 also attenuated the positive chronotropic and dromotropic responses and the shortening of atrial ERP in response to epinephrine but not the shortening of ventricular ERP. A selective beta 1-adrenoceptor antagonist, atenolol, inhibited each electrical cardiac response to sympathetic stimulation and epinephrine infusion in a similar manner. These results suggest that beta 2-adrenoceptor-mediated electrical cardiac responses to endogenous catecholamines also exist in addition to the predominant beta 1-adrenoceptor-mediated responses, and that the order of the proportion of beta 2-adrenoceptor-mediated cardiac effects was SA node pacemaker activity much greater than AV conductivity = atrial ERP much greater than ventricular ERP in the dog heart.

We investigated the blocking effects of vecuronium and pancuronium on the negative chronotropic and dromotropic responses to stimulation of the parasympathetic nerves in the anesthetized, open-chest dog. We stimulated the intracardiac parasympathetic nerves to the SA nodal region (SAP stimulation) or to the atrioventricular nodal region (AVP stimulation). SAP stimulation or AVP stimulation selectively decreased heart rate or increased atrioventricular conduction time, respectively. Vecuronium and pancuronium inhibited the chronotropic response to SAP stimulation and the dromotropic response to AVP stimulation in a dose-dependent manner. The ID50 of each drug for the dromotropic response was less than that for the chronotropic response. The blocking effect of vecuronium on the negative cardiac responses to parasympathetic stimulation was about 10-fold less potent than that of pancuronium. These results suggest that the blocking effects of vecuronium and pancuronium on the negative chronotropic and dromotropic responses to parasympathetic stimulation differ from those of atropine in the heart. In the isolated right atrium perfused with blood from the support dog, vecuronium, injected into the external jugular vein of the support dog, dose-dependently inhibited the negative chronotropic and inotropic responses to carbachol or SAP stimulation and the negative followed by positive chronotropic and inotropic responses to nicotine. The ID50 values for carbachol, nicotine and SAP stimulation were not significantly different. These results suggest that parasympatholytic effects of vecuronium are mediated by not only muscarinic receptors but also neuronal nicotinic receptors in hearts of anesthetized dogs.

The chronotropic and inotropic effects of vecuronium bromide and its interaction with the autonomic nervous system were investigated in the isolated, cross-circulated right atrial and left ventricular preparations of the dog. Vecuronium, injected into the external jugular vein of the support dog, induced dose-dependent decreases in heart rate and arterial blood pressure, and increased atrial contractile force with no change in sinus rate in isolated atrial preparations. Vecuronium (1-3,000 micrograms), injected into the sinus node artery of the isolated atrium, induced dose-dependent increases in atrial contractile force with small increases in sinus rate. Vecuronium also increased the ventricular contractile force in a dose-dependent manner. The positive inotropic effect was attenuated in part by propranolol, but not by either tetrodotoxin or imipramine. Vecuronium inhibited in a dose-related manner the negative chronotropic and inotropic responses to parasympathetic nerve stimulation and carbachol (CCh) and the negative followed by positive cardiac responses to nicotine, but did not attenuate the positive responses to sympathetic nerve stimulation. The ID50s for the responses to parasympathetic stimulation, CCh, and nicotine were not significantly different. Vecuronium enhanced the positive chronotropic and inotropic responses to sympathetic nerve stimulation, tyramine, norepinephrine, and isoproterenol. These results indicate that (a) vecuronium causes the positive inotropic responses mediated by nonadrenergic mechanisms and beta-adrenoceptors, (b) vecuronium blocks ganglionic and presynaptic nicotinic and postsynaptic muscarinic receptor-mediated responses similarly, and (c) vecuronium enhances beta-adrenoceptor-mediated responses in the dog heart.

Circulatory maintenance with a left ventricular assist device (LVAD) alone during cardiac arrest until heart transplantation has been evaluated. To assess the effect on the autonomic nervous system, the sympathetic neurogram was analyzed by power spectrum and coherence function. LVAD were inserted between the left atrium and the descending aorta in seven adult mongrel dogs and ventricular fibrillation was induced electrically. Renal sympathetic nerve activity (RSNA) was detected by bipolar electrodes attached to the left renal sympathetic nerve. Values of squared coherence between the arterial pulse wave and RSNA were calculated. Under the condition of circulatory maintenance with only LVAD, coherence at the cardiac rhythm frequency was decreased, and coherence at the LVAD pumping rhythm frequency was increased. These results indicate that the arterial pulse wave observed during maintenance of the circulation with only LVAD contributed to the sympathetic neurogram.

