Robert D. Reynolds

Pharmacology and pharmacokinetics of esmolol

Esmolol is an ultra‐short‐acting beta‐adrenergic blocking agent that possesses minimal partial agonist activity or direct membrane depressant activity. The short duration of action of esmolol is attributable to rapid enzymatic hydrolysis by red blood cell esterases, forming ASL‐8123 and methanol. Experiments in the constant‐flow‐perfused isolated canine hindlimb indicate that therapeutic (beta blocking) doses of esmolol lack direct vascular effects and alpha‐adrenergic blocking activity and that therapeutic doses do not interfere with vascoconstrictor effects of peripheral sympathetic nerve stimulation. Esmolol produces cardiac electrophysiologic and hemodynamic effects consistent with those of beta blockade. Specifically, esmolol decreases heart rate, depresses atrioventricular nodal conduction, and decreases determinants of myocardial oxygen demand. The beneficial antiarrhythmic and infarct‐size limiting effects of esmolol have been demonstrated in several experimental models. Whereas beta blockers in general are effective in settings of supraventricular arrhythmias, sinus tachycardia, and myocardial ischemia, esmolol provides the added dimension of “titratability.” Thus, the short duration of action of esmolol allows for (1) very rapid titration to a preferred steady‐state level of beta blockade; (2) rapid adjustment to different steady‐state levels of beta blockade, as may be required by changing status of the patient, and (3) rapid disappearance of beta blockade following discontinuation of esmolol infusion, should this be necessary in the event of deleterious cardiac hemodynamic effects. Thus, esmolol is ideally suited for use in the treatment of patients in whom beta blockade is desirable, but in whom level of beta blockade must be very carefully modulated.

Ultra-short acting beta-blockers: A proposal for the treatment of the critically ill patient

Beta-blockade is of proven value in the therapy of acute myocardial infarction but, unfortunately, may produce cardiac failure by removal of needed sympathetic support. The long duration of action of available blockers (hours) makes reversal of failure a complicated problem and precludes rapid modification of therapy to match changing autonomic conditions. To improve the safety and efficacy of beta-blockade in this setting we have developed the concept of ultra-short beta-blockade and have identified a novel beta-blocker (ASL-8052) which possesses a duration of action less than 15 minutes. This compound is cardioselective and possesses efficacy in an animal model of acute myocardial infarction. It, therefore, appears to be suitable for rapid attainment of controlled levels of beta-blockade via intravenous infusion and rapid recovery from beta-blockade if required by the clinical situation. The compound should, therefore, be useful for safe therapy in critically ill cardiac patients.

Induction of the Hepatic Amino Acid Transport System and Tyrosine Aminotransferase in Rats on Controlled Feeding Schedules

In considering the “biochemical responses to environmental stress” in mammalian organisms it is appropriate to examine the adaptive changes that occur in the liver. This organ is not only concerned with the detoxification of toxic environmental hazards but it is also primarily responsible for maintaining homeostasis in the internal environment despite uneven variations in the time of food ingestion and in the proportions of dietary carbohydrate, protein and fat. The concept of environmental stress is coupled with the concept of physiological adaptation and both have been given definitions that range from the idea that stress is something harmful to the idea that some stress and adaptation is part of everyday living and that indeed we have to inquire about the range of stress levels that might be regarded as part of an “optimum environment” (see Aschoff, 1967, The Handbook of Physiology, Sect. 4 and discussions by Potter, 1969, 1970).

Induction of a previously non-inducible enzyme in Morris hepatoma 9618A.

Abstract Experimental conditions have been devised which brought about induction of tyrosine aminotransferase in Morris hepatoma 9618A, an enzyme which was previously thought to be non-inducible in and possibly deleted from the genetic information in this tumor line. Serine dehydratase has not been induced in this tumor by any of the experimental conditions applied. It is emphasized that even though an enzyme is not induced in a tumor by means which induce the enzyme in the parent cell, it cannot be assumed to be deleted from the genetic information present in the tumor cell. Induction procedures which are well beyond the limits of in vivo physiological conditions may be necessary in order to demonstrate the desired induction. Should all attempts at induction fail, the results are not significant with respect to possible deletion of the enzyme information, and the status of that particular enzyme must remain in question.

Further studies on the induction of tyrosine aminotransferase in Morris hepatoma 9618A.

Summary Tyrosine aminotransferase and the amino acid transport system in the host liver and hepatoma of rats bearing Morris hepatoma 9618A responded positively to a combined injection of glucagon and theophylline or to glucagon alone, injected s.c., but only the host liver responded to an injection of theophylline alone. Glucagon injected s.c. was more effective than that injected i.p. in inducing tyrosine aminotransferase and the amino acid transport system and lowering tissue glycogen levels in normal liver, host liver and hepatoma 9618A. Hepatoma glycogen levels in rats bearing hepatoma 9618A were increased by injections of hydrocortisone and were lowered by an injection of glucagon. Chronic treatment with hydrocortisone of rats bearing hepatoma 9618A was not necessary in order to get induction of tyrosine aminotransferase and the amino acid transport system when the glucagon was injected s.c. However, this hydrocortisone treatment abolished the differential effect of the route of administration of glucagon injected.

Comparison of Antiarrhythmic Effects of Procainamide, N-Acetylprocainamide, and p-Hydroxy-N-(3-diethylaminopropyl)benzamide

Abstract The antiarrhythmic effects of p-hydroxy-N-(3-diethylaminopropyl)benzamide (PP), procainamide (PA), and N-acetylprocainamide (NAPA) were compared. ED50 values for PP, PA, and NAPA in the mouse chloroform arrhythmia model were not significantly different. Mean effective doses in the ouabain-intoxicated dog were: PP 34, PA 25, and NAPA 122 mg/kg. PP was effective in 3/5, PA in 5/6, and NAPA in 0/5 dogs at 24 hr after ligation of the left anterior descending coronary artery. Thus, PP has antiarrhythmic potency and efficacy intermediate to PA and NAPA.

Comparison of the parasympatholytic activity of ACC-9358 and disopyramide

1 ACC‐9358 (N‐[(3,5‐di(pyrrolidinylmethyl)‐4‐hydroxy)benzoyl]aniline) is a newly developed analