Decrease In Atrial Rate Research Articles

Neurocardiogenic syncope in chronic atrioventricular block

We report a 37-year-old man with type I second-degree atrioventricular (AV) block (atypical Wenckebach's periodicity) referred to our department for pacemaker implantation because of an episode of syncope. After exhaustive evaluation, including electrophysiological test, in which Wenckebach's cycles with block within the AV node was demonstrated, syncope was considered to be neurally mediated. Head-up tilt testing with sublingual isosorbide dinitrate was positive. The decrease in atrial rate at the beginning of the vasovagal reaction was not immediately accompanied by a depressed AV node conduction. Only at the moment of syncope did incomplete AV block appear. This observation illustrates (1) a neurally mediated origin of syncope in a patient with chronic AV block, and (2) the different time-course responses of the sinus and AV nodes to autonomic tone.

M(3)-receptor knockout mice: muscarinic receptor function in atria, stomach fundus, urinary bladder, and trachea.

Negative chronotropic and smooth muscle contractile responses to the nonselective muscarinic agonist carbamylcholine were compared in isolated tissues from M(3)-muscarinic receptor knockout and wild-type mice. Carbamylcholine (10(-8)-3.0 x 10(-5) M) induced a concentration-dependent decrease in atrial rate that was similar in atria from M(3)-receptor knockout and wild-type mice, indicating that M(3) receptors were not involved in muscarinic receptor-mediated atrial rate decreases. In contrast, the M(3) receptor was a major muscarinic receptor involved in smooth muscle contraction of stomach fundus, urinary bladder, and trachea, although differences existed in the extent of M(3)-receptor involvement among the tissues. Contraction to carbamylcholine was virtually abolished in urinary bladder from M(3)-receptor knockout mice, suggesting that contraction was predominantly due to M(3)-receptor activation. However, approximately 50-60% maximal contraction to carbamylcholine occurred in stomach fundus and trachea from M(3)-receptor knockout mice, indicating that contraction in these tissues was also due to M(2)-receptor activation. High concentrations of carbamylcholine relaxed the stomach fundus from M(3)-receptor knockout mice by M(1)-receptor activation. Thus M(3)-receptor knockout mice provided unambiguous evidence that M(3) receptors 1) play no role in carbamylcholine-induced atrial rate reduction, 2) are the predominant receptor mediating carbamylcholine-induced urinary bladder contractility, and 3) share contractile responsibility with M(2) receptors in mouse stomach fundus and trachea.

Changes in right atrial catecholamine content in naïve rats and after naloxone-induced withdrawal

In this study, we determined if changes in heart catecholamine content during naloxone-induced withdrawal correlated with modifications in heart rate. In addition, we determined plasma concentrations of corticosterone as an index of the hypothalamo-pituitary-adrenal (HPA) axis. The effects of naloxone on norepinephrine, epinephrine or dopamine content and turnover, plasma concentrations of corticosterone and the mechanical response of the right atria of the rat were studied. Male rats were implanted with placebo or morphine pellets for 7 days. On the day of sacrifice, animals were injected with saline or naloxone 1 mg kg-1 s.c. to precipitate a withdrawal syndrome. Administration of naloxone to morphine-treated (tolerant) animals induced a decrease in atrial content of norepinephrine, epinephrine and dopamine (290.2 (11.9) ng g-1, 15.6 (2.1) ng g-1 and 9.52 (0.5) ng g-1, respectively) and an increase (1.38 (0.2) ng g-1 in the dihydroxy phenyl acetic acid/dopamine (DOPAC/DA) ratio. Administration of naloxone to morphine-treated animals enhanced plasma concentrations of corticosterone (435.8 (27.6) ng ml-1). In the isolated right atria, L-naloxone induced an increase in atrial rate in preparations from morphine-treated rats whereas in placebo-pelleted (naïve) rats, L-naloxone induced a decrease. In contrast, administration of D-naloxone (inactive isomer) produced a decrease in atrial rate in preparations from placebo or morphine-treated rats. We conclude that this study has provided evidence that naloxone-induced withdrawal was characterized by activation of catecholaminergic neurones in the heart that was accompanied by an increase in atrial rate.

