Mechanism of the antiarrhythmic effect of laser irradiation]

Acute experiments were performed to study the role of afferent impulses from the heart receptors which pass by different vagal fibers during intraatrial laser irradiation. Double laser irradiation of the right atrium seemed more effective than a single one as to decreasing ventricular arrhythmias during cardiac ischemia. It is shown that the antiarrhythmic effect of intraatrial laser irradiation may be due to the change of the afferent information passing by myelinated vagal fibers.     

Transposition of the pacemaker in the right atrium during stimulation of the vagus nerve in the dog

The heart rate and intraatrial latencies between epicardial electrograms from three sites of the right atrium have been studied during vagal stimulation in open-chest dogs. It has been shown that alterations of latencies started at a certain cardiac cycle length irrespective of pacing frequency. A transitional process of changes from a steady latency value in the control to another steady value during vagal stimulation has been observed. The transitional process has been simulated in experimental procedure in which two sites of the right atrium were paced at close and constant frequencies. To interpret the results obtained one-dimensional model of the sinus node has been constructed. According to the model, pacemaker shift within the sinus node results from a competition between two foci of automaticity with close intrinsic frequencies.     

Analysis of the ultrastructure of atrial cardiomyocytes in rats after alimentary dehydration

By means of water deprivation primary- and secondary-compensated and decompensated degrees of dehydration have been caused in 24 rats. Electron microscopical investigation has demonstrated a more pronounced granularity of cardiomyocytes in the left than in the right cardiac auricles. During the alimentary dehydration granularity of the atrial cardiomyocytes in the right auricles increases at the primary- and secondary-compensated degrees of dehydration, in the stage of decompensated dehydration it decreases, the character of distribution of the secretory granules, however, shows certain processes of exhaustion. Granularity of the atrial cardiomyocytes in the left auricles during alimentary dehydration of the organism does not change. Changes of the endocrine apparatus in the atrial cardiomyocytes occur against the background of microcirculatory disturbances in both auricles of the heart and are combined with dystrophic changes in cardiomyocytes.     

Interaction of the autonomic nervous system with intrinsic cardiac rate regulation in the guinea-pig, Cavia porcellus.

In the denervated mammalian heart a change in right atrial pressure will still alter heart rate (intrinsic rate response, IRR). We have examined the IRR in isolated right atria of the guinea-pig maintained in oxygenated Krebs-Henseleit solution at 37 degrees C, to compare with and extend studies in other species, and to determine whether the guinea-pig is a suitable model for electrophysiological studies of the IRR. Baseline diastolic transmural pressure was set at 2 mmHg. A 6-mmHg increase in right atrial pressure (RAP) caused an increase in atrial rate that reached a steady value of 15 min(-1) after 1-2 min. This response was enhanced by carbamylcholine and attenuated by isoprenaline. The influence of RAP on the rate response to vagal stimulation was examined. With RAP set at 8 mmHg, the reduction in atrial rate following vagal stimulation was 72+/-5% of that at 2 mmHg (n=6, mean+/-S.E., P<0.005). Continuous vagal stimulation produced a sustained bradycardia, and the effect of this bradycardia on the IRR was examined. When atrial rate was reduced 6% by vagal stimulation, the IRR was augmented to 202+/-21% of the control (n=6, P<0.005). This augmentation was larger (P<0.05) than that seen when atrial rate was reduced 8% by carbamylcholine (130+/-8% of control; n=7, P<0.05). Overall, the IRR in the guinea-pig is similar to that in the rabbit, and shows similar interactions with the autonomic nervous system.     

