Effects of N6-endonorbornan-2-yl-9-methyladenine, N0861, on negative chronotropic and vasodilatory actions of adenosine in the canine heart in vivo.

The pharmacology of N6-endonorbornan-2-yl-9-methyladenine (N0861), a new selective antagonist of adenosine at the A1 adenosine receptor subtype (A1-AdoR), was studied in vivo using a canine model. First, the pharmacokinetics of N0861 were determined in anesthetized dogs. The time-dependent decay of plasma levels of N0861 fitted a two-compartment polyexponential model with alpha-phase t1/2 = 3.80 min and beta-phase t1/2 = 80.55 min. Secondly, the effect of N0861 on the negative chronotropic and vasodilatory actions of adenosine in the canine heart were determined. N0861 attenuated the negative chronotropic action of adenosine (1-6 mumol/kg; rapid bolus into the right atrium) on sinus node pacemaker activity in a dose-dependent manner (pA2 = 4.23). For example, the maximal prolongation of sinus cycle length induced by 6 mumol/kg adenosine was 82 +/- 13% under baseline conditions and 57 +/- 10, 34 +/- 5 and 34 +/- 6% during infusion of N0861 at incremental rates leading to plasma levels of 7.75 +/- 1.02, 14.15 +/- 0.87, and 19.71 +/- 1.83 micrograms/mL, respectively. In contrast, N0861 did not inhibit but had a tendency to potentiate the vasodilatory action of adenosine (thought to be mediated by the A2 adenosine receptor subtype (A2-AdoR)) on the left anterior descending and circumflex coronary arteries. These data indicate that two different receptors, similar to the typical A1-AdoR and A2-AdoR, mediate the electrophysiologic and vasodilatory actions of adenosine in the canine heart, respectively, and that N0861 is a selective antagonist of adenosine at A1-AdoR in the canine heart in vivo.     

The effect of sinus node depression on heart rate variability in humans using zatebradine, a selective bradycardic agent

Zatebradine is a bradycardic agent with a selective effect on the pacemaker current in the sinus node. The effect of such drugs on heart rate variability is not known. Thirty-six patients without structural heart disease were randomly assigned to receive 10 mg of zatebradine i.v. (n = 24) or isotonic saline (n = 12). Heart rate variability (HRV) was recorded as power in the very low frequency (VLF, 0.003-0.040 Hz), low frequency (LF, 0.040-0.150 Hz), and high frequency (HF, 0.150-0.400 Hz) spectral bands as well as total power (TP, 0.003-0.400 Hz) during 5-min ECG acquisitions at baseline, 30, and 60 min following the start of the infusion. No change in heart rate variability was detected in the control group. Zatebradine significantly reduced heart rate variability at 60 min in all frequency bands: VLF (-12+/-4%, p<0.001), LF (-19+/-4%, p<0.001), and HF (-26+/-5%, p<0.001). The reduction in HRV following zatebradine is due to depression of sinus node response to all external stimuli and underscores the need for documentation of normal sinus node function in HRV research.     

Effects of propafenone on sinus node function in the rabbit heart

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

Impaired sinus node function and global atrial conduction time after high rate atrial pacing in dogs

In animal and human studies, it has been shown that atrial fibrillation shortens the atrial refractory period and impairs its rate adaptation. The objective of this study was to evaluate the effects of high-rate pacing on sinus node function and intra-atrial conduction. Eight dogs were subjected to rapid atrial pacing (AP) at 400 bpm for 16 days. Sinus node recovery time (SNRT) and P-wave duration were measured at baseline, immediately after AP and four weeks after the termination of AP. SNRT immediately after AP was significantly prolonged at all pacing rates compared to the baseline values. P-wave duration was significantly longer after AP relative to the baseline values. All the variables were completely reversible four weeks after the termination of pacing. Rapid AP induces sinus node dysfunction and prolongs the intra-atrial conduction time. It is possible that the electrical remodelling extends to the sinus node as well.     

