Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces.

Angiotensin-converting enzyme inhibitors have beneficial effects that are presumably mediated by decreased angiotensin II (ANG II) production. In this study, we measure for the first time ANG I and ANG II levels in the interstitial fluid (ISF) space of the heart. ISF and aortic plasma ANG I and II levels were obtained at baseline, during intravenous infusion of ANG I (5 microM, 0.1 ml/min, 60 min), and during ANG I + the angiotensin-converting enzyme inhibitor captopril (cap) (2.5 mM, 0.1 ml/min, 60 min) in six anesthetized open-chested dogs. ISF samples were obtained using microdialysis probes inserted into the left ventricular myocardium (3-4 probes/dog). ANG I increased mean arterial pressure from 102+/-3 (SEM) to 124+/-3 mmHg (P < 0.01); addition of cap decreased MAP to 95+/-3 mmHg (P < 0.01). ANG I infusion increased aortic plasma ANG I and ANG II (pg/ml) (ANG I = 101+/-129 to 370+/-158 pg/ml, P < 0.01; and ANG II = 22+/-40 to 466+/-49, P < 0.01); addition of cap further increased ANG I (1,790+/-158, P < 0.01) and decreased ANG II (33+/-49, P < 0.01). ISF ANG I and ANG II levels (pg/ml) were > 100-fold higher than plasma levels, and did not change from baseline (8,122+/-528 and 6,333+/-677), during ANG I (8,269+/-502 and 6, 139+/-695) or ANG I + cap (8,753+/-502 and 5,884+/-695). The finding of very high ANG I and ANG II levels in the ISF vs. intravascular space that are not affected by IV ANG I or cap suggests that ANG II production and/or degradation in the heart is compartmentalized and mediated by different enzymatic mechanisms in the interstitial and intravascular spaces.

Atrioventricular junctional tachycardia during heart block.

The response of the atrioventricular (AV) junction to brief intense adrenergic stimulation applied during episodes of second degree heart block achieved by acetylcholinesterase paralysis in the AV junction was examined in six dogs. Despite profound depression of AV conduction due to enhanced cholinergic activity, strong local adrenergic stimulation still readily elicited AV junctional tachycardia. Increase in cholinomimetic influences in the AV junction did not prolong transatrial or His bundle-ventricular conduction times. During AV junctional rhythm and retrograde atrial capture (n = 4), neither the sequence of retrograde atrial activation nor the atrial electrogram configurations were altered. In the two remaining dogs the AV junctional tachycardia was associated with AV dissociation. These findings suggest that the acetylcholine-induced depression of AV conduction is located in the AV node region exclusively. More important, however, is the demonstration that retrograde atrial activation originating from a pacemaker located in the AV node or immediate vicinity could actually precede the inscription of the H spike by a considerable amount of time, further suggesting that anterograde conduction from the pacemaker site to the bundle of His is far more depressed by acetylcholine than is the concomitant retrograde conduction from the pacemaker site to the atrium. Thus, inference of the origin of a subsidiary pacemaker from the P wave configuration or the relation of the A wave to the His bundle electrogram, or both, may lead to erroneous conclusions.

Differential modulation of autonomic activity by ethmozin and ethacizin (analog of ethmozin) on the canine sinus node and atrioventricular junction.