Effect of the vagus nerve on isolated rabbit atria in ganglionic blockade due to hexamethonium]

By quantitative stimulation of the vagus nerves of isolated rabbit atria frequency-response relations were obtained for both the electrotropic effect (reduction of the area of the monophasic action potential) and the inotropic response. An addition of hexamethonium in a final concentration of 10(-5) g/ml resulted in a diminution of vagal effectivity in the range of lower and medium frequencies of stimulation, and was connected with a shift of the frequency-response characteristic to the right. At higher frequencies vagal effectivity was increased. In contrast to the inhibitory effect of hexamethonium the facilitating action is irreversible. By raising the concentration up to 4-10(-5) g/ml the vagal effects were reduced to a large extent, and the frequency dependence of the response was abolished at medium frequencies. In the range of 20 sec(-1) to 100 sec(-1) this dependence was re-established and may be considered as a part of a normal frequency-response relation extremely shifted to the right. The time courses of both types of effect are characterized by a steep rise and a decay of the response during the stimulation period. A mathematical handling of the frequency-response characteristics provides quantitative evidence for the extent of the hexamethonium blockade of vagal ganglion cells in the atria; furthermore it leads to the conception of these cells to act as a distributing system for a homogeneous innervation by a widespread divergency of postganglionic fibres.     

Possible role of lipid peroxidation in the pathogenesis of arrhythmias in myocardial infarct

The effect of myocardial infarction sustained by rats on the resistance of their isolated auricles to H2O2, an inductor of lipid peroxidation (LP), was studied. Atrial resistance to the LP inductor depends on the level of developed tension (DT) and the decrease of DT leads to augmentation of atrial resistance to the arrhythmogenic effect of LP. The experimental myocardial infarction causes appreciable disturbances in the function of automatism of the auricles, 60% of which lose their capability of spontaneous contractile activity. When compared with the control under equal DT, the auricles of the "infarction" series are less resistant to H2O2: the time of arrhythmias and arrests in them are 2.3 times as much as in the control. In infarction, the pretreatment with ionol reduces both the quantity of the auricles which stopped before H2O2 administration and the quantity of the auricles responding by arrhythmia to LP induction. The data point to the possibility of the use of antioxidants for preventing arrhythmias in experimental myocardial infarction.     

Vagal effects on sinoatrial and atrial conduction studied with epicardial mapping in dogs: the influence of pacemaker shifts on the measurement of sinoatrial conduction time

The influence of pacemaker shifts on sinoatrial conduction time (SACT) was studied by investigating the effects of vagal stimulation on SACT and atrial conduction in anesthetized open-chest dogs. Isochronal maps were drawn from unipolar electrograms simultaneously recorded at 60 epicardial sites on the right atrial free wall and the inferior and superior vena cava. Vagal stimulation caused atrial conduction velocity to increase from 0.99 +/- 0.10 m/s (mean +/- SD) to 1.23 +/- 0.23 m/s (p less than 0.01), and the pacemaker to shift to lower positions along the superior vena cava - right atrial junction. As a result of the changes, the distances and the atrial conduction times from the stimulating and recording electrodes to the pacemaker site varied, and hence, the SACT values obtained indirectly by premature atrial stimulation varied. The isochronal maps were used to measure the atrial conduction times from stimulating to recording electrodes (a), from stimulating electrode to pacemaker site (b), and from pacemaker site to recording electrode (c). Indirect SACT was lengthened by vagal stimulation from 43 +/- 16 to 64 +/- 22 ms (p less than 0.02). After correcting by subtracting the atrial conduction time (b + c - a), these values became 26 +/- 6 ms (control) and 40 +/- 11 ms (vagal stimulation) (p less than 0.01). SACT values measured directly from the electrograms were 27 +/- 7 ms (control) and 42 +/- 10 ms (vagal stimulation) (p less than 0.01). Corrected indirect SACTs were closer to direct SACTs than were the uncorrected indirect SACTs.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of vagus nerves in different changes of the right atrial pressure following intravenous injection of pressor vasoactive drugs

