Peter E. Dresel

Relationship of the Functional Refractory Period to Conduction in the Atrioventricular Node

The functional refractory period of atrioventricular (AV) transmission has been accepted as a measure of AV nodal refractoriness and has been assumed to be determined solely by conduction of interpolated extrasystoles through the AV node when it is partially refractory. In the present study, we found an important effect of the conduction time of the regular beats by measuring AV nodal conduction times of atrial extrasystoles from the His bundle of isolated, blood-perfused dog hearts. We separated three independent components that determine AV nodal conductivity: (1) a “basal conduction time” measured with a “postmature” extrasystole at low heart rates ( < 120 /min), (2) a rate-dependent increment in conduction time (previously called “fatigue”) that affects both normal and premature cycles equally and (3) an exponential change in conduction time that depends entirely on the immediately preceding interval and, therefore, is not further affected by heart rate. The functional refractory period is one point defining this continuous exponential function. We showed that an important cause of the decrease in the functional refractory period that occurs when heart rate is increased is the change in the conduction time of the regular beats.

Pathogenesis of "Electrolyte-Steroid-Cardiopathy"

The production of acute necrotic lesions of the myocardium and concomitant changes in myocardial and skeletal muscle potassium concentrations were investigated in rats. Lesions were induced by the administration of 2α inethyl-9α-chlorocortisol plus oral Na2SO4 (which caused a profuse catharsis), steroid plus an irritant cathartic (croton oil), steroid plus low-potassium diet, and low-potassium diet alone. Lesions in the various groups were grossly and microscopically indistinguishable. Their incidence and severity were well correlated with the degree of myocardial potassium depletion below a threshold value of approximately 72 mEq./Kg. wet weight. Skeletal muscle potassium was decreased roughly parallel to that of the myocardium, but some what more variably. Other treatments, including steroid or oral Na2SO4 alone and steroid plus subcutaneous Na2SO4 which failed to produce comparable reductions in myocardial potassium, failed to induce morphological lesions. Any specific interaction between steroid and electrolyte in the production of the myocardial lesions appears to be ruled out by the ineffectiveness of Na2SO4 administered sub cutaneously. It is concluded that the “electro lyte-steroid-cardiopathy” results from a simple intracellular potassium deficiency and its sequelae, and that the roles of the steroid-cathartic electrolyte, and other agents and procedures are to induce potassium depletion by various mechanisms.

Role of the Atrium in Determining the Functional and Effective Refractory Periods and the Conductivity of the Atrioventricular Transmission System

Relative contributions of the atria and the atrioventricular (AV) node to AV conduction were studied in isolated, blood-perfused dog hearts. The functional refractory period of the atria, although shorter than that of the AV node, determined the functional refractory period of the entire transmission system in 50% of the hearts. Slow atrial conduction of early beats greatly influenced the shape of the curve used to determine the functional refractory period of the transmission system. The atrial effective refractory period was also shorter than the effective refractory period of the AV node. However, the effective refractory period of the entire transmission system was equal to that of the atrium when the driving interval was longer than 320 msec, and it decreased as the driving interval was shortened. At driving intervals of 320 msec or less, the effective refractory period of the AV transmission system abruptly increased and became equal to the effective refractory period of the node. Conduction of early premature responses from near the sinoatrial node to the AV node was supernormal in 50% of the hearts. Supernormal conduction of premature atrial responses in the ventricles was also observed. The period of supernormal conduction in both tissues shifted toward greater prematurity as heart rate increased. The importance of the atrium in determining the functional properties of the AV transmission system has been previously underestimated.

Factors Modifying Cyclopropane-Epinephrine Cardiac Arrhythmias

Constantly coupled bigeminal rhythm of long duration induced by infusion of epinephrine into cyclopropane-anesthetized dogs may be converted to multifocal ventricular tachycardia by increasing the blood pressure without changing the infusion rate. Multifoeal arrhythmia may be converted to bigerniny or to sinus rhythm by decreasing the blood pressure but is not converted to ventricular fibrillation by an increase in systemic pressure. Stimulation of the peripheral end of either vagus can convert bigerniny to normal rhythm or increase the coupling interval. Multifocal ventricular tachycardia is converted to sinus rhythm or to bigeminy by stimulation of the vagus. The vagal effect, which is blocked uniformly by atropine, also may be demonstrated when the atrial rate is maintained constant. Vagal stimulation does not increase the threshold dose of epinephrine necessary for induction of ventricular fibrillation. It is concluded that multifocal ventricular tachycardia is due to a mechanism similar to that causing bigeminy, which was shown previously not to be due to the emergence of a focus of increased ventricular automaticity. Both of these arrhythmias probably originate in the bundle of His and differ fundamentally from ventricular fibrillation.

Contractility, Metabolism and Pharmacological Reactions of Isolated Gas-Perfused Cat Hearts

Cat hearts were perfused through the aorta with substrate-free Krebs solution for 5 min, then with 5% CO2-95% O2 saturated with water vapor at 37.5°C. Heart rate decreased rapidly but contractility was maintained at pre-gas levels for 3 to 4 hours, decreasing to 25% at 10 hours. Driving the preparations at 168 beats/min did not appreciably change the time course of change in contractility. The hearts developed more tension at all resting tensions and were able to perform more work than hearts perfused with substrate-free Krebs solution, but their work capacity was less than that of hearts perfused with glucose-Krebs solution. They reacted normally to sympathomimetic amines and blocking agents. They were very sensitive to increases in perfusion pressure, developing completely reversible arrhythmias at pressures 80 to 150% above the control (60 mm Hg). Most hearts developed contractile alternans which usually was not accompanied by electrical alternation. Glycogen, lactate, pyruvate content decreased rapidly, the first to a residual level and the others to undetectable levels.

Induction of Failure in Gas-Perfused Hearts by Intermittent Administration of Krebs Solution: The Effect Of Digitalis Glycosides

Our previous work has shown that kitten hearts perfused with a warm, moist mixture of 5% CO2-95% O2 beat strongly for many hours. We now show that after 1 hr of gas perfusion, intermittent administration of small volumes of Krebs solution (5 ml every 30 min to total of 20 ml) causes progressive failure of the heart. Washout cardiac failure is accompanied by loss of protein from the hearts. We have isolated a cardiotonic material from the washout liquid by precipitation with ammonium sulfate. This material is more active in failed than in normal isolated kitten atria. Preperfusion with digitalis glycosides (10−10 to 10−9 g/ml) protects hearts against failure and loss of protein during periods of washout with saline.

Metabolic requirement for the inotropic effects of digitalis and BAY K 8644.

The positive inotropic effects of ouabain and of BAY K 8644 are not apparent in rabbit atria suspended in substrate free medium or in a medium containing 5 mM pyruvate. Addition of glucose in graded concentrations (1–11 mM) during continued exposure of the preparations to the inotropic agents yields graded inotropic effects. The possible involvement of the glycolytic pathway to the development of the inotropic effect of ouabain and BAY K 8644 was tested by using inhibitors of glycolysis that act at two different steps. Iodoacetic acid completely blocks the inotropic effect of ouabain in atria at 0.1 mM and papillary muscles at 0.05 mM. The inotropic effect of BAY K 8644 was blocked partially in atria and papillary muscles. Iodoacetic acid did not change the inotropic effects of isoproterenol and Ca2+. Addition of 1 mM fluoride did not affect significantly the inotropic effect of either ouabain or BAY K 8644 in atria but partially blocked the effect of BAY K 8644 in papillary muscles. The response of atria to ouabain was not changed significantly when glyceraldehyde (10 mM) was substituted for glucose. We suggest that glycolytic ATP may be important for the full inotropic effect of ouabain and BAY K 8644.

REPORT ON THE DISCUSSION OF SESSION I: GENERAL CONCEPTS OF RECEPTORS

There were three discussion periods during this session. All were lively, controversial and did much to set the tone for the rest of the meeting. Nickerson had mentioned the interaction or possible identity of the 5hydroxytryptamine (5-HT) and epinephrine receptors in the spleen. Ariens asked whether protection against phenoxybenzamine blockade of epinephrine receptors had been studied using reversible competitive antagonists of 5-HT such as bromlysergic acid (BOL). I . R. Innes (University of Manitoba) stated that “5-HT receptors” in the cat spleen can be protected from nonequilibrium blockade by reversible alpha adrenergic blocking agents, and “alpha adrenergic receptors” can be protected by BOL; both types of blocking agents block both agonists equally. These and other results represent very strong evidence that the two receptors are identical in this preparation. J. Kohli (Food and Drug Directorate of Canada) has observed some degree of crossprotection between these agonists in rabbit aortic strips and feels that there is a very close chemical or morphological similarity between the receptors in all tissues. Kohli asked for discussion of cocaine potentiation of norepinephrine in aortic strips because he has observed that cocaine potentiation is always difficult, and commonly impossible to demonstrate in this preparation. This would indicate that there was little if any of the uptake mechanism operative. Potentiation by 1.5-2-fold was the more usual response to cocaine of aortic strips in Furchgott’s laboratory. This slight effect indicated to him that the nerve ending uptake mechanism was present but that the nerve endings were largely located in the adventitia of the tissue rather than in the media with the smooth muscle. Because of this spatial displacement, they would not be very effective in removing norepinephrine from the environment of the smooth muscle cells and cocaine would show less effect. This interpretation is difficult to accept. Were this the reason for the minimal potentiation by cocaine, then one would be forced to conclude that norepinephrine released by the nerve endings would have equal difficulty in reaching the smooth muscle cells; this would make questionable a physiological role for the adrenergic innervation of the tissue. I t is important to realize that the present acceptance of blockade of the uptake mechanism as the mechanism of cocaine potentiation is based solely on correlation. Causality has not been shown, and many workers do not believe that cocaine potentiation is due solely to this action. Belleau’s paper received a great deal of attention, particularly with respect to his integration of calcium into the primary receptor site and his

THE ROLE OF POTASSIUM IN EPINEPHRINE-INDUCED CARDIAC ARRHYTHMIAS

Five series of experiments have been performed to investigate a possible causal relationship between the induced hyperkalemia and epinephrin-induced ventricular arrhythmias in pentobarbital anesthetized dogs. It is concluded that no causal relationship exists on the basis of the following observations. The hyperkalemic response to epinephrine is not quantitatively correlated with the induction of arrhythmias, and the ability of subthreshold doses of epinephrine to induce arrhythmias is not potentiated by the injection of exogenous potassium unless the plasma levels attained are considerably above those occurring after an arrhythmia -inducing dose of epinephrine. The ability of isoproterenol to induce cardiac arrhythmias is not enhanced by the infusion of potassium to produce blood levels comparable to those resulting from an arrhythmia-inducing dose of epinephrine. Infusion of potassium chloride to produce blood levels comparable to those induced by a previously arrhythmia-inducing dose of epinephrine does not allow the production of arrhythmias after Dibenamine blockade. Exclusion of the liver from the circulation and consequent abolition of the epinephrine-induced hyperkalennia does not prevent the production of arrhythmias by epinephrine. It was observed that very high plasma potassium levels, above those resulting from an arrhythmia-inducing dose of epinephrine, can facilitate the production of arrhythmias. The administration of exogenous potassium is particularly effective when peak levels are reached early in the course of the epinephrine action before the beginning of the epinephrine hyperkalemia. After exclusion of the liver from the circulation, the animals become more sensitive to this action of potassium. In one case potassium infusion alone induced ventricular fibrillation.