The cardiovascular effects of green beans ( Phaseolus aureus), common rue ( Ruta graveolens), and kelp ( Laminaria japonica) in rats

1. 1. The hypotensive effect of green beans, common rue and kelp was recently shown in normotensive rats in vivo. A number of mechanisms of action of these aqueous extracts was identified. The present study examined these actions at the tissue level in vitro with possible interactions of these extracts. 2. 2. Rue showed positive chronotropic and inotropic effects on isolated right atria. Green beans and kelp alone showed negative chronotropic effects on isolated right atria but no effect on atrial tension (AT). A combination of green beans and kelp showed no additive effect on the decrease in atrial rate (AR) nor any negative inotropic responses. Combinations of rue and green beans and of rue and kelp showed responses that were either positive or negative chronotropically, were not dose dependent and were less than the sum total of their individual responses (i.e., subtractive). A combination of all three showed subtractive effects on the decrease in AR that were dose related. No change in AT was observed upon treatment with a combination of the three plant extracts in spite of the positive inotropic effect of rue. 3. 3. Rue and kelp alone relaxed KCl preconstricted rat tail artery strips probably by a direct effect of vascular smooth muscle. Green beans had no effect. The combination of rue and kelp exerted a subtractive relaxation effect. These plants therefore contained cardiovascular active substances that had a direct effect on the cardiovascular system. These substances further interacted to modify their cardiovascular effects. 4. 4. Data explained why herbs, as in herbal medicine, should be used together therapeutically.

Interactions of the cardiac chronotropic effects of rilmenidine with the autonomic nervous system in conscious dogs: comparison with clonidine

1. The cardiac chronotropic effects of rilmenidine (10-100 micrograms kg-1) and clonidine (1-10 micrograms kg-1) were studied in conscious dogs with chronic atrioventricular block. 2. Rilmenidine and clonidine initially (< 3 min) decreased atrial rate, although the effect was not related to dose. More lastingly, ventricular rate was decreased in a dose-related manner (ratio, 1:21). Rilmenidine lowered mean blood pressure only at 100 micrograms kg-1, while clonidine had the same effect at doses of 5 micrograms kg-1 upward (ratio, 1:15). 3. When administered after atropine and pindolol, rilmenidine (50 micrograms kg-1) produced a decrease in atrial rate, with an identical intensity but longer duration than under basal conditions. When clonidine (2.5 micrograms kg-1) was given after atropine, no chronotropic atrial effect was observed. However, when clonidine (2.5 micrograms kg-1) was given after pindolol, it produced a decrease in atrial rate that was more marked, both in intensity and duration, than under basal conditions. After phenoxybenzamine, rilmenidine decreased atrial rate with a more marked and lasting effect than observed under basal conditions. Clonidine produced a bradycardic atrial effect identical to the basal effect. After yohimbine, rilmenidine and clonidine decreased atrial rate with an intensity similar to that under basal conditions, although the time course was totally different. 4. When given after atropine, rilmenidine (50 micrograms kg-1) and clonidine (2.5 micrograms kg-1) decreased ventricular rate as under basal conditions, whereas after pindolol and phenoxybenzamine, both drugs decreased ventricular rate less markedly than under basal conditions, both in intensity and duration. After yohimbine, rilmenidine and clonidine produced no chronotropic ventricular effect. 5. These results show that (a) the initial atrial bradycardia caused by rilmenidine results from both a decrease in sympathetic tone and an increase in cholinergic activity; while the effect of clonidine is caused mainly by the enhancement of cholinergic activity. For both drugs, alpha 2-adrenoceptors are involved at least in the initiation of the effect; (b) the very short duration of atrial bradycardia may result from reflex buffering in response to ventricular bradycardia. This buffering is less effective when heart rate was high; and (c) the ventricular bradycardia caused by both drugs is mainly the result of a decrease in sympathetic tone in response to the stimulation of alpha 2-adrenoceptors. The results also suggest that negative chronotropic postsynaptic alpha 2-adrenoceptors could be involved in the ventricular bradycardia.

Effects of 5-hydroxy-propafenone in guinea-pig atrial fibres.