The chronotropic and dromotropic actions of ethmozin and its diethylamine analog ethacizin were studied in the presence and absence of combined muscarinic, beta- and alpha-adrenoreceptor blockade in the intact canine heart in situ (n = 38). Injections of ethacizin, 5, 10 and 25 micrograms/ml, into the sinus node artery caused an immediate and significant (p less than 0.001) sinus bradycardia of 2, 6 and 11%, respectively. Injection of 25 and 50 micrograms/ml of ethacizin into the atrioventricular (AV) node artery significantly (p less than 0.001) prolonged AV conduction time with occasional second degree heart block. Conduction delay was located exclusively during the AH interval of the His bundle electrogram. Autonomic blockade did not alter the negative chronotropic or negative dromotropic effects of ethacizin. Ethacizin, 25 micrograms/ml, injected into the sinus node artery immediately reduced the sinus node response to vagal stimulations by 30% and the effect of acetylcholine, 0.1 micrograms/ml, injected into the sinus node artery by 50%. Ethacizin, 25 micrograms/ml, injected into the AV node artery immediately reduced the duration of complete AV block elicited by vagal stimulation or intranodal acetylcholine, 0.5 micrograms/ml, by 90%. Ethacizin caused a minor reduction in sinus node response to right stellate stimulations without, however, altering the sinus node response to intranodal norepinephrine. Ethmozin injections of up to 50 micrograms/ml into the sinus and AV node arteries had no chronotropic or dromotropic effects. Ethmozin had a minor and variable vagolytic action but significantly (p less than 0.05) reduced the sinus node response to sympathetic nerve stimulation. Hence, ethacizin, in contrast to ethmozin, has a direct depressing action on both the sinus node and the AV junction.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial production of controlled periods of temporary heart block used to unmask and assess latent ventricular automaticity during experimental acute myocardial ischemia.

This study examined the onset, time course of development and response to overdrive stimulation of ventricular tachycardia in 10 dogs that underwent a Harris two-stage ligation of the left anterior descending coronary artery. Transient (12 +/- 3 minutes) complete atrioventricular (AV) block was produced 2, 3, 4, 5, 8, 12, 16, 20 and 24 hours after onset of infarction through selective injection of physostigmine salicylate into the AV node artery. Seven of the 10 dogs had early transient arrhythmic episodes that occurred within 20 to 40 minutes after coronary occlusion but none of the dogs had any spontaneous ventricular tachycardia in the ensuing 2 hours. Two hours after left anterior descending coronary artery ligation, complete AV block unmasked in every dog a slow (37 +/- 9 beats/min) AV junctional rhythm readily suppressed by overdrive. Three hours after coronary ligation, AV block revealed a monomorphic ventricular tachycardia (106 +/- 10 beats/min) in 3 of the 10 dogs. Four and five hours after coronary ligation, five and eight dogs, respectively, had ventricular tachycardia during AV block and in three the tachycardia was polymorphic. The two remaining dogs did not develop ventricular tachycardia during the 24 hours of observation. Ventricular tachycardia always began abruptly, first with brief and then longer bursts. Soon after onset the rate of tachycardia began to increase to reach a plateau 2 to 3 hours later at frequencies 21 +/- 9% greater than the initial tachycardia rate. Concomitant with this increase in rate there was a steady decline of overdrive suppressibility and during the plateau phase there was little or no overdrive suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Parasympathetic and sympathetic efferent traffic during a cardiogenic hypertensive chemoreflex.

Activation of a cardiac chemoreceptor with serotonin elicits a reflex which includes changes in heart rate, contractile force, regional blood flow and hypertension. In six anaesthetised dogs we simultaneously recorded parasympathetic and sympathetic efferent traffic elicited during this cardiogenic reflex. The parasympathetic fibres were confirmed by reciprocal frequency changes with changes in blood pressure. The sympathetic fibre activity (anterior ansa subclavia) was attenuated or eliminated by ganglionic blockade or by clonidine. Whereas the phasic sympathetic multifibre discharge was only followed by a quiet period, the parasympathetic multifibre discharge was both preceded and followed by a quiet period. The sympathetic discharge preceded the parasympathetic discharge by 683 +/- 170 ms. These autonomic efferent discharges were not elicited by administration of serotonin into the carotid artery, but were abolished by pretreatment with the serotonin antagonist, cyproheptadine. Cyproheptadine blockade could be overcome by increasing the serotonin concentration tenfold. This remarkable neural asynchrony has important implications concerning the electrical stability of the heart.

Clonidine attenuation of a cardiogenic hypertensive chemoreflex.