We investigated the nonuniform effects of autonomic nerve stimulation of the effective refractory period (ERP) of the right atrium in the anesthetized dog. Stimulation of the discrete intracardiac sympathetic nerves to the sinoatrial (SA) nodal region uniformly shortened ERPs at three sites in the right atrium after administration of atropine. Right ansa subclavia (RS) stimulation similarly shortened ERPs in the absence of atropine. Stimulation of the discrete intracardiac parasympathetic nerves to the SA nodal region (SAP stimulation) shortened ERPs of the right atrium in a nonuniform manner. Simultaneous RS and SAP stimulation additively shortened ERPs at each site and decreased sinus rate much more than SAP stimulation alone. Shortening of ERP induced by SAP stimulation was greater than that induced by RS stimulation at similar absolute changes in heart rate. These results suggest that simultaneous activation of sympathetic and parasympathetic nerves nonuniformly shortens the ERP in the right atrium as the algebraic sum of the individual responses to each stimulation. However, parasympathetics exert the principal neural control over atrial ERP.

We investigated blocking effects of pirenzepine, AF-DX 116 and atropine on the negative chronotropic and dromotropic responses to stimulation of the intracardiac vagus nerves in the anesthetized, open-chest dogs. Stimulation of the intracardiac vagus nerves to the sinoatrial nodal region (stimulation of the intracardiac parasympathetic nerves to the sinoatrial nodal region) or to the atrioventricular nodal region (stimulation of intracardiac nerves to the atriventricular region) selectively decreased heart rate or increased atrioventricular conduction time, respectively. Pirenzepine at lower doses (0.3-3 microgram/kg i.v.) attenuated the stimulation of the negative chronotropic response to the intracardiac parasympathetic nerves to the sinoatrial nodal region to 80% of the control response significantly but did not affect the negative dromotropic one. Similarly, higher doses (10-1000 micrograms/kg i.v.) of pirenzepine inhibited the chronotropic and dromotropic responses to each stimulation in a dose-dependent manner. AF-DX 116 (0.3-300 microgram/kg i.v.) inhibited the chronotropic and dromotropic responses to each stimulation in a similar dose-dependent manner. Atropine (1-30 microgram/kg i.v.) blocked the cardiac responses to each stimulation. However, the ID50 of atropine for the chronotropic response was less than that for the dromotropic one, although ID50s of pirenzepine and AF-DX 116 for the chronotropic and dromotropic responses were not different.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of nicotine on the sinus rate and atrial or left ventricular contractile force were investigated in the isolated, blood-perfused dog right atrium and left ventricle. Nicotine (3-300 nmol) in the right atrium induced dose-dependent negative followed by positive chronotropic and inotropic responses, whereas nicotine caused only a positive inotropic response in the left ventricle. The negative responses to nicotine were blocked by atropine, hexamethonium (C6), and tetrodotoxin (TTX). The positive effects of nicotine were abolished by propranolol and C6. TTX significantly inhibited the positive responses to nicotine by about 50% in the atrial preparation and totally suppressed them in the left ventricle. Imipramine inhibited the positive cardiac responses to nicotine and tyramine, but potentiated the responses to noradrenaline (NA) in atrial and ventricular preparations. These results suggest that (a) nicotine induces negative and positive cardiac effects mediated by parasympathetic ganglionic nicotinic receptors and presynaptic nicotinic receptors of the postganglionic sympathetic nerves, respectively, in the dog heart; (b) there are few parasympathetic ganglionic cells in the dog left ventricle; (c) the positive cardiac responses to nicotine are caused by both TTX-sensitive and TTX-insensitive NA release mechanisms; and (d) imipramine inhibits the positive cardiac responses to nicotine at the presynaptic nicotinic receptor sites of the postganglionic sympathetic nerves.

The effects of eperisone, an antispastic agent, on the chronotropic and inotropic responses to acetylcholine, nicotine or stimulation of intracardiac autonomic nerves were evaluated in isolated, blood-perfused canine atrium. Eperisone (10-300 micrograms) injected into the sinus node artery of the isolated atrium produced dose-related negative chronotropic and inotropic effects, which were not affected by atropine. In the same doses, eperisone inhibited the negative chronotropic and inotropic responses to an injection of acetylcholine and intracardiac parasympathetic stimulation. Eperisone also suppressed the negative followed by positive cardiac responses to nicotine, but did not modify the positive responses to intracardiac sympathetic stimulation or norepinephrine. The inhibitory effect persisted much longer for the responses to nicotine or parasympathetic stimulation than for those to acetylcholine. These results suggest that eperisone at doses that induce direct cardiac depressant effects exerts its blocking action on nicotinic receptors at parasympathetic ganglia and sympathetic nerve terminals and on muscarinic receptors at the effector cells in the dog heart.

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.

