Gertrude Lange

Action of Driving Stimuli from Intrinsic and Extrinsic Sources on in Situ Cardiac Pacemaker Tissues

The interactions between pacemakers, and the effects on pacemakers, of terminating imposed driving were studied in the in situ heart of anesthetized dogs. Following atrial fibrillation or termination of a fast drive imposed through an artificial pacemaker, pacemaker action in intrinsic pacemakers is suppressed. Pacemakers tend to accelerate and compete with imposed drives which exceed control rates by only a small percentage (10 to 15%). Arrhythmias may result if imposed drive is slower than or identical with intrinsic pacemaker rate. Post-drive depression of pacemakers and the resulting deceleration of the heart is followed normally by an overshoot or supranormal acceleration. The magnitudes and durations of depression and late acceleration are proportional, within limits, to the rate and duration of drive. Atrioventricular and ectopic atrial pacemakers are much more readily depressed than is the sinoatrial pacemaker. Furthermore, beats of ectopic origin are much more likely to occur while subsidiary pacemakers are recovering from post-drive depression. Augmentation of depression by Prostigmin, its diminution by atropine, and the potentiation of late acceleration by cocaine and its absence after reserpine or guanethidine pretreatment, indicate that acetylcholine and catecholamines are liberated by driving stimuli. Placement of the pacemaker over the sinoatrial node, or near to regions where nerve terminals are concentrated, results in the greatest post-drive effects. The fact that propagated action potentials cause depressions and accelerations subject to drug block or potentiation indicates that mediators are also released in the course of propagated activity. Since atropine does not completely block post-drive depression, it is thought that a potassium ion shift may be involved.

Factors Controlling Pacemaker Action in Cells of the Sinoatrial Node

Rapid drive of isolated pacemaker tissues from cats resulted in a post-drive depression followed by a late acceleration to supernormal rates of pacemaker activity. These effects were similar to those occurring after drive of the pacemaker in situ. Lower SA nodal pacemakers discharged more slowly and irregularly than did upper SA nodal pacemaker cells. They were more readily depressed by rapid imposed drive. The balance between depression and acceleration varied in different preparations. Drive at only slightly above the intrinsic rate resulted frequently in acceleration not preceded by depression. Within limits, the greater the frequency and duration of drive, the greater the intensity and duration of both the depression and the late acceleration. Prostigmin augmented and atropine reduced post-drive depression. Cocaine potentiated the late acceleration. Excess potassium reduced post-drive depression and, in concentrations used, caused some acceleration. Pacemaker cells could be driven less rapidly than could other SA nodal cells. Drive generally shifted pacemaker action to a distant site; the first post-drive propagated responses originated from other pacemaker cells and dominance by the original unit was reestablished slowly. Rapid drive reduced amplitudes of action potentials and prepotentials. It also raised threshold potentials and during the post-drive period the durations of pacemaker cell action potentials were temporarily prolonged. In some preparations membrane potentials remained at a subnormal value after drive. Subthreshold potentials occurred at a somewhat subnormal rhythm but gradually developed an effective amplitude. Conduction block was observed in isolated SA nodal tissue. This was augmented during the post-drive period of depression. This work lends support to the hypothesis1 that dominating action by pacemaker cells influences the pacemaker activity in other potential pacemaker tissues.

Comparative studies of electrical and mechanical alternation in heart cells

Abstract The major purpose of this and related projects has been the study of processes integrating cardiac and cardiac tissue activity. Factors modifying the effectiveness of integrative processes have been identified. In the present instance a comparative study of pulsus alternans was made using cat papillary muscle, guinea pig, frog and turtle ventricular strips. Alternation due to population participation variation was found in amphibian and reptilian hearts, but no “uncoupling” such as seen in mammalian tissue even at low temperatures and under hyperosmotic conditions. Rate thresholds for various alternations were determined for mammalian papillary muscle and the effects of temperature, of calcium and magnesium ion concentration change, and of various drugs (epinephrine, acetylcholine, DNP) were determined. The fact that action potentials associated with the stronger contractions had a shorter peak or early repolarization phase duration was noted. Possible explanations of the alternations observed were offered.

Influence of Sympathomimetic Pressor Drugs on Arrhythmias Caused by Multiple Stimuli

A technic of administering successive stimuli to the heart at various ectopic foci was devised. Under normal circumstances the heart had sufficient power of integration to resist disorganization of its action by these multiple stimuli. Methoxamine, mephentermine and metaraminol had less tendency to increase vulnerability to fibrillation than did levarterenol under these conditions of stress. A new compound (Lilly #20522) blocked for a time the arrhythmia-producing action of levarterenol.

Patterns of reflex action, their autonomic components, and their behavioral significance

This is a discussion of the evidence that autonomic system reflexes are invariably triggered by stimuli that evoke both simple and complex somatic reflexes. Stimuli not only initiate reverberatory activity but sequences of reinforcements from higher centers. Reflexes come in chains, one reaction triggering another. Reflex actions are patterned, and these patterns are appropriate to the behavioral requirement indicated by stimuli. Reciprocal action produces a powerful braking or stimulatory action. Coactivation or synergic action of autonomie “antagonists” also occurs and can effect a greater cardiac output in certain vascular reflexes than can sympathetic action alone. Coactivation of vagus and sympathetic fibers occuring in reflex action or resulting from stimulation of specific areas in the hypothalamus has a physiologic importance to attainment of maximal cardiac function. Finally, two additional suggestions are made: (1) that the rhythmic reflex feedback discharge of the vagus from the baroreceptors aids in maintaining the regularity of cardiac rhythm as by interaaction of oscillators and (2) that the autonomic system, due to its early and often conditioned response, can be determinative as well as modulatory and supportive of behavior.

The phenomenon of accommodation in the ventricular myocardium

SummaryThe ventricular and auricular myocardium was found to possess an ability to accommodate to applied electrical current pulses.Accommodation to cathodal current flow was observed even when nonpolarizable electrodes were employed and also when tests were made with chronically implanted metal electrodes in intact anesthetized dogs.Accommodation tended to attain its maximum within 40 to 45 msec after the beginning of the conditioning pulse. It reduced the facilitatory action of the conditioning pulse by 50 to 60%.Post-cathodal and post-anodal changes in excitability occurred. They were of 10 to 15 msec duration following a 70 msec conditioning current flow. They were of lesser magnitude then the average residual facilitation remaining just before termination of conditioning stimuli.Evidence that various circumstances can modify the ability of cardiac tissue to accommodate to intrinsic and applied stimuli was discussed. The possible importance of this phenomenon to the maintenance of effective action of the heart under abnormal circumstances was considered.

EFFECTS OF VASOCONSTRICTOR AGENTS ON CARDIAC IRRITABILITY

A study was made of the effects of the vasoconstrictor drugs epinephrine, levarterenol, methoxamine and mephentermine, on excitability, refractory period, rhythmic abnormalities, conduction times and action potential of the heart. The principal observations were as follows: These drugs with the exception of methoxamine, in doses so graded as to maintain blood pressure levels 30 to 50 mm. Hg above control values, induced ectopic pacemaker action, abnormal spontaneous beats, and abnormal and multiple responses to test stimuli. The action of methoxamine on the heart can be said to be depressant in that it prolonged the action potential and the absolute refractory period, raised the threshold to stimulation and slowed A-V conduction significantly. This was not due to reflex vagal action. All four drugs exhibited some degree of tachyphylaxis with respect to blood pressure maintenance and some other actions. Other details of the comparative effects of these drugs are given in the discussion of results obtained.