Clonidine is an antihypertensive agent with a primary action mediated by alpha adrenergic stimulation in the central nervous system, thus inhibiting sympathetic efferent activity. Serotonin activates a cardiogenic hypertensive chemoreflex which induces discharges of sympathetic efferent neurons. The purpose of this study was to determine the effects of intravenous clonidine upon the thoracic sympathetic efferent discharges in chloralose-anesthetized dogs, their peripheral autonomic receptors being blocked with atropine, propranolol, and phentolamine. Efferent nerve traffic was quantified using a Schmitt trigger and Digital PDP8/e computer. Control spontaneous activity (tone) following autonomic blockade was normalized at 100%. Serotonin (100 microgram/ml, 2 ml, left atrium) caused an increase in the reflex efferent sympathetic activity to 192% +/- 16% of control (p less than 0.001). Following clonidine, the tone was decreased to 63% +/- 6% of control, and the reflex sympathetic discharge elicited by serotonin was significantly (p less than 0.001) reduced from 192% to 116% +/- 9% of control tone (before clonidine). The attenuation of the reflexly elicited discharge was significantly (p less than 0.05) greater than the attenuation of the tone. In four dogs that did not receive atropine, the vago-vagal reflex sinus bradycardia induced by serotonin was not affected by clonidine.

Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog.

Studies from our laboratory suggest that the afferent renal nerves from the clipped kidney enhance sympathetic nervous system activity in established one-kidney, one clip and two-kidney, one clip Goldblatt hypertension. Because adenosine is released during renal ischaemia and adenosine has been shown to increase the frequency of afferent renal nerve signals, we proposed the hypothesis that intrarenal adenosine might produce hypertension by activating the sympathetic nervous system via the afferent renal nerves. To examine this hypothesis, changes in arterial pressure and activity of the sympathetic nervous system were measured during renal artery infusion of adenosine before and after renal denervation in uninephrectomized sodium replete conscious dogs. Intrarenal adenosine infusion produced a 21 +/- 3 mmHg mean arterial pressure rise in association with an increase in plasma norepinephrine. Ganglionic blockade during intrarenal adenosine infusion resulted in a significantly greater decrease in arterial pressure compared to control responses. After renal denervation, intrarenal adenosine infusion resulted in no change in arterial pressure, plasma norepinephrine or arterial pressure response to ganglionic blockade. To further assess sympathetic activity changes, right renal norepinephrine secretion and multifibre efferent neural traffic were measured during left renal artery adenosine infusion in alpha-chloralose-anaesthetized dogs. Left renal artery adenosine infusion resulted in increased right renal vascular resistance in association with increased renal norepinephrine secretion and increased efferent neural activity. The data indicate that in the dog with intact renal nerves, intrarenal adenosine produces hypertension by activating the sympathetic nervous system.

Reflex heart block. Baroreflex, chemoreflex and bronchopulmonary reflex causes.

Reflex heart block was studied in 20 dogs anesthetized with sodium pentobarbital and in 5 trained unanesthetized dogs. Three different vagal reflexes were produced: the Marey response during hypertension caused by administering methoxamine, a cardiogenic hypertensive chemoreflex activated by injection of serotonin into the left atrium and the Hering-Breuer reflex observed during normal respiration of unanesthetized dogs. In every dog during any of the three reflexes heart block was consistently observed after the normal slowing response of the sinus node had been selectively eliminated by the direct perfusion of 10 microgram of atropine into the sinus node artery. This was a uniform response despite its being variously produced by a pressor reflex, a chemoreflex or an extracardiac bronchopulmonary reflex. Transient heart block is therefore to be anticipated during reflexes with vagal efferent components if for any reason the sinus node is incapable of slowing suitably. The possible clinical relevance of these experimental observations is discussed.

Cardiac dysrhythmias in the conscious dog after surgically induced autonomic imbalance.