Whereas i.v. administration of vasoactive intestinal peptide (VIP) to support dogs increased heart rate and decreased systemic blood pressure, sinus rate and contractile force increased in isolated right atria perfused with blood from the support dogs. VIP injected intraarterially into isolated atria induced dose-dependent positive chronotropic and inotropic effects. Intracardiac parasympathetic nerve stimulation attenuated the positive cardiac responses to VIP, but neither propranolol, imipramine, nor tetrodotoxin influenced the responses to VIP. VIP given to isolated left ventricles also increased the contractile force in a dose-dependent manner. However, VIP induced a greater maximum atrial contractility than ventricular contractility. This may indicate that VIP receptor density in the ventricle was lower than in the atrium, as it has recognized that VIP-ergic nerves innervate the right atrium more densely than the left ventricle. We therefore suggest that the positive cardiac responses to VIP, together with the VIP-ergic innervation in dog hearts and vagal activation, attenuate the VIP-mediated responses at site(s) in the cyclic AMP cascade.

The cardiovascular effects of the novel compound WEB 1881-FU (4-amino-methyl-1-benzyl-pyrrolidine-2-one-fumarate) were investigated using cross-circulated dog atrial preparations. Intravenous injections of WEB 1881 induced a hypotensive effect with slight tachycardia at a large dose in anesthetized dogs. At the same time, it produced slight positive chronotropic and inotropic effects in the isolated atrium perfused with the donor's arterial blood. Direct injections of WEB 1881 into the sinus node artery of the isolated and perfused atrium induced positive chrono- and inotropic effects in a relatively small dose range. At higher doses, it caused biphasic chrono- and inotropic effects, i.e., initial brief negative effects followed by long-lasting positive chrono- and inotropic effects. The negative chrono- and inotropic responses to WEB 1881 were not blocked by atropine in doses which significantly suppressed ACh-induced negative chrono- and inotropic responses. The positive chrono- and inotropic responses to WEB 1881 were significantly inhibited either by a beta-blocker (propranolol) or by an uptake blocker (imipramine). From these results, it is concluded that WEB 1881 has a tyramine-like, catecholamine releasing property. Although a large dose of WEB 1881 has a direct cardiac depressant action, it does not affect muscarinic mechanisms in the heart.

Positive chrono- and inotropic responses to denopamine (TA-064, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol), a new and orally active cardiotonic agent, were investigated in the canine isolated right atrial or left ventricular preparation which was cross-circulated with blood from another support dog. Denopamine dose-dependently increased the sinus rate, right atrial and left ventricular contractile force. Denopamine was one to two orders of magnitude less potent than isoproterenol. The positive chrono- and inotropic effects of denopamine in isolated, blood-perfused right atria were dose-dependently inhibited by treatment with propranolol and atenolol. The effects of denopamine were only slightly attenuated by ICI 118,551 in doses which completely suppressed the positive chrono- and inotropic effects of procaterol. The increases in sinus rate and atrial contractility induced by denopamine were partially but significantly attenuated by treatment with imipramine in a dose which suppressed the effects of tyramine and potentiated the effects of norepinephrine. These results indicate that denopamine is a highly selective beta-1 adrenoceptor agonist in isolated, blood-perfused dog heart preparations, and they also suggest a mild catecholamine-releasing activity through tyramine-like action in isolated right atria.

The cardiovascular effects of DN-9693, a newly synthesized cyclic AMP phosphodiesterase inhibitor, and sulmazole were investigated in an isolated right atrial or left ventricular preparation which was cross-perfused with blood from another support dog. Each substance dose-dependently increased heart rate and decreased blood pressure of the support dog when administered i.v. The hypotensive effects of DN-9693 were about 40 times more potent than those of sulmazole. The positive chronotropic effect of DN-9693 was about 10 times more potent, but the maximal increase in heart rate was much less than that produced by sulmazole. Each substance dose-dependently increased the sinus rate, the right atrial and the left ventricular developed tension in isolated preparations when administered selectively into cannulated arteries. The effects of DN-9693 were about 10-30 times more potent than those of sulmazole, although the maximal positive chronotropic response to DN-9693 was significantly smaller. Positive chrono- and inotropic effects induced by both substances in the isolated, blood-perfused right atrial preparation were not inhibited by treatment with propranolol, but they were consistently attenuated by electrical stimulation of intramural vagal nerve fibers. These results suggest that DN-9693 and sulmazole produce cardiotonic effects by directly increasing the cyclic AMP level in the dog heart. DN-9693 possesses more potent cardiotonic and vasodilating effects than sulmazole, and has a smaller effect on heart rate.

The effects of intravenous administration of sodium nitroprusside to a donor dog on cardiac pacemaker activity and contractility were investigated in a cross-circulated dog heart preparation; i.e., the isolated atrial muscle was perfused with blood from a pentobarbital anesthetized donor dog. Intravenous administration of nitroprusside (1-10 micrograms/Kg) caused a hypotension with tachycardia, and occasionally with bradycardia. This effect was blocked by atropine injections into the donor dog, but no significant chronotropic and inotropic changes were observed in the isolated atria. Larger doses (over 100 micrograms/Kg) of nitroprusside produced positive chronotropic and inotropic effects in isolated atria, which were inhibited completely by propranolol. Moreover, direct intraarterial injection of nitroprusside (10-1,000 micrograms) had no significant chronotropic and inotropic effects in isolated atria, although acetylcholine (0.01-0.1 micrograms) induced negative chronotropic and inotropic effects. From these results, it is concluded that nitroprusside has no direct cardiac effect and that it causes a release of catecholamines in doses which produce a profound hypotension.

Effects of temperature for inducing cardiac arrest by cooling and the reactivation by rewarming were investigated in the spontaneously beating canine atrium. Moreover, effects of temperature on paced atria and ventricles were also studied. By cooling, atrial rate was linealy decreased from 111 beats/min and then sinus arrest occurred at 20 +/- 0.3 degrees C (mean +/- SE). Just before the arrest, sinus rate was 29 +/- 2.7 beats/min in 6 atrial preparations. On the other hand, atrial contraction was rather increased until about 25 degrees C and then slightly decreased by cooling. In paced preparations, contraction of the atrium and ventricle initially increased and then decreased with pulsus alternans below the control level by cooling. Finally, pacing failure usually occurred. When the reactivation was induced by rewarming after atrial arrest, atrial rhythm was suddenly recovered at about 25 degrees C, but the contraction was minimum and gradually recovered to the control level. From these results, it is suggested that atrial arrest by cooling may be due to sinoatrial conduction block and that the sinoatrial junction area may have an important role on the reactivation by rewarming. Moreover, the recovery of contraction by rewarming may be affected by several factors which may depress the tension development.

The effects of DJ-7141, a new alpha-2 agonist, on an isolated atrial preparation cross-perfused with arterial blood from a support dog were investigated. In the isolated atrium, a selective injection of DJ-7141 (1-100 micrograms) into the sinus node artery induced dose-dependent positive chronotropic and inotropic effects. The positive cardiac effects of DJ-7141 were not only inhibited by propranolol and by imipramine, but reversed to negative effects, whereas the positive cardiac effects of norepinephrine were blocked by propranolol and potentiated by imipramine. Tetrodotoxin (TTX) did not modify the cardiac responses to DJ-7141. After propranolol treatment, the negative chronotropic and inotropic responses to DJ-7141 were not influenced by atropine, which completely blocked acetylcholine-induced cardiac responses. When DJ-7141 was injected into the support dog at a dose of 10-300 micrograms/Kg i.v., it induced a brief increase in femoral arterial blood pressure and a long-lasting decrease in heart rate in the support dog and increases in atrial rate and contractile force in the isolated atrium. These results suggest that the new alpha-2 agonist, DJ-7141, induces indirect positive chronotropic and inotropic effects due to a tyramine-like action and direct negative cardiac effects in the isolated dog heart, and that the tyramine-like effect may be partially responsible for the increase in blood pressure seen with DJ-7141 in in situ dogs.

The effect of clonidine on pacemaker activity and contractility was studied in the isolated dog atrium which was perfused with arterial blood of the support dog. Clonidine caused dose-dependent negative chronotropic and inotropic effects, and a large dose of clonidine slightly suppressed the positive chronotropic and inotropic responses to norepinephrine and sympathetic cardiac nerve stimulation (5 and 30 Hz) but not consistently.

The effects of aminophylline and pentoxifylline were investigated on the blood pressure and heart rate in the intact dog and on the atrial rate and contractile force in isolated atrial muscle which was perfused with arterial blood of the donor dog. Firstly, each drug was intravenously administered to the donor dog. Both compounds produced a dose-dependent hypotension. Aminophylline frequently caused bradycardia in intact dogs and positive chrono- and inotropic effects in isolated atria. However, pentoxifylline usually produced only tachycardia in the donor dog and positive chrono- and inotropic effects on the isolated atrium. When the compounds were administered into the sinus node artery, positive chrono- and inotropic effects were induced, with aminophylline being approximately 3--10 times more potent than pentoxifylline. Larger doses of aminophylline or pentoxifylline when administered intravenously might cause a release of catecholamine, because increased sinus rate and developed tension in isolated atria which was perfused with donor's blood were partially, but significantly, suppressed by propranolol treatment. In the isolated atrium, aminophylline, but not pentoxifylline, significantly inhibited the negative chronotropic and inotropic effects of adenosine.