Effects of Regulatory Peptides on Electrophysiological Properties of the Human Heart

During transesophageal electrical stimulation of the left atria in patients with heart diseases, an intravenous administration of Sandostatin prolonged the cardiac cycle and the effective refractory period of the atrioventricular junction, slowed down the sinoatrial conduction and the sinus node recovery time, and shifted the Wenckebach's point downwards. Neurotensin produced effects opposite to those of Sandostatin. During the Valsalva maneuver, Sandostatin strengthened bradycardia and broadened the range of heart rate changes associated with the vagal tone variations. The latter effect was also observed after the administration of neurotensin. Met-enkephalin and dalargin shortened the cardiac cycle, increased the corrected time of sinus node recovery time, but did not affect the cardiac rhythm dynamics during the Valsalva maneuver. These findings suggest that the regulatory peptides can be involved in control mechanisms determining the electrophysiological parameters of the human heart.     

Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. V. Role of purinergic receptors

The mechanism of extracellular ATP-triggered vagal depressor reflex was further studied in a closed-chest canine model. Adenosine and ATP were administered individually in equimolar doses (0.01-1.0 mumol/kg) into the right coronary artery (RCA) and left circumflex coronary artery (LCA). When administered into the RCA, adenosine and ATP exerted an identical and relatively small negative chronotropic effect on sinus node automaticity; the time to peak negative chronotropic effect was >/=7 s. When administered into the LCA, adenosine had no effect on sinus node automaticity, whereas ATP markedly suppressed sinus node automaticity. This effect of ATP 1) reached its peak in <2 s after its administration, 2) was short lasting, and 3) was completely abolished by either intravenous administration of the muscarinic cholinergic blocker atropine (0.2 mg/kg) or intra-LCA administration of 2',3'-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP), a potent P2X(2/3) purinergic receptor (P2X(2/3)R) antagonist, but not by diinosine pentaphosphate (Ip(5)I), a potent inhibitor of P2X(1)R and P2X(3)R. Repetitive administrations of ATP were not associated with reduced effects, indicative of receptor desensitization, thereby excluding the involvement of the rapidly desensitized P2X(1)R in the action of ATP. It was concluded that ATP triggers a cardio-cardiac vagal depressor reflex by activating P2X(2/3)R located on vagal sensory nerve terminals localized in the left ventricle. Because these terminals mediate vasovagal syncope, these data could suggest a mechanistic role of extracellular ATP in this syndrome and, in addition, give further support to the hypothesis that endogenous ATP released from ischemic myocytes is a mediator of atropine-sensitive bradyarrhythmias associated with left ventricular myocardial infarction.     

Effect of Ibutilide on the Canine Cardiac Conduction System

The objective of the study was to evaluate the effect of ibutilide on canine cardiac sinoatrial and atrioventricular nodes (AVNs). For this purpose, 18 mongrel dogs were injected intravenously with ibutilide and the changes in heart rate, sinus node recovery time, and AVN were measured. Our data show that ibutilide administration caused significant suppression of the sinus atrial node, the peak response time was 20?C30?min, and the heart rate was restored to pre-drug administration level. After receiving ibutilide, 1 animal had a 5?s sinus pause, and after 5?min of ibutilide administration, 1 dog showed 2:1 atrioventricular conduction. Therefore, it was concluded that ibutilide had a suppressive effect on the sinoatrial node and AVN.     

Effects of ritanserin on transmembrane action potentials in canine Purkinje fibers.

Ritanserin has been reported to be a potential antiarrhythmic. We studied the cellular electrophysiologic effects of ritanserin in canine Purkinje fibers. Ritanserin produced significant depressant effects on transmembrane action potentials elicited in canine Purkinje fibers. At concentrations of 10 and 40 mg/liter, ritanserin decreased Vmax (the upstroke velocity) of action potential in a dose-dependent fashion and shortened the duration of fast response action potential. These concentrations of ritanserin also reduced the amplitude and duration of the slow response action potentials induced in Purkinje fibers treated with isoproterenol (10(-5) M) and high K+ (22 mM). These in vitro results suggest that the cellular electrophysiologic actions of ritanserin may be due to its direct actions on cardiac sodium and calcium channels, which, in turn, may account for its antiarrhythmic effects.     