The ventrolateral cardiac nerve in the dog is a primary branch of the left sympathetics and represents a direct neural link between the central nervous system and the heart. Its electric excitation elicits characteristic shifts in pacemaker and tachydysrhythmias related to its explicit innervation of the inferior atrial, atrioventricular (A-V) junctional and ventricular tissues. Total denervation of the canine heart, sparing the ventrolateral cardiac nerve, produced a long-term model in which only these portions of the heart retained their sympathetic innervation. The trained unanesthetized model dog was subjected to severe exercise in order to determine the effects of elevated levels of sympathetic tone upon these important regions of the conduction system. Reproducible tachydysrhythmias were elicited in all six animals completing the regimen of periodic testing over a period of 136 to 378 days after operation. The abnormal rhythms consisted of shifting cardiac pacemakers and supraventricular A-V junctional and ventricular tachycardias with frequent premature systoles. Comparable abnormalities were not observed in a similarly tested sham-operated animal or in dogs with a totally denervated heart. The exercise-induced dysrhythmias gradually disappeared with time, presumably in relation to autonomic reinnervation of the heart. The characteristic patterns of ventrolateral cardiac nerve and upon its presumed influence upon Purkinje fiber and A-V nodal automaticity and temporal dispersion of refractoriness in myocardial tissues.

Chronotropic and dromotropic effects of histamine on the canine heart.

The actions of 2-methylhistamine (H1 agonists), 4-methylhistamine (H2 agonist), and histamine were studied by selective perfusion of the sinus node artery and atrioventricular node artery in 75 dogs anesthetized with pentobarbital sodium. 2-Methylhistamine and histamine had variable and inconsistent effects on the sinus rate. 4-Methylhistamine (100 microgram/ml) produced acceleration of the sinus rate from 158 +/- 4 to 173 +/- 5 beats per minute (P less than 0.05) when perfused via the sinus node artery. The effects of the histamine agonists on atrioventricular junctional rhythms were similar to the effects on sinus rhythm. The response of the sinus node to vagal stimulation was attenuated by selective perfusion with histamine; however, the direct negatively chronotropic action of acetylcholine was not affected by histamine. Neither 2-methylhistamine nor 4-methylhistamine affected the response of the sinus node to vagal stimulations. Both 4-methylhistamine and histamine (but not 2-methylhistamine) attenuated (P less than 0.05) the response of the sinus node to stimulation of the right stellate ganglion. The positively chronotropic effects of directly perfused norepinephrine were unaffected by histamine or 4-methylhistamine. These results suggest a neural depressing action of histamine on autonomic efferent fibers. In the atrioventricular junction, both histamine and 2-methylhistamine (but not 4-methylhistamine) had negatively dromotropic effects. Cimetidine (an H2 antagonist) had no significant direct effects on the sinus rate or atrioventricular conduction and failed to prevent the acceleration of the sinus rate produced by local perfusion with 4-methylhistamine.

Enhanced induction of ventricular arrhythmias during sympathetic stimulation before and during coronary artery occlusion.

We used programmed electrical stimulation to examine the arrhythmogenic influence of the sympathetic nervous system before and during coronary artery occlusion. In 29 anesthetized dogs the left and/or right stellate ganglia were stimulated at 2-8 hertz. Program-induced ventricular arrhythmias included single premature ventricular depolarizations, doublets, triplets, ventricular tachycardia and ventricular fibrillation. Both the number of extrastimuli and the duration of coronary occlusion significantly influenced ventricular arrhythmia induction. After pooling the number of extrastimuli, type of artery occluded, and the duration of occlusion, the influences of unilateral and bilateral stellate stimulations were evaluated. The incidence of induced ventricular arrhythmias was 54% during control conditions (prior to sympathetic stimulation). Right stellate stimulation had no influence on arrhythmogenesis, causing ventricular arrhythmia induction in 52% (NS) of the trials. Left stellate stimulation resulted in increased ventricular arrhythmias (68%; P less than 0.05) in response to programmed electrical stimulation. Bilateral stellate stimulation elevated program-induced ventricular arrhythmias (63%; P less than 0.05). The effects of the stellate stimulations on arrhythmia induction were similar during and up to 180 minutes of coronary occlusion. Thus, the arrhythmogenic influence of sympathetic stimulation was present before and during coronary artery occlusion.