The cardiovascular effects of alinidine were studied on the donor dog and on the isolated dog right atrial or left ventricular preparation which was cross-perfused with arterial blood from the donor dog. When heart rate and systemic arterial blood pressure of the donor dog were decreased dose-dependently by i.v. administration of alinidine (10-300 micrograms/kg), decreases in atrial rate and atrial developed tension of the isolated preparation were induced in a dose-dependent manner, confirming that i.v. administration of alinidine directly induced negative chronotropic and inotropic effects in situ dog heart. The negative chronotropic effects at lower doses of alinidine were more prominent than the decrease in blood pressure of the anesthetized dog and the negative inotropic effect of the isolated atrium, respectively. Direct injection of alinidine (1-300 micrograms) into the sinus node artery of the isolated atrium induced predominant negative chronotropic responses at lower doses. In paced left ventricular muscle preparations, alinidine reduced the developed tension at higher doses. Ratios (decreases in atrial developed tension per decreases in atrial rate) for alinidine ranged from 1.2 to 2.1, which were smaller than those of acetylcholine, adenosine and verapamil, suggesting that alinidine has a predominant bradycardic property and induces bradycardia due to a different mechanism from those of other bradycardic agents in the isolated and blood-perfused dog heart. The responses to isoproterenol and norepinephrine were suppressed significantly by treatment with alinidine (300 micrograms) predominantly on chronotropism. The alinidine-induced decreases in atrial rate were relatively greater when the rate had been augmented by dibutyryl cyclic AMP and norepinephrine infusion, but the relative depression of contractility was slight. From these results, it is suggested that alinidine attenuates the positive chronotropic effects induced by increases in cyclic AMP without decreasing the positive inotropic ones in the blood-perfused dog atrium.

The cardiac effects of mildronate were studied in isolated and blood-perfused atrial and ventricular preparations from mongrel dogs. Mildronate (10(-9)-10(-6) mol) did not induce any chronotropic or inotropic responses in spontaneously beating isolated right atria at 37 degrees C. However, it produced negative chronotropic and inotropic effects at large doses (10(-5)-10(-4) mol). Mildronate-induced responses were not significantly inhibited by treatment with atropine, suggesting that they do not involve muscarinic mechanisms. Mildronate produced only a slight negative inotropic effect in electrically paced, isolated left ventricular preparations at extremely large doses. Intravenous injections of 10(-4) mol/kg mildronate to the support (donor) dog induced a slight, non-significant, depressor effect, and did not significantly influence either atrial pacemaker activity or atrial developed tension. From these results, it is concluded that a therapeutic dose of mildronate has no direct influence on SA nodal pacemaker activity and atrial contractility, but that it has a slight cardiac depressant property at large doses.

The effects of butropium on chronotropic and inotropic activity were investigated in 10 isolated atrial preparations which were suspended in a bath and perfused with arterial blood led from a carotid artery of heparinized support dog. Butropium injected into the cannulated sinus node artery in a dose range of 3 to 100 microgram produced a dose-dependent positive chronotropic and inotropic effect. At relatively higher doses above 30 microgram, slight and brief initial negative chronotropic and inotropic effect followed by a long-lasting positive effect was observed. The positive effect of butropium was markedly suppressed by propranolol or carteolol, but it was not affected by tetrodotoxin or desmethylimipramine. From these results, a large amount of butropium may induce positive chronotropic and inotropic effect through cholinergic blockade and in part stimulation of adrenergic beta-receptors.

The effects of a newly synthetic alpha- and beta-adrenoceptor blocking agent, YM-09538, on SA nodal pacemaker activity and contractility of atria and intact dogs were studied using isolated and blood-perfused canine atrial muscle preparations supported by a donor dog. Intravenous administration of YM-09538 (10-100 micrograms/Kg) caused hypotension without tachycardia, but was accompanied with bradycardia in anesthetized dogs. In these cases, the SA nodal pacemaker activity and atrial contractility in isolated atria was influenced little. This indicates that the concentration of YM-00538 that induces hypotension has no direct cardiac effects. Direct administration of YM-09538 to isolated atria caused dose-dependent negative chronotropic and inotropic effects, and the potency was 3-30 times less than that of propranolol. In electrically paced preparations, a large dose of YM-09538 produced a uniform depression of the developed tension at all frequencies examined (2-3 Hz). On the other hand, verapamil caused a greater suppression of developed tension at higher frequencies, indicating that the mode of action of YM-09538 is different from that of verapamil.