In acute experiments on anesthetized cats, intravenous injection of the norepinephrine and angiotensin caused different changes of right atrial pressure in intact animals (decreasing--I group, of animals, and increasing--II group). After right and left vagus nerves had been cut, the right atrial pressure in the I group of animals decreased, but its changes were lesser than in intact animals due to slowing down of the increase of the right ventricular myocardial contractility and venous return. The latter was the result of severe diminution of the increase of the superior vena cava flow compared with the intact animals, meanwhile the value of the inferior vena cava flow did not change. In the II group animals after vagotomy and intravenous injection of the noripinephrine and angiotensin the sign of the right atrial pressure became negative, i. e. the direction of its shifts changed to the opposite, compared with intact animals. In this case, the changes of the sign of the right atrial pressure was caused by the removal of the reflectory inhibitory vagal influences on the heart, because the values of the right ventricular myocardial contractility and venous return were the same as in intact animals of the group, due to decreasing of the value of the superior vena cava flow and increasing of the shifts of the inferior vena cava flow. The vagotomy alone caused also different changes (decreasing or increasing) of right atrial pressure following increasing of the right ventricular myocardial contractility, meanwhile the changes of the venous return were insignificant. Direct electrical stimulation of both the right and the left vagus nerves caused the increasing of the right atrial pressure and decreasing of the right ventricular myocardial contractility and venous return. Thus we concluded, that different changes of the right atrial pressure in animals following intravenous injection of the pressor vasoactive drugs could be the result of different manifestations of the vagal afferent impulsation, which has influence on the sympathetic tonic discharges on the vessels of the regions of the superior and inferior vena cava, and the vagal reflectory inhibitory influences on the heart.     

Modification of efferent vagal effects on the isolated atrium by increased extracellular K+ concentrations

Isolated vagal-innervated rabbit atria are electrically driven. Alterations of action potential, contraction, and electrotropic and inotropic vagal effects are investigated during variations of the external potassium concentration. Action potential area and contraction amplitude decrease by increasing external potassium concentration. If the potassium concentration is higher than 11 mM, the action potential disappears. At 24 mM potassium concentration the contraction amplitude of the driven atrium is reduced to 2%. Adrenaline (2.10(-5) g/ml) causes a restitution of the action potential and the contraction. With increasing potassium concentration the inotropic and the electrotropic vagal effectivity increases also. The vagal effects at the adrenaline restituted action potentials and contractions (15 mM potassium, 2.10(-5) g/ml adrenaline) are also higher than in normal solutions. The relations of electromechanical coupling are altered by potassium variation at the same coupling curve. With increasing potassium concentration the reproducibility of the vagal effects decreases.     

Decreased content in left atrium and increased plasma concentration of atrial natriuretic polypeptide in spontaneously hypertensive rats (SHR) and SHR stroke-prone

The atrial contents and concentrations, and the plasma concentrations of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR) and SHR stroke-prone (SHRSP) were measured and compared with those of age-matched Wistar Kyoto rats (WKY) using a specific radioimmunoassay (RIA) for alpha-rat ANP (alpha-rANP). The contents of alpha-rANP-LI in the atria of SHR (19.0 +/- 0.9 micrograms, mean +/- SEM) and SHRSP (19.3 +/- 0.6 micrograms) were significantly lower than that of WKY (22.8 +/- 1.4 micrograms) (p less than 0.05). The atrial concentration of alpha-rANP-LI was also significantly lower in SHR (248.2 +/- 11.3 ng/mg, p less than 0.05) and tended to be lower in SHRSP (272.2 +/- 12.4 ng/mg) than that of WKY (300.0 +/- 14.2 ng/mg). Furthermore, the concentrations in the left auricles of SHR and SHRSP were significantly lower than that of WKY (p less than 0.01 and p less than 0.05, respectively). In contrast, no significant difference was observed in the alpha-rANP-LI concentrations in the right auricles of WKY, SHR and SHRSP. Gel filtration studies coupled with RIA showed that gel filtration profiles of the extracts from the right and left auricles of WKY, SHR and SHRSP were essentially identical. The plasma alpha-rANP-LI levels in SHR (260 +/- 34 pg/ml) and SHRSP (319 +/- 19 pg/ml) were significantly higher than that in WKY (170 +/- 17 pg/ml) (p less than 0.05 and p less than 0.01, respectively). These results suggest that the secretion of ANP from the heart is increased in SHR and SHRSP compared with WKY.     