On the pathogenesis of angina pectoris and its silence.

Recent interest in silent angina deals in a sense with a double unknown since the pathogenesis of angina pectoris remains unexplained. In this report, we present evidence from two human postmortem studies and from experiments conducted in eleven awake dogs which supports a hypothesis that angina pectoris may be mediated by an intracardiac chemoreceptor receiving its primary blood supply from the proximal coronary circulation. The clinical events and the postmortem findings in both human subjects supported the hypothesis. The somatic responses observed in the awake dogs resembled those of humans with angina pectoris. Because the cardiogenic hypertensive chemoreflex in dogs is maximally elicited by serotonin normally carried by the platelets and released during their aggregation, angina pectoris as well as numerous other clinical events observed during acute myocardial ischemic episodes could be similarly explained as consequences of the activation of a coronary chemoreceptor in man. Thus, at least some and possibly most examples of angina pectoris may be mediated via the coronary chemoreceptor and vagal afferents to the brain, and injury or destruction of this chemoreceptor could interdict the perception of anginal pain.

A sample computer system for physiological data acquisition and analysis.

This report outlines a sample configuration of a system which records, stores and analyses, graphically and statistically, neurophysiological and cardiovascular recordings during an experiment. The system is composed of sensitive physiological amplifiers, an analog to digital signal conversion board, scientific software, a 80286-based computer with 640 Kb of RAM, and a laser printer. Each component of the system is described along with the specific task(s) it performs.

[Action of ethacizin on normal and anomalous forms of Purkinje fiber automaticity in the dog]. / Deistvie étatsizina na normal'nuiu i anomal'nye formy avtomatii volokon Purkin'e sobaki.

The effect of a new anti-arrhythmic drug etacysin was studied in various forms of dog Purkinje's fibres automativity: normal and abnormal arising at a late stage of experimental myocardial infarction (24 hrs after coronary artery ligation) and induced by ions Ba2+. An average 57% decrease in the frequency of automaticity of normal Purkinje's fibres due to steepening the slope of slow diastolic depolarization and almost complete depression of an abnormal one was observed for the drug concentrations 5 X 10(-7) and 10(-6) g/ml. Reduced automaticity was also related to decreased slow diastolic depolarization. Maximal values of diastolic potential were found unchanged.

Attenuation of baroreflex changes in cardiac sympathetic efferent activities during acute myocardial ischemia.

Sympathetic efferent activities to the heart during blood pressure changes were investigated in 11 dogs with acute myocardial ischemia. Normalized sympathetic efferent activities recorded in thoracic cardiac nerves decreased or increased as anticipated in response to transient changes in mean arterial pressure (15 to 25 mm Hg with nitroglycerin or phenylephrine, 2 to 8 micrograms/kg, intravenously). A branch of the left circumflex coronary artery was occluded, and the arterial pressure challenges were repeated at 5, 15, and 25 minutes after the occlusion. The control (preocclusion) responses in sympathetic efferent activities to the heart ranged from +/- 2% to 70% (changes relative to steady state normalized at 100%). Reflex sympathetic efferent responses were diminished at 15 and 25 minutes of ischemia. Several sympathetic efferent baroreflex responses during myocardial ischemia were paradoxic. Reflex sympathetic efferent changes were not affected in sham animals. These results indicate that both increases and decreases in cardiac sympathetic efferent activities during baroreflex challenges are attenuated within 15 to 25 minutes of acute coronary artery occlusion. These findings suggest that an abnormal buffering of blood pressure changes during acute myocardial ischemia might lead to autonomic dysfunction that promotes arrhythmogenesis and sudden cardiac death.