The effects of 5-hydroxy-propafenone (5-OH-P), an active metabolite of propafenone, were studied on isolated atrial muscle fibres obtained from non-treated guinea-pigs and from animals pretreated with 5-OH-P, 3 mg kg-1, for 28 days. In untreated atria 5-OH-P, 10(-8) M-10(-4) M, produced a dose-dependent decrease in amplitude and df/dtmax and reduced the amplitude of the slow contractions induced by isoprenaline and histamine in high K+ media. 5-OH-P also produced a dose-dependent decrease in atrial rate, prolonged the sinus node recovery time and reduced the maximum chronotropic responses to isoprenaline. In untreated atrial muscle fibres 5-OH-P depressed action potential amplitude and Vmax, reduced the resting membrane potential and prolonged the action potential duration (ADP) and the effective refractory period, lengthening the effective refractory period relative to APD. Pretreatment with 5-OH-P reduced atrial rate and increased contractile force, but did not modify the action potential characteristics from the values obtained in untreated atria. Further addition of 5-OH-P produced similar but more marked changes than in untreated atria. It is concluded that in guinea-pig isolated atrial muscle fibres 5-OH-P, like propafenone, exhibits class I (membrane stabilizing), class II (antisympathetic) and class IV (Ca antagonistic) antiarrhythmic actions. Therefore, this metabolite could be responsible, at least in part, for some of the antiarrhythmic effects previously attributed to propafenone.

Negative inotropic effect of somatostatin in guinea-pig atrial fibres.

The effect of somatostatin (SS, 1 X 10(-7) M-5 X 10(-6) M) was studied on the electrical and mechanical properties of isolated atria of the guinea-pig. On spontaneously beating right atria, SS produced a dose-dependent negative inotropic effect which was accompanied by a decrease in atrial rate and a prolongation of the sinus node recovery time. In electrically driven left atria, SS produced a dose-dependent negative inotropic effect which occurred concomitantly with a decrease in the amplitude and duration of the plateau phase of the action potential of atrial fibres. SS also decreased the amplitude and maximum rate of depolarization of the slow action potential as well as the amplitude of the slow contractions induced by isoprenaline and caffeine in K-depolarized atrial fibres. The negative inotropic effect of SS varied with the concentration of Ca and Na in the bathing media and the frequency of stimulation. SS, 1 X 10(-6) M and 5 X 10(-6) M, decreased 45Ca uptake in electrically driven atria. All these results suggest that the negative inotropic effect produced by SS on rat isolated atria is related to its ability to reduce Ca influx via the slow inward Ca current.

Chronotropic, dromotropic and inotropic effects of dilazep in the intact dog heart and isolated atrial preparation.

When dilazep was administered intravenously to the anesthetized donor dog, mean systemic blood pressure was dose dependently decreased. At a dose of 0.1 mg/Kg i.v., the mean blood pressure was not changed but a slight decrease in heart rate was usually observed in the donor dog. At the same time, a slight but significant decrease in atrial rate and developed tension of the isolated atrium was induced. Within a dose range of 0.3 to 1 mg/Kg i.v., dilazep caused a dose related decrease in mean blood pressure, bradycardia in the donor dog, and negative chronotropic, dromotropic and inotropic effects in the isolated atrium. At larger doses of 3 and 10 mg/Kg i.v., dilazep caused marked hypotension, frequently with severe sinus bradycardia or sinus arrest, especially in isolated atria. When dilazep was infused intraarterially at a rate of 0.2-1 micrograms/min into the cannulated sinus node artery of the isolated atrium, negative chrono- and inotropic effects were dose dependently induced. With respect to dromotropism, SA conduction time (SACT) was prolonged at infusion rates of 0.2 and 0.4 micrograms/min. But at 1 microgram, dilazep caused an increase or decrease of SACT, indicating a shift of the SA nodal pacemaker. It is concluded that dilazep has direct negative chrono-, dromo- and inotropic properties on the heart at doses which produced no significant hypotension.

Interaction between calcium and slow channel blocking drugs on atrial rate.