Interaction of the autonomic nervous system with intrinsic cardiac rate regulation in the guinea-pig, Cavia porcellus

In the denervated mammalian heart a change in right atrial pressure will still alter heart rate (intrinsic rate response, IRR). We have examined the IRR in isolated right atria of the guinea-pig maintained in oxygenated Krebs–Henseleit solution at 37°C, to compare with and extend studies in other species, and to determine whether the guinea-pig is a suitable model for electrophysiological studies of the IRR. Baseline diastolic transmural pressure was set at 2 mmHg. A 6-mmHg increase in right atrial pressure (RAP) caused an increase in atrial rate that reached a steady value of 15 min⁻¹ after 1–2 min. This response was enhanced by carbamylcholine and attenuated by isoprenaline. The influence of RAP on the rate response to vagal stimulation was examined. With RAP set at 8 mmHg, the reduction in atrial rate following vagal stimulation was 72±5% of that at 2 mmHg (n=6, mean±S.E., P<0.005). Continuous vagal stimulation produced a sustained bradycardia, and the effect of this bradycardia on the IRR was examined. When atrial rate was reduced 6% by vagal stimulation, the IRR was augmented to 202±21% of the control (n=6, P<0.005). This augmentation was larger (P<0.05) than that seen when atrial rate was reduced 8% by carbamylcholine (130±8% of control; n=7, P<0.05). Overall, the IRR in the guinea-pig is similar to that in the rabbit, and shows similar interactions with the autonomic nervous system.     

IDENTIFICATION OF LARGE LEFT ATRIAL THROMBUS BY CROSS-SECTIONAL AND M-MODE ECHOCARDIOGRAPHY

In addition to a typical pattern indicative of mitral stenosis, the M-mode echo-cardiogram of a patient with mitral valve disease revealed a broad band of dense echoes within an enlarged left atrial cavity that was suggestive of an intraatrial thrombus. Subsequent cross-sectional echocardiography demonstrated a globular cluster of echoes inside the left atrial cavity, thus corroborating our interpretation of the M-mode recording. When open mitral commissurotomy was performed, a large, partially calcified thrombus was found protruding from the posterior wall and left atrial appendage into the atrial cavity. Postoperative M-mode and cross-sectional echocardiography did not show the previously noted abnormal echoes within the left atrium.     

Interactions within the intrinsic cardiac nervous system contribute to chronotropic regulation

The objective of this study was to determine how neurons within the right atrial ganglionated plexus (RAGP) and posterior atrial ganglionated plexus (PAGP) interact to modulate right atrial chronotropic, dromotropic, and inotropic function, particularly with respect to their extracardiac vagal and sympathetic efferent neuronal inputs. Surgical ablation of the PAGP (PAGPx) attenuated vagally mediated bradycardia by 26%; it reduced heart rate slowing evoked by vagal stimulation superimposed on sympathetically mediated tachycardia by 36%. RAGP ablation (RAGPx) eliminated vagally mediated bradycardia, while retaining the vagally induced suppression of sympathetic-mediated tachycardia (-83%). After combined RAGPx and PAGPx, vagal stimulation still reduced sympathetic-mediated tachycardia (-47%). After RAGPx alone and after PAGPx alone, stimulation of the vagi still produced negative dromotropic effects, although these changes were attenuated compared with the intact state. Negative dromotropic responses to vagal stimulation were further attenuated after combined ablation, but parasympathetic inhibition of atrioventricular nodal conduction was still demonstrable in most animals. Finally, neither RAGPx nor PAGPx altered autonomic regulation of right atrial inotropic function. These data indicate that multiple aggregates of neurons within the intrinsic cardiac nervous system are involved in sinoatrial nodal regulation. Whereas parasympathetic efferent neurons regulating the right atrium, including the sinoatrial node, are primarily located within the RAGP, prejunctional parasympathetic-sympathetic interactions regulating right atrial function also involve neurons within the PAGP.     