Thirteen isolated canine right atria were perfused with blood conducted from a support dog. The selective injection of verapamil into the cannulated sinus node artery at a dose level above 1 mug usually induced dose-dependent negative chronotropic and negative inotropic effects. At a dose of 30 mug, verapamil caused sinus arrest in 4 cases out of 7 with marked suppression of the isometric tension development. At 100 mug, in all cases it caused sinus arrest which continued about 1 hour. When calcium chloride was injected into the sinus node artery, a positive inotropic effect was dose-relatedly produced above a dose level of 100 mug, but the threshold dose for inducing a positive chronotropic effect of calcium chloride was approximately 1 mg. On the other hand, norepinephrine when injected into the sinus node artery simultaneously induced a positive chronotropic and inotropic effect at the same threshold dose. A dose level of 10-30 mug of verapamil did not significantly inhibit positive chronotropic and inotropic responses to norepinephrine and a positive inotropic response to calcium chloride in per cent. The negative inotropic response as well as the positive chronotropic and inotropic responses to electric stimulation of the epicardium were not blocked by verapamil which caused marked suppression of the tension development.

When a new cardiotonic, OPC-8490 (3, 4-dihydro-6-[4-(4-oxo-4-phenylbutyl)-1-piperazinylcarbonyl]- 2(1H)- quinolinone citrate), was administered into the jugular vein of a support dog, at doses of 0.1, 0.3 and 1 mumol/kg, decreases in heart rate and arterial blood pressure were dose-dependently induced in intact support dogs. One and a half min after administration, positive inotropic and slight negative chronotropic responses were observed in isolated right atria perfused with arterial blood of support dogs. Administration of OPC-8490 into the sinus node artery of the isolated atrium induced positive inotropic and biphasic chronotropic effects, an initial brief positive (Ph1) followed by a long-lasting negative (Ph2) chronotropic effect in a dose-related manner. OPC-8490 at 1000 nmol caused a triphasic, Ph1 followed by Ph2 and slight positive (Ph3) chronotropic effects and an inotropic effect. In the left ventricular muscle preparation driven electrically at 2 Hz, 10-3000 nmol of OPC-8490 increased contractile force in a dose related manner. OPC-8490-induced responses were not significantly modified by propranolol or atropine. When isoproterenol (0.04 nmol/min) increased the basal sinus rate and contractile force of isolated atria, the Ph1 was suppressed and the Ph3 became clear, although the negative phase (Ph2) was not changed. The positive inotropic effect was not significantly changed. When intramural vagal nerve stimulation decreased sinus rate and contractile force, the positive inotropic and negative (Ph2) chronotropic effects were depressed. Verapamil significantly depressed the positive inotropic but not the chronotropic responses to OPC-8490. The positive inotropic effect of OPC-8490 was depressed by pinacidil but not changed by ouabain, although the chronotropic responses to OPC-8490 were not changed. These results suggest that cardiac responses to OPC-8490 involve several mechanisms including cyclic AMP dependent, Ca channel-dependent, potassium current-inhibitory and/or other mechanisms in the dog heart.

Electrical stimulation on the posterior portion in the caval margin of the right atrium caused a biphasic chronotropic and inotropic response, i.e., a negative response followed by a positive response, in the isolated blood-perfused canine atrial preparation. The threshold of pulse duration for inducing negative responses was approximately 0.05 msec at 2 v and 20 Hz, but that for inducing positive responses was approximately 0.5 msec. When the voltage and pulse duration of electrical stimulation were increased, both the degree of negative and positive responses became greater. However, muscle contracture was frequently induced by increasing the voltage or pulse duration. The optimal frequency was 20 to 40 Hz for inducing marked chronotropic and inotropic responses. The negative chronotropic and inotropic response to subthreshold electrical stimulation was significantly suppressed by the treatment with tetrodotoxin, hexamethonium or atropine, while it was enhanced by physostigmine treatment. These suggest that subthreshold electrical stimulation readily caused a release of acetylcholine by excitation of parasympathetic preganglionic fibers in this atrial preparation. The positive chronotropic and inotropic response was significantly suppressed not only by treatment with propranolol but also by tetrodotoxin, while it was enhanced by imipramine, hexamethonium, or atropine. From these results, it is indicated that this blood-perfused preparation is very suitable to evaluate both cardiac mechanisms controlled by autonomic nervous system and drug actions on effects of endogenous hormone.

The effects of imipramine were investigated on the blood pressure and heart rate in the intact dog and on the atrial rate and contractile force in the isolated atrial muscle perfused with arterial blood of the donor dog. A continuous infusion of small doses of imipramine (30 micrograms/Kg/min, i.v., 30 min) produced an increase in the blood pressure and heart rate of the donor dog and the positive chronotropic and inotropic effects of isolated atria. These responses were blocked by treatment with propranolol. When a large dose of imipramine (1 mg/Kg/min, i.v., 15 min) was administered to the donor dog, the blood pressure fell and the heart rate initially increased and then decreased (i.e., 15 min later it decreased approximately 20% under the control level), and in isolated atria and the developed tension initially increased and 15 min later decreased but the atrial rate maintained over the control level. Examined doses of imipramine caused a potentiation of norepinephrine-induced action, and a large dose of imipramine significantly diminished norepinephrine-induced reflex bradycardia and/or frequently inverted to tachycardia. Moreover acetylcholine-induced reflex tachycardia was suppressed by imipramine treatment. From these results, it is concluded that imipramine may cause a hypotension mainly due to peripheral vasodilation, and may induce a suppression of baroceptive reflex mechanism.