The effects of sympathetic denervation on spontaneous ventricular defibrillation in the rat.

Ventricular tachycardia or ventricular fibrillation was electrically induced in 38 normal rats (group 1) and 24 sympathetically denervated rats (6-hydroxydopamine) (group 2). The time for spontaneous reversion to sinus rhythm was measured during (1) control, (2) isoproterenol, and (3) the combination of isoproterenol and phenylephrine. The time for spontaneous reversion was the same in both groups in the three states. The reversion time was prolonged threefold by isoproterenol, and restored to control values when phenylephrine was added to the infusion of isoproterenol. The tachycardia duration and the refractory period were inversely related: log10 (tachycardia duration) = 3.466-0.091 (refractory period). Ventricular tachycardia/fibrillation induction was examined as follows: (i) Ventricular tachycardia/fibrillation was induced in 100% of normal rats (group 1), but only 42% of the denervated rats (group 2, p less than 0.001); (ii) during isoproterenol, ventricular tachycardia/fibrillation was induced in 100% of rats of both groups; and (iii) when phenylephrine was added to isoproterenol, ventricular tachycardia/fibrillation was induced in 100% of group 1 rats versus 82% of group 2 rats, (p = NS). These observations suggest (1) the induction of ventricular tachycardia/fibrillation is highly dependent on intact sympathetic innervation, and (2) exogenous adrenergic agonists modulate the duration of ventricular fibrillation through their effects on ventricular refractory period, independent of sympathetic innervation.     

Incidence of dual AV node physiology following termination of AV nodal reentrant tachycardia by adenosine-5'-triphosphate: a comparison with drug administration in sinus rhythm

Administration of adenosine triphosphate (ATP) in sinus rhythm identifies dual atrioventricular node physiology (DAVNP) in 75% of patients with inducible slow/fast AV nodal reentrant tachycardia (AVNRT). The incidence of DAVNP following termination of AVNRT with ATP is unknown. Incremental doses of ATP (10-60 mg) were administered, first in sinus rhythm and then during tachycardia induced at electrophysiologic study, to 84 patients with inducible AVNRT and to 18 control patients with inducible AV reentrant tachycardia (AVRT) and no electrophysiologic evidence of DAVNP. Study end-points were the occurrence of DAVNP or > or = 2nd degree AV block following administration of ATP in sinus rhythm and tachycardia termination following administration of ATP during tachycardia. Of the 82 patients with AVNRT who completed the study, 62 (75.6%) exhibited DAVNP following administration of 17.1 +/- 9.4 mg ATP in sinus rhythm, while 30 (36.5%) exhibited DAVNP at the termination of AVNRT following administration of 10.6 +/- 2.4 mg ATP. The occurrence of DAVNP following the administration of 10 mg ATP in sinus rhythm.was a good predictor (62%) of its occurrence after termination of AVNRT with ATP. The dose of ATP had a strong correlation between the presence of DAVNP following AVNRT termination and the ATP doses needed for tachycardia termination. Of the 18 control patients, none had DAVNP at ATP test during sinus rhythm but 1 (5.5%) showed slight (60 msec) PR jump after termination of AVRT with ATP. In conclusion, DAVNP is present in a relatively high proportion (36.5%) of patients following termination of AVNRT with ATP but is much less frequent (5.5%) in control patients. Thus, findings at termination of tachycardia by ATP may be useful in the noninvasive diagnosis of the mechanism of a paroxysmal supraventricular tachycardia.     