The relationship between extracellular calcium concentration and the chronotropic effect of prenylamine, verapamil and nifedipine was studied in isolated spontaneously beating rat atria. The three slow channel blocking drugs produced a concentration-dependent decrease in atrial rate, though with different relative potencies. The order of potency for decreasing atrial rate, independently of the calcium level (1.0, 3.0, 6.0 or 9.0 mmol/l) was: verapamil greater than nifedipine greater than prenylamine. Increasing calcium from 1.0 to 6.0 and 9.0 mmol/l increased atrial rate from 251 +/- beats . min-1 to 265 +/- 6 beats . min-1 and 285 +/- 9 beats . min-1 (mean +/- 1 standard error) respectively (P less than 0.05). Despite their positive chronotropic effect high calcium levels failed to reverse the negative chronotropic effect of the slow channel blockers. Furthermore, the negative chronotropic effect of both verapamil and nifedipine was enhanced at high calcium levels. Raising calcium from 1.0 to 6.0 mmol/l in the presence of verapamil (1 X 10(-7) mol/l) or nifedipine (3 X 10(-7) mol/l) increased 2-fold the negative chronotropic effect of the calcium channel blockers. In addition, the concentration-effect curves for verapamil and nifedipine shifted to the left by 0.50 +/- 0.14 and 0.50 +/- 0.16 log units, respectively, when calcium increased from 1.0 to 6.0 mmol/l. The data show that increasing calcium may produce positive or negative chronotropic effects depending on whether or not the calcium channels are blocked. This paradoxical effect of calcium ions can be produced either by opposite chronotropic effects on automatic cells or by shifting the pacemaker activity to a group of cells which respond in a different way to an increment of calcium.

Effects of midodrine, ST 1059, methoxamine and glycine on spontaneously beating guinea-pig atria.

The chronotropic effects of midodrine, glycine (10(-8) to 3.10(-3) M), ST1059 and methoxamine (10(-8) to 10(-3) M) were investigated in the spontaneously beating guinea-pig right atrial preparation. Midodrine and glycine produced a slight, but significant rise in atrial rate over a wide concentration range. The midodrine-induced rise in atrial rate was not influenced by the beta-adrenergic receptor blocking drug propranolol (10(-6) M). The histamine (H2)-receptor blocking drug metiamide (3.10(-5) M) abolished the positive chronotropic actions of both midodrine and glycine. No positive chronotropic effect was seen after the administration of ST 1059 or methoxamine. A decrease in atrial rate was elicited by high concentrations (above 10(-4) to 10(-3) M) of the sympathomimetic agents midodrine, ST 1059, and methoxamine, but not by the amino acid glycine.

Additive effects of acetylcholine released by vagal nerve stimulation on atrial rate

In reserpinized dogs, the decrease in atrial rate (AR) as a function of the frequency of stimulation (supramaximal strength) of a single vagal nerve can be described satisfactorily by a rectangular hyperbola (RH). If the RH of one vagal nerve has been determined and if one point of the RH of the other vagal nerve is known, then the latter RH can be determined. Both RHs being known and assuming that the acetylcholine released by the right and left vagal nerves is additive, the slowing of AR by simultaneous stimulation of both nerves can be predicted. A minor systematic deviation from the predicted AR during simultaneous stimulation is usually found, which could be accounted for by a time dependent decrease of the effect of vagal nerve stimulation. The results are qualitatively similar during norepinephrine infusion. We propose that, although the vagal innervation may vary from pacemaker cell to pacemaker cell, the ratio of the activities of the two vagal nerves is constant throughout the sinoatrial node.

The action of promazine and thioridazine in isolated rat atria.2. Effects of varying concentrations of potassium and sodium on automaticity, mechanical performance, refractoriness and excitability

Isolated rat atria were suspended in a water-jacketed organ bath. An increase in the potassium concentrations, [K +] o, of the Ringer solution from 1.325 to 10.6 meq/1 had little effect on the spontaneous rate of atrial contractions, whereas the mechanical performance (work index) was depressed when [K +] o was raised above 5.3 meq/l. The threshold for electrical stimulation increased at potassium levels above 5.3 meq/l; the effective refractory period increased at potassium levels above 7.95 meq/l. Promazine, 2.5 × 10 −5M, and thioridazine, 5 × 10 −5M, reduced the rate and the work index, and these effects wer the threshold values and in effective refractory period caused by the two drugs were enhanced when [K +] o was raised. Replacement of 59.2 mM/l NaCl with equinolar concentrations of choline chloride did not change the spontaneous atrial rate nor the work index. The threshold values and effective refractory period were, however, increased. The decrease in atrial rate and work index caused by thioridazine, 5 × 10 −5M, was not influenced by a reduction in [Na +] o. The drug induceded increase in the threshold for electrical stimulation and in the effective refractory period was potentiated in the presence of low [Na +] o. The results show that the effects of the phenothiazine derivatives on the electrical activity of isolated rat atria is accentuated by a decrease in [Na +] o and a rise in [K +] o, and conversely, counteracted by low [K +] o.