The isolated right dog atrium was perfused through the sinus node artery with blood led from a heparinized support dog under constant perfusion pressure of 100 mmHg. The positive chronotropic and inotropic responses to norepinephrine were not significantly suppressed by treatment with large amounts of quinidine or procainamide, but completely blocked by propranolol. From these results, it was demonstrated that quinidine and procainamide have no adrenergic beta-blocking activity on chronotropism and on inotropism in the heart.

The effects of right vagal nerve stimulation on changes in heart rate, mean coronary sinus blood flow, and noradrenaline overflow rate induced by right cardiac sympathetic nerve stimulation were investigated in anaesthetised decentralised, open chest dogs, when autonomic nerve fibres were stimulated tonically at a frequency of 4 or 5 Hz for 2.5 min. Sympathetic nerve stimulation produced a mean(SEM) increase in each of the variables (50(7.0)% in heart rate, 48(6.3)% in coronary sinus blood flow, and 87.0(12.3) ng.min-1 in noradrenaline overflow rate into coronary sinus blood at 30 s), and the increments remained almost constant during continued stimulation. Vagal nerve stimulation induced a decrease of 34(3.4)% in heart rate and of 22(4.5)% in coronary sinus blood flow and a slight reduction (-9(3.2) ng.min-1) in noradrenaline overflow rate at 30 s. Only the decrease in heart rate faded slightly with time. Combined stimulation of the sympathetic and parasympathetic nerves induced a decrease of 19(5.0)% in heart rate and 4(7.5)% in coronary sinus blood flow and an increase of 34.3(12.0) ng.min-1 in noradrenaline overflow rate at 30 s. The decrease in heart rate and coronary sinus blood flow faded, and noradrenaline overflow rate increased significantly to 86.4(17.3) ng.min-1 at 120 s. The temporal changes in heart rate, coronary sinus blood flow, and noradrenaline overflow rate caused by combined nerve stimulation were readily inhibited by treatment with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial protection of dilazep HCl, which is an antianginal drug and a potent calcium antagonist against myocardial damage following acute ischemia and reperfusion, was studied on myocardial contractility in isolated blood perfused canine left ventricular muscle. Myocardial function was expressed by percent recovery rate of maximum net developed tension. 1. The coronary infusion of dilazep revealed significant myocardial protection during normothermic ischemic arrest of 45 min and reperfusion. 2. The i.v. administration of dilazep to the donor dog and Young's infusion also showed significant myocardial protection during normothermic ischemic arrest of 45 min and reperfusion. 3. The combination of i.v. administration of dilazep to the donor dog, Young's infusion, and hypothermia showed significant myocardial protection during prolonged ischemia and reperfusion even in hypertrophied ventricle. 4. Dilazep prevents abnormal calcium accumulation in myocardial cells during reperfusion. These results demonstrate that dilazep provides effective myocardial protection during ischemic arrest and reperfusion, and they may support its clinical application as a myocardial protective agent for open-heart surgery.

The canine right atrium was perfused with arterial blood led from a carotid artery of the heparinized support dog and suspended in a bath filled with blood. In 5 non-spontaneously beating preparations, the frequency-force relationship was investigated by electric stimulation at a frequency range from 0.017 to 3 Hz. At a low frequency level, a large peak tension developed. At 0.5 Hz, minimum values of developed tension were obtained. At a range of 0.5-3 Hz, the developed tension increased with the frequency. Higher frequencies than 4 Hz usually caused pulsus alternans. The staircase phenomena were not influenced by treatment with propranolol or atropine. Therefore, there may be no participation of the autonomic nerve stimulation on the frequency-force relationship. Effects of pentobarbital, (+/-)-verapamil and manganese on the frequency-force relationship were investigated with both the blood-perfused, isolated atrium preparations and isolated ventricular preparations. Pentobarbital and manganese chloride produced a uniform depression of the developed tension at all frequencies but the depression with (+/-)-verapamil was greater at higher frequencies in both atrial and ventricular muscles.

Effects of papaverine on sinus rate and atrial contractility were investigated using the isolated atrium preparation of the dog perfused with heparinized arterial blood led from a support dog. When papaverine was injected into the cannulated sinus node artery, positive chronotropic and inotropic responses were dose-relatedly produced from about 3 mug. At a dose level above 100 mug, papaverine induced initially slightly negative chronotropic and inotropic effects followed by marked positive ones. Papaverine-induced positive chronotropic and inotropic effects (P-PCIE) were not influenced by treatment with tetrodotoxin which blocked the action of nicotine. P-PCIE were slightly suppressed by an adrenergic beta-blocking agent, alprenolol, which blocked the action of norepinephrine. They were however potentiated by treatment with desmethylimipramine which completely blocked the action of tyramine. A large amount of MnCl2 suppressed the actions of both papaverine and norepinephrine. Papaverine-induced negative chronotropic and inotropic effects were not influenced by atropine treatment. In addition, papaverine slightly potentiated the negative chronotropic and inotropic responses to adenosine. From these results, it appears that papaverine has a direct stimulating property on sinus rate and atrial contractility which may be due to inhibition of phosphodiesterase and successive accumulation of cyclic AMP. Moreover, papaverine may partially cause catecholamine release from adrenergic nerve fibers and it may inhibit the adenosine uptake mechanism.

Effects of nicardipine, a newly synthesized dihydropyridine vasodilator exhibiting cyclic phosphodiesterase inhibitory properties, were studied in the isolated canine atrium which was cross-perfused with blood from a donor dog. When nicardipine (1.0-10 micrograms/kg) was administered intravenously to the donor dogs, the systemic blood pressure decreased and the heart rate did not significantly change. However, the contraction and beat rate of the isolated atrium were only slightly decreased. At larger doses (30-100 micrograms/kg, i.v.), the systemic blood pressure fell markedly and was usually accompanied by marked bradycardia, which was greater than that of the isolated atrium. Nicardipine injected into the sinus node artery of the isolated atrium caused dose-related negative chronotropic and inotropic effects which were less pronounced than those of verapamil. In contrast, papaverine increased right atrial rate and contractile force. Nicardipine similarly to verapamil and unlike manganese ion caused greater inhibition of the right atrial contraction at higher than lower pacing frequencies. From these results, it is concluded that nicardipine may produce predominantly cardiac depressant properties as a calcium antagonistic, and that such may not be related to phosphodiesterase inhibition in cardiac tissues.

1. Effects of (+/-)-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.- butylamino-ethanol hydrochloride (mabuterol) on pacemaker activity and atrial contractility were investigated in the isolated and blood-perfused right atrium of the dog. 2. Mabuterol, injected into the sinus node artery of the isolated atrium, dose-dependently increased atrial rate and contractile force at doses of 0.01-10 nmol but the responses to over 10 nmol of mabuterol gradually decreased and mabuterol at higher doses induced biphasic cardiac responses, i.e., negative followed by positive cardiac responses. 3. The maximal increases in atrial rate and contractile force induced by mabuterol were 41.4% and 12.9%, respectively, of the maximal chronotropic and inotropic effects of isoprenaline. 4. Positive chronotropic and inotropic responses to mabuterol were dose-dependently inhibited by a selective beta 2-adrenoceptor antagonist, ICI 118,551. These responses were only slightly attenuated by atenolol. 5. Mabuterol (1-300 nmol) dose-dependently inhibited both dobutamine- and procaterol-induced positive chronotropic and inotropic responses. 6. These results indicate that mabuterol causes weak positive chronotropic and inotropic effects on the perfused canine right atrium by activating beta 2-adrenoceptors, and that higher concentrations non-selectively block both beta 1-and beta 2-adrenoceptors.

The effects of quinidine and procainamide were studied in isolated canine atria cross-perfused with heparinized arterial blood from donor dogs as well as in these donor dogs. When administered intravenously to donor dogs, both drugs produced dose-related hypotensive effects, but quinidine was 3-10 times more potent than procainamide. Quinidine frequently caused tachycardia in the donor dogs, while procainamide usually produced bradycardia. Quinidine-induced tachycardia was partially suppressed by vagotomy and completely inhibited or changed to bradycardia after propranolol. In isolated atria, small doses of drugs caused slight negative chronotropic and inotropic effects, frequently accompanied by small and short-lasting increases in contractile force and heart rate. Only decreases in contractile force and rate were observed with large doses. Administration of quinidine and procainamide into the sinus node artery of the isolated atrium induced negative, biphasic, or triphasic changes in chronotropism and inotropism. In isolated atria, quinidine and verapamil depressed the contractile force to a greater extent at higher stimulation frequencies. Procainamide showed less of this effect, because atrial muscle became unresponsive to high-frequency pacing with the larger doses of procainamide. These results suggest that quinidine and procainamide have both cardiac-depressant and -stimulating properties.