Ectopic atrial arrhythmias arising from canine thoracic veins during in vivo stellate ganglia stimulation

The purpose of the present study was to determine whether thoracic veins may act as ectopic pacemakers and whether nodelike cells and rich sympathetic innervation are present at the ectopic sites. We used a 1,792-electrode mapping system with 1-mm resolution to map ectopic atrial arrhythmias in eight normal dogs during in vivo right and left stellate ganglia (SG) stimulation before and after sinus node crushing. SG stimulation triggered significant elevations of transcardiac norepinephrine levels, sinus tachycardia in all dogs, and atrial tachycardia in two of eight dogs. Sinus node crushing resulted in a slow junctional rhythm (51 +/- 6 beats/min). Subsequent SG stimulation induced 20 episodes of ectopic beats in seven dogs and seven episodes of pulmonary vein tachycardia in three dogs (cycle length 273 +/- 35 ms, duration 16 +/- 4 s). The ectopic beats arose from the pulmonary vein (n = 11), right atrium (n = 5), left atrium (n = 2), and the vein of Marshall (n = 2). There was no difference in arrhythmogenic effects of left vs. right SG stimulation (13/29 vs. 16/29 episodes, P = nonsignificant). There was a greater density of periodic acid Schiff-positive cells (P < 0.05) and sympathetic nerves (P < 0.05) at the ectopic sites compared with other nonectopic atrial sites. We conclude that, in the absence of a sinus node, thoracic veins may function as subsidiary pacemakers under heightened sympathetic tone, becoming the dominant sites of initiation of focal atrial arrhythmias that arise from sites with abundant sympathetic nerves and periodic acid Schiff-positive cells.     

Effects of acetylcholine, propranolol, and verapamil on sinus node refractoriness of the rabbit

At a critical premature interval, atrial premature beats encounter sinus node refractoriness and are blocked on entering and fail to reset the sinus node, resulting in interpolation of the premature beat. The transition from reset to interpolated response has been used to define the effective refractory period of the sinus node (SNERP). In an in vitro preparation of rabbit sinus node, we evaluated the effects of acetylcholine, propranolol, and verapamil on SNERP. Results obtained in the control state were compared with those obtained during superfusion with drugs, all of which prolonged refractoriness: acetylcholine from 233 +/- 41 (SD) to 325 +/- 88 ms; propranolol from 215 +/- 60 to 241 +/- 67 ms; and verapamil from 192 +/- 69 to 254 +/- 79 ms (p less than 0.005 with all drugs). The site of block of premature beats was mapped between sinus node and crista terminalis with an intracellular microelectrode. All three drugs resulted in block of premature beats at sites farther from the primary pacemaker site. Thus, acetylcholine, propranolol, and verapamil prolong sinus node refractoriness.     

Effects of sympathetic stimulation on use dependence of lidocaine, mexiletine, and quinidine in an intact canine model.

The use- or rate-dependent effects of a continuous infusion of lidocaine (n = 6, serum level 3.1 +/- 0.34 micrograms/mL), mexiletine (n = 8, serum level 7.08 +/- 0.90 micrograms/mL), and quinidine (n = 6, serum level 6.8 +/- 1.22 micrograms/mL) were studied in an open chest canine preparation. A use-dependent effect on conduction was assessed by measuring the change in the His to surface ventricular activation (HV) time at differing atrial paced rates during drug infusion. Global sympathetic activation was achieved by nondecentralized left stellate ganglion stimulation (4-10 Hz, 6-12 V, 2 ms) and use dependence at the same cycle lengths was compared. Repolarization times were measured from epicardial monophasic action potentials recorded from the anterior left ventricle throughout the study. There was no significant change in the HV time during control studies with or without left stellate stimulation. Use-dependent slowing of conduction was seen in all studies during drug infusion. This was evident at cycle lengths of 300-190 ms for quinidine and at cycle lengths less than 250 ms for lidocaine and mexiletine. Stellate stimulation attenuated use dependence in all studies. This effect was significant from cycle lengths of 300-190 ms for lidocaine and quinidine and at cycle lengths shorter than 230 ms for mexiletine (p less than 0.05). Stellate stimulation significantly reduced use-dependent prolongation of the HV interval by an average of 60%. During stellate stimulation there was a nonsignificant trend towards cycle length independent shortening of action potential duration both at baseline and in the presence of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of hirsutine and dihydrocorynantheine on the action potentials of sino-atrial node, atrium and ventricle