Effects of pituitary adenylate cyclase-activating polypeptide on canine atrial electrophysiology

We hypothesized that pituitary adenylate cyclase-activating polypeptide (PACAP) activates intracardiac postganglionic parasympathetic nerves and has a different effect than cervical vagal stimulation. We measured effective refractory period (ERP) and conduction velocity at four atrial sites [high right atrium (HRA), low right atrium (LRA), high left atrium (HLA), and low left atrium (LLA)] and minimum atrial fibrillation (AF) cycle length at 12 atrial sites during cervical vagal stimulation and after PACAP in 26 autonomically decentralized, open-chest, anesthetized dogs. PACAP shortened ERP to a similar extent at all four sites (HRA, 58 +/- 2.0 ms; LRA, 60 +/- 6.3 ms; HLA, 68 +/- 11.5 ms; and LLA, 60 +/- 8.3 ms). Low- and high-intensity vagal stimulation shortened ERP at the HRA, but not in the other atrial sites (low-intensity stimulation: HRA, 64 +/- 4.0 ms; LRA, 126 +/- 5.1 ms; HLA, 110 +/- 9.5 ms; and LLA, 102 +/- 11.5 ms; high-intensity stimulation: HRA, 58 +/- 4.2 ms; and HLA, 101 +/- 4.0 ms). Conduction velocity was not altered by any intervention. Minimum AF cycle length after PACAP was similar in both atria but was shorter in the right atrium than in the left atrium during vagal stimulation. After atropine administration, no interventions changed ERP. These results suggest that PACAP shortens atrial refractoriness uniformly in both atria through activation of intrinsic cardiac nerves, not all of which are activated by cervical vagal stimulation.     

Controlled atrial fibrillation and a possible mechanism of its genesis

In experiments on cats a single premature beat or vagal stimulation shortened the effective refractory period without any spontaneous heart rate disturbances, while the combined action of these factors always led to paroxysmal tachycardia or atrial fibrillation. It is suggested that contracting myocardium possesses a covert ability for self-excitation revealed only in critical shortening of the action potential. Since the excitation occurring in such conditions is also a premature beat, the fibrillation process becomes self-maintaining.     

Selective AV nodal vagal stimulation improves hemodynamics during acute atrial fibrillation in dogs

Although the atrioventricular node (AVN) plays a vital role in blocking many of the atrial impulses from reaching the ventricles during atrial fibrillation (AF), a rapid irregular ventricular rate nevertheless persists. The goals of the present study were to explore the feasibility of novel epicardial selective vagal nerve stimulation for slowing of the ventricular rate during AF and to characterize the hemodynamic benefits in vivo. Electrophysiological-echocardiographic experiments were performed on 11 anesthetized open-chest dogs. Hemodynamic measurements were performed during three distinct periods: 1) sinus rate, 2) AF, and 3) AF with vagal nerve stimulation. AF was associated with significant deterioration of all measured parameters (P < 0.025). The vagal nerve stimulation produced slowing of the ventricular rate, significant reversal of the pressure and contractile indexes (P < 0.025), and a sharp reduction in one-half of the abortive ventricular contractions. The present study provides comprehensive evidence that slowing of the ventricular rate during AF by selective ganglionic stimulation of the vagal nerves that innervate the AVN successfully improved the hemodynamic responses.     

Augmented synthesis of beta-human atrial natriuretic polypeptide in human failing hearts

To elucidate the synthesis of atrial natriuretic polypeptide (ANP) in the failing heart, eighteen human right auricles obtained at cardiovascular surgery were studied. The concentration of alpha-human ANP-like immunoreactivity (alpha-hANP-LI) in human right auricles ranged from 13.8 to 593.5 micrograms/g, and the tissue alpha-hANP-LI concentration in severe congestive heart failure (CHF) (New York Heart Association (NYHA) functional class III or IV) was much higher than those in mild CHF of NYHA class I and class II. The alpha-hANP-LI in the human auricle consisted of 3 major components of ANP, gamma-human ANP (gamma-hANP), beta-human ANP (beta-hANP) and alpha-human ANP (alpha-hANP). The predominant component of alpha-hANP-LI was gamma-hANP in the mild CHF, whereas beta-hANP and/or alpha-hANP were prevailing in the severe CHF and, especially, beta-hANP was markedly increased in human failing hearts.     

Hypercholesterolemia induces up-regulation of KACh cardiac currents via a mechanism independent of phosphatidylinositol 4,5-bisphosphate and Gβγ

Hypercholesterolemia is a well-known risk factor for cardiovascular disease. In the heart, activation of K(ACh) mediates the vagal (parasympathetic) negative chronotropic effect on heart rate. Yet, the effect of cholesterol on K(ACh) is unknown. Here we show that cholesterol plays a critical role in modulating K(ACh) currents (I(K,ACh)) in atrial cardiomyocytes. Specifically, cholesterol enrichment of rabbit atrial cardiomyocytes led to enhanced channel activity while cholesterol depletion suppressed I(K,ACh). Moreover, a high-cholesterol diet resulted in up to 3-fold increase in I(K,ACh) in rodents. In accordance, elevated currents were observed in Xenopus oocytes expressing the Kir3.1/Kir3.4 heteromer that underlies I(K,ACh). Furthermore, our data suggest that cholesterol affects I(K,ACh) via a mechanism which is independent of both PI(4,5)P(2) and Gβγ. Interestingly, the effect of cholesterol on I(K,ACh) is opposite to its effect on I(K1) in atrial myocytes. The latter are suppressed by cholesterol enrichment and by high-cholesterol diet, and facilitated following cholesterol depletion. These findings establish that cholesterol plays a critical role in modulating I(K,ACh) in atrial cardiomyocytes via a mechanism independent of the channel's major modulators.     

A Canine Model of Sustained Atrial Fibrillation Induced by Rapid Atrial Pacing and Phenylephrine

Atrial fibrillation is a common arrhythmia with considerable morbidity and mortality. Limitations in studying both the mechanisms and therapy of atrial fibrillation arise due to the paucity of models that yield sufficiently high-quality data, are not costly, and in which atrial fibrillation is sustained long enough to make the necessary observations. The canine model we present is based on the hypothesis that atrial fibrillation requires heterogeneity of repolarization, that distribution of vagal fibers is heterogeneous in the atria, and that atrial fibrillation will persist after reflex stimulation of vagal efferents by increased systemic arterial pressure. Dogs were anesthetized with morphine–chloralose because this combination maintains nearly intact autonomic control. Systemic arterial pressure was elevated approximately 75 mm Hg during infusion of phenylephrine (2 μg/kg · min⁻¹). The right atrium was paced for 20 min at 40 Hz. Atrial fibrillation was sustained after cessation of atrial pacing in dogs receiving phenylephrine, but terminated within seconds in normotensive animals. In conclusion, atrial fibrillation can be maintained for at least 40 min after cessation of rapid atrial pacing in dogs with phenylephrine-induced hypertension.Atrial fibrillation is a common arrhythmia that affects more than 2 million persons in the United States.¹ This condition is characterized by chaotic asynchronous activation and contraction of hundreds of regions of the atria, resulting in both absence of active atrial transport of blood and a rapid ventricular response. With chronic atrial fibrillation, patients can develop thromboembolism and stroke;²² and 15% of strokes in the United States occur in patients with atrial fibrillation.¹ Despite prodigious efforts to understand the mechanism of this condition and to prevent and remediate it, atrial fibrillation leads to enormous morbidity and mortality.³ One factor hindering studies of atrial fibrillation is the absence of a model in which fibrillation can be sustained for more than several seconds, although the arrhythmia can be sustained nearly permanently after weeks of rapid atrial pacing in animals with either heart failure or physical injury to the left atrium.⁸Rapid atrial pacing decreases the atrial effective refractory period, slows atrial conduction, and increases electrophysiologic heterogeneity.^10,11,20 Recently, phenylephrine was shown to increase the difference between left and right atrial and intraatrial refractory periods, thus creating heterogeneity of atrial refractoriness.¹⁶ We therefore postulated that rapid atrial pacing together with phenylephrine infusion would induce relatively sustained atrial fibrillation for at least 40 min in dogs—a duration likely to be sufficient for testing of agents with potential to convert atrial fibrillation. This report describes a simple canine model using rapid atrial pacing in which atrial fibrillation was sustained for at least 40 min.