Effects of a sulfhydryl reagent, [formula omitted], on electrical and mechanical activities of isolated atria

Rabbit sino-atrial node-right atrium preparations, sympathetic nerve-atria preparations and left atrium preparations were used. N- ethylmaleimide (NEM) in concentrations higher than 10 −5 M produced a dose-dependent decrease in atrial rate. At 10 −3 M activities the S-A node and right atrium were abolished. The activities were not restored by cysteine and ATP. Transmembrane potentials of S-A nodal pacemaker fibers were affected by 10 −3 M NEM. The major changes consisted of a decrease in the slope of diastolic depolarization and an acceleration of repolarization velocity. A tendency for the maximal diastolic potential and the overshoot to decrease were observed. Pacemaker shift frequently occurred. S-A nodal activities were more resistant to NEM than those of the right atrium. Left atrial preparations were driven electrically at different rates. The developed tension-driving rate relationship was not influenced by 10 −5 M NEM but was measurably depressed by 10 −4 M. The depression of the tension developed at high driving rates (60 to 240 beats/min) was more marked than that at low rates (6 to 30 beats/min). The negative chronotropic response to transmural electrical stimulation applied at the S-A node was slightly reduced in some preparations exposed to 10 −7 to 10 −5 M NEM, but was blocked by 10 −4 M. At the same concentration, slowing of atrial rate produced by acetylcholine was also blocked. The positive chronotropic effect of sympathetic nerve stimulation and of noradrenaline was reduced by 10 −4 M NEM. Since the effects of NEM were prevented by preincubation with isomolar concentrations of cysteine, the changes observed were considered to result from an inhibition of the SH groups. Thus, it was concluded that SH groups are involved in the process of contraction and the bioelectrical activity of pacemaker membrane linking automaticity and chronotropic actions of acetylcholine.

CAROTID CHEMORECEPTOR REFLEX EFFECTS ON CORONARY FLOW AND HEART RATE.

The innervated Langendorff's dog heart preparation in ventricular fibrillation with completely separated cross circulations to the head and heart was used for clarifying the mechanism of the carotid chemoreceptor reflex induced by nicotine, lobeline, 5-hydroxytryptamine, and acetylcholine. The effects of carotid chemoreflex were studied on the atrial rhythm and the coronary blood flow at constant pressure. A prompt decrease in atrial rate followed by a delayed acceleration was observed. Coronary dilation followed by constriction was observed concomitantly. In the atropinized heart evidences of a sympathetic component in the chemoreceptor reflex became evident. The sympathetic activity disappeared upon cooling of the head perfusion to 31 C, while the vagal action persisted. Warming to 40 C made the sympathetic effect more prominent. The reciprocal relation between the atrial rate and the coronary vascular tone may indicate a vagal coronary dilator and a sympathetic coronary constrictor effect in the dog.

Cardiac effects of synthetic oxytocin (Syntocinon)

The direct effect of synthetic oxytocin (Syntocinon) on cardiac tissue was studied in isolated atria and isolated papillary muscle preparations. No change in atrial rate or amplitude of contraction was noted until the oxytocin concentration was increased to 90 milliunits per milliliter. At this concentration a significant decrease in atrial rate occurred. In the papillary muscle preparation the amplitude of contraction increased significantly at a concentration of 15 milliunits per milliliter of oxytocin. The only other change produced by oxytocin was a prolongation of the refractory period without a concomitant reduction in conduction velocity. On the basis of the oxytocin effect on the ventricular refractory period, the potential antiarrhythmic activity of oxytocin was studied in hypothermia. A dose of 1 I. U. per kilogram per minute of oxytocin significantly reduced the incidence of ventricular fibrillation in hypothermic dogs from 83 to 25 per cent. The data suggest that the antiarrhythmic activity of oxytocin may be a function of its ability to prolong the refractory period of cardiac muscle without causing a concomitant reduction in conduction velocity.