The effects of hirsutine, an indole alkaloid from Uncaria rhynchophylla MIQ. JACKSON with antihypertensive, negative chronotropic and antiarrhythmic activity, and its C3 structural epimer, dihydrocorynantheine, on membrane potentials of rabbit sino-atrial node and guinea-pig right ventricle and left atrium were studied with microelectrode techniques. In sino-atrial node preparations, hirsutine and dihydrocorynantheine (0.1 microM to 10 microM) concentration-dependently increased cycle length, decreased slope of the pacemaker depolarization (phase 4 depolarization), decreased maximum rate of rise and prolonged action potential duration. In atrial and ventricular preparations, both compounds (0.1 microM to 30 microM) concentration-dependently decreased maximum rate of rise and prolonged action potential duration. These results indicate that hirsutine and dihydrocorynantheine have direct effects on the action potential of cardiac muscle through inhibition of multiple ion channels, which may explain their negative chronotropic and antiarrhythmic activity.     

Peripheral vasodilator and cardiac properties of the 1,5-benzothiazepine calcium antagonist analog, TA-3090, in dogs

Diltiazem, a 1,5-benzothiazepine, has demonstrated efficacy in the treatment of numerous cardiovascular diseases. TA-3090, a newly synthetized 1,5-benzothiazepine compound was studied in open-chest anesthetized dogs to characterize its hemodynamic properties, to compare it with diltiazem, and finally to correlate hemodynamic properties and plasma level concentrations. Anesthetized open-chest dogs were instrumented with electronic devices and fluid-filled catheters to monitor cardiac, coronary, and peripheral hemodynamic changes. A cumulative intravenous bolus administration of TA-3090 (n = 16) or diltiazem (n = 15) (15, 50, 200, and 400 micrograms/kg) was carried out, and blood samples were taken before and 5 min following each dose administration. Hemodynamic changes were followed for 30 min after each administration, at which time most hemodynamic parameters were back to baseline levels. The results indicate that both TA-3090 and diltiazem elicit slight peripheral and coronary vasodilator properties at low doses (15 and 50 micrograms/kg). With higher dosage, hemodynamic effects were maximal: coronary blood flow increased by 75%, arterial pressure decreased by 25%, and reflex positive inotropic effects were also observed. Heart rate was significantly reduced (10%). Comparison between TA-3090 and diltiazem indicates that both drugs elicit coronary vasodilator selectivity and TA-3090 has a prolonged duration of action compared with that of diltiazem. A straightforward relationship is demonstrated between vasodilator properties and plasma levels of either TA-3090 or diltiazem. Our data suggest that with plasma levels between 40 and 80 ng/mL, significant hemodynamic changes were observed with TA-3090. Changes of heart rate were not correlated with plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

兔右房超速驱动后阻抑机制的初步探讨

本文用微电极技术,在20份离体兔心窦房结标本上观察了不同驱动频率和驱动时程对窦房结超速驱动后阻抑的影响。结果表明,在一定范围内右房超速驱动后阻抑及驱动后的负性变速效应,随驱动频率和驱动时程增加而加强。高频驱动期间和驱动停止后,优势起搏细胞跨膜电位幅度减小。驱动停止后第一个窦性动作电位4相自动去极化斜率和0相上升速率均降低,与驱动前相比有非常显著的差异(P<0.01)。毒扁豆碱可加强驱动后阻抑及驱动后的负性变速效应,阿托品不能完全阻断驱动后阻抑。我们初步认为:右房超速驱动后阻抑效应可能是内源性乙酰胆碱的释放和[Na~ ]_i 及[Ca~2 ]_i 的增加等多种因素作用的结果。     

Emergency epicardial dissection of the accessory pathway in a patient with atrioventricular nodal reentrant tachycardia]

