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The medical treatment of coronary insufficiency. New drugs and new methods of evaluation
710
Abstracts
EFFECT
OF
POTASSIUM
ARRHYTHMIAS
AND
AND A-”
DIGITALIS
CONDUCTION
:
ON
VENTRICULAR
A
REAPPRAISAL
DIGITALIS AND POTASSIUM RELATIONSHIP. Charles Firh, M.D., B. L. Mark, M.D. and Fred H. P&be, M.D. Marion County General Hospital, and Indiana University School of Medicine, Indianapolis, Ind. OF
The present study was designed to reevaluate the relationship of potassium and digitalis at the (1) arrhythmia and (2) A-V conduction levels. (1) Ventricular arrhythmia was produced in dogs with acetyl strophanthidin and at that point an injection of isotonic potassium phosphate (155 mEq./L.) was given at a rate of 1 to 1.2 mEq./minute. When the arrhythmia was abolished the infusion was terminated and the duration of the S-A rhythm and the recurrent arrhythmia were carefully observed. The acetyl strophanthidin-induced ventricular arrhythmia was abolished uniformly by the administration of potassium in amounts varying from 2.1 to 6 mEq./L. with an average of 3.9 mEq./L. However, within a half to two minutes after the infusion was discontinued the ventricular arrhythmia reappeared. The plasma potassium at the time the arrhythmia was abolished varied from 5.6 to 6.9 with an average of 6.4 mEq./L. The potassium level when the arrhythmias recurred varied from 5.3 to 5.7 with an average of 5.5 mEq./L. The control potassium in dogs submitted to this study varied from 3.5 to 3.9 mEq./L. with an average of 3.8 mEq./L. (2) Second degree A-V block was produced by infusion of potassium phosphate. The animals were then given 0.5 mg./kg. (not to exceed 5 mg.) of Forty-eight hours later the digitoxin intramuscularly. potassium was again infused to second degree block. Prior to administration of digitoxin 12.7 to 26.3 (average 18.3) mEq. of potassium was necessary to induce second degree block. After digitoxin was given, second degree block appeared after the infusion of 4.8 to 9.7 (average 5.8) mEq. of potassium. Our studies indicate that (1) the depression of ventricular arrhythmia by potassium is transient and probably related to levels of extracellular potassium and (2) that the A-V conduction system is more sensitive to the depressing effects of potassium after intoxication with digitoxin. The results do not confirm the existence of a specific digitalis and potassium antagonism. THE
MEDICAL
NEW
DRUGS
TREATMENT AND
Fremont, M.D.,
NEW
OF
METHODS
F.A.C.C.
CORONARY OF
INSUFFICIENCY.
EVALUATION.
V. A. Hospital,
Brooklyn,
Rudolph N. Y.
Nitroglycerine, which was discovered in 1860, is still considered by most physicians the only truly reliable means of relieving attacks of angina pectoris. Recently developed methods of objective drug evaluation have led to the discarding of a host of drugs heretofore claimed to have a coronary dilatory effect. The persistent need for a nitroglycerine-like medication of prolonged activity has led, however, to the search and discovery of two new groups of drugs. One consists of nitrates of a new type (sorbide dinitrate) or in a new form of administration (sublingual erythroltetranitrate) which may influence coronary blood flow directly. The other group is made up of monoamine oxidase (MAO) inhibitors which may modify the perception of pain in general or influence myocardial oxygenation by interaction with norepinephrine and related compounds.
This report is based on personal observations of thirty ambulatory patients with a typical angina1 syndrome most of whom had sustained a well documented attack of myocardial infarction or had an abnormal exercise electrocardiogram. Their response to both types of antianginal drugs was evaluated over a period of at least two years. Both subjective and objective response analyses were carried out. The first included the use of daily report cards listing the amount of effort causing angina1 attacks, the frequency of rest pain and the amount of nitroglycerine used in either instance. In addition, closely matching placebo therapy was employed in the nitrate study and a double blind technic in that of MAO inhibitors. Serial ballistocardiograms at rest and frequently also after smoking were obtained on all patients. Serial exercise electrocardiograms were obtained when considered safe. The results of these observations in terms of drug response and tolerance, and as correlated with all factors known to affect the natural course of coronary disease are discussed in detail. The over-all advantage of nitrate therapy in coronary insufficiency as noted with erythroltetranitrate and sorbide dinitrate over that of MAO inhibition is demonstrated with the help of representative cases. The particular methods of observation are discussed in detail and the pitfalls occurring even with the most objective methods are demonstrated. AN
INVESTIGATION
CANGLIONIC
OF
THE
STIMULATING
VASODEPRESSOR DOSES
OF
RESPONSE
TO
ACETYLCHOLINE.
R. W. Gardier M.D., P. C. Johnson, M.D., R. P. Roesch, M.D. and V. K. Stoelting, M.D., with the technical assistance of S. L. Graham. Indiana University School of Medicine, Indianapolis, Ind. Previous studies have shown that an alkyl substituted urea compound, N,N diisopropyl, N isoamyl diethylamino ethyl urea (P-286) is capable of reversing the pressor effect of large intravenous doses (1 mg./kg.) of acetylcholine in the atropinized dog. It has been determined further that this vasodepression results from specific blockade of adrenal medullary discharge. This study was undertaken to elucidate the mechanism responsible for the acetylcholine blood pressure fall. The reversal is not affected by dichloroisoproterenol given in doses adequate to prevent an isoproterenol vasodepression of similar magnitude. In addition, animals treated with reserpine, sufficient to expect a depletion of peripheral catecholamine stores, still demonstrate the reversal. Since other workers have shown that P-286 can decrease the catecholamine content of the heart and other visceral organs, the vascular action of acetylcholine was studied on an isolated segment of dog ileum in situ. P-286 has a transient vasodepressor action per se which presently appears to be due to a decrease in vascular resistance. This vasodilation is more prominent in the innervated versus the denervated preparation, and most likely results from the weak ganglionic blocking action previously shown for this compound. Regarding the mechanism of acetylcholine reversal, the following has been noted. Prior to P-286, marked vasoconstriction (85 per cent of cases) accompanied the acetylcholine pressor effect. After P-286 the resistance changes following acetylcholine could not be unequivocally implicated for the depressor effect noted. Further studies are needed to determine whether the fall in blood THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Abstracts
EFFECT
OF
POTASSIUM
ARRHYTHMIAS
AND
AND A-”
DIGITALIS
CONDUCTION
:
ON
VENTRICULAR
A
REAPPRAISAL
DIGITALIS AND POTASSIUM RELATIONSHIP. Charles Firh, M.D., B. L. Mark, M.D. and Fred H. P&be, M.D. Marion County General Hospital, and Indiana University School of Medicine, Indianapolis, Ind. OF
The present study was designed to reevaluate the relationship of potassium and digitalis at the (1) arrhythmia and (2) A-V conduction levels. (1) Ventricular arrhythmia was produced in dogs with acetyl strophanthidin and at that point an injection of isotonic potassium phosphate (155 mEq./L.) was given at a rate of 1 to 1.2 mEq./minute. When the arrhythmia was abolished the infusion was terminated and the duration of the S-A rhythm and the recurrent arrhythmia were carefully observed. The acetyl strophanthidin-induced ventricular arrhythmia was abolished uniformly by the administration of potassium in amounts varying from 2.1 to 6 mEq./L. with an average of 3.9 mEq./L. However, within a half to two minutes after the infusion was discontinued the ventricular arrhythmia reappeared. The plasma potassium at the time the arrhythmia was abolished varied from 5.6 to 6.9 with an average of 6.4 mEq./L. The potassium level when the arrhythmias recurred varied from 5.3 to 5.7 with an average of 5.5 mEq./L. The control potassium in dogs submitted to this study varied from 3.5 to 3.9 mEq./L. with an average of 3.8 mEq./L. (2) Second degree A-V block was produced by infusion of potassium phosphate. The animals were then given 0.5 mg./kg. (not to exceed 5 mg.) of Forty-eight hours later the digitoxin intramuscularly. potassium was again infused to second degree block. Prior to administration of digitoxin 12.7 to 26.3 (average 18.3) mEq. of potassium was necessary to induce second degree block. After digitoxin was given, second degree block appeared after the infusion of 4.8 to 9.7 (average 5.8) mEq. of potassium. Our studies indicate that (1) the depression of ventricular arrhythmia by potassium is transient and probably related to levels of extracellular potassium and (2) that the A-V conduction system is more sensitive to the depressing effects of potassium after intoxication with digitoxin. The results do not confirm the existence of a specific digitalis and potassium antagonism. THE
MEDICAL
NEW
DRUGS
TREATMENT AND
Fremont, M.D.,
NEW
OF
METHODS
F.A.C.C.
CORONARY OF
INSUFFICIENCY.
EVALUATION.
V. A. Hospital,
Brooklyn,
Rudolph N. Y.
Nitroglycerine, which was discovered in 1860, is still considered by most physicians the only truly reliable means of relieving attacks of angina pectoris. Recently developed methods of objective drug evaluation have led to the discarding of a host of drugs heretofore claimed to have a coronary dilatory effect. The persistent need for a nitroglycerine-like medication of prolonged activity has led, however, to the search and discovery of two new groups of drugs. One consists of nitrates of a new type (sorbide dinitrate) or in a new form of administration (sublingual erythroltetranitrate) which may influence coronary blood flow directly. The other group is made up of monoamine oxidase (MAO) inhibitors which may modify the perception of pain in general or influence myocardial oxygenation by interaction with norepinephrine and related compounds.
This report is based on personal observations of thirty ambulatory patients with a typical angina1 syndrome most of whom had sustained a well documented attack of myocardial infarction or had an abnormal exercise electrocardiogram. Their response to both types of antianginal drugs was evaluated over a period of at least two years. Both subjective and objective response analyses were carried out. The first included the use of daily report cards listing the amount of effort causing angina1 attacks, the frequency of rest pain and the amount of nitroglycerine used in either instance. In addition, closely matching placebo therapy was employed in the nitrate study and a double blind technic in that of MAO inhibitors. Serial ballistocardiograms at rest and frequently also after smoking were obtained on all patients. Serial exercise electrocardiograms were obtained when considered safe. The results of these observations in terms of drug response and tolerance, and as correlated with all factors known to affect the natural course of coronary disease are discussed in detail. The over-all advantage of nitrate therapy in coronary insufficiency as noted with erythroltetranitrate and sorbide dinitrate over that of MAO inhibition is demonstrated with the help of representative cases. The particular methods of observation are discussed in detail and the pitfalls occurring even with the most objective methods are demonstrated. AN
INVESTIGATION
CANGLIONIC
OF
THE
STIMULATING
VASODEPRESSOR DOSES
OF
RESPONSE
TO
ACETYLCHOLINE.
R. W. Gardier M.D., P. C. Johnson, M.D., R. P. Roesch, M.D. and V. K. Stoelting, M.D., with the technical assistance of S. L. Graham. Indiana University School of Medicine, Indianapolis, Ind. Previous studies have shown that an alkyl substituted urea compound, N,N diisopropyl, N isoamyl diethylamino ethyl urea (P-286) is capable of reversing the pressor effect of large intravenous doses (1 mg./kg.) of acetylcholine in the atropinized dog. It has been determined further that this vasodepression results from specific blockade of adrenal medullary discharge. This study was undertaken to elucidate the mechanism responsible for the acetylcholine blood pressure fall. The reversal is not affected by dichloroisoproterenol given in doses adequate to prevent an isoproterenol vasodepression of similar magnitude. In addition, animals treated with reserpine, sufficient to expect a depletion of peripheral catecholamine stores, still demonstrate the reversal. Since other workers have shown that P-286 can decrease the catecholamine content of the heart and other visceral organs, the vascular action of acetylcholine was studied on an isolated segment of dog ileum in situ. P-286 has a transient vasodepressor action per se which presently appears to be due to a decrease in vascular resistance. This vasodilation is more prominent in the innervated versus the denervated preparation, and most likely results from the weak ganglionic blocking action previously shown for this compound. Regarding the mechanism of acetylcholine reversal, the following has been noted. Prior to P-286, marked vasoconstriction (85 per cent of cases) accompanied the acetylcholine pressor effect. After P-286 the resistance changes following acetylcholine could not be unequivocally implicated for the depressor effect noted. Further studies are needed to determine whether the fall in blood THE
AMERICAN
JOURNAL
OF
CARDIOLOGY