Diagnostic and therapeutic problems in 14 year old patient with concealed WPW syndrome were presented. Paroxysms of atrio-ventricular reentrant tachycardia 180-220/min were frequently recurring, usually with normal QRS pattern. Tachycardias often had to be terminated by intravenous administration of antiarrhythmic drugs. Long term treatment with various antiarrhythmic agents did not prevent recurrence of tachycardias but they became sustained and were recurring more often. Their other side effects manifested with sinus node disfunction and depression of the heart muscle. The electrophysiologic study revealed right anterior septal accessory pathway. Epicardial dissection of the accessory pathway was urgently performed. The control electrophysiologic study revealed no evidence of conduction through the accessory pathway. The patient did not require antiarrhythmic treatment. During the 12 months follow up no tachycardia occurred.     

Effects of L-carnitine in acute myocardial ischaemia

Data in the literature suggest that exogenous L-carnitine improves the metabolic function of ischaemic heart cells: it enhances the transport of long-chain fatty acids into the mitochondria, stimulates the slowed beta-oxidation, and moderates the accumulation of amphiphilic acyl esters. A study has therefore been made of the cardiac effects of L-carnitine in dog experiments (n = 8). The left anterior descending coronary artery (LAD) was isolated in anaesthetized, thoracotomized animals in situ. After a control occlusion and equilibration period, the LAD was again ligated at the time of L-carnitine infusion (100 mg/kg iv. during 10 min). The agent diminished the maximal conduction delay and the degree of epicardial ST-segment elevation in the ischaemic myocardial region, and the free fatty acid concentration of the arterial blood, but it did not influence the frequency of ventricular extrasystoles. The anti-ischaemic effect of L-carnitine was manifest only during the infusion, and its discontinuation was immediately followed by an enhanced ST-segment elevation. In the dose applied, the substance did not affect the heart rate, systemic mean arterial pressure, left ventricular end-diastolic pressure (LVEDP), or left ventricular contractility (LV dP/dtmax). In the canine myocardial infarction model employed it was observed that the duration of the anti-ischaemic effect of L-carnitine (100 mg/kg iv.) is very short, and it has no significant antiarrhythmic action.     

Effect of adrenaline on the mitosis-inhibiting action of a chalone-containing preparation in Ehrlich ascites tumor

The effect of adrenaline and Ehrlich ascite carcinoma (EAC) chalone on cell division was studied. It has been established that EAC chalone inhibited cell proliferation. The action of adrenaline was also accompanied by a decrease in mitotic index, but the inhibitory effect of the hormone was weaker than that of chalone, it occurred later and its duration was less. A combined effect of adrenaline and chalone depended on the time interval between the administration of the substances. It has been found that chalone administration 1 h after adrenaline administration prolonged mitotic inhibitory effect by 4 h and its synchronous action on cell division in EAC was weak during the experiment. Combined effect of adrenaline and chalone did not differ from the effect of chalone alone if chalone was administered 3 h after adrenaline administration.     

植物性雌激素三羟异黄酮对家兔房室结细胞自发活动的电生理效应

本研究旨在应用经典玻璃微电极方法观察植物性雌激素三羟异黄酮（genistein,GST）对家兔房室结细胞自发活动的电生理效应及其作用机制。GST（10－100μmol/L）不仅以剂量依赖性方式抑制房室结起搏细胞的动作电位0相最大上升速度（Vmax）、4期去极化速率（VDD）、自发起搏频率（RPF）和动作电位幅值（APA）,而且延长复极化90％的时间（APD90）。如提高灌流液中钙离子浓度以及应用L型钙通道开放剂Bay K8644(0.25μmol/L）,则可拮抗GST对起搏细胞的上述电理效应,但NO合酶阻断剂L－NAME（0.5nmol/L）对GST的效应并无影响,以上结果提示,GST可抑制家兔房室结的自发活动,这些效应可能与其抑制钙离子内流有关,但此作用机制中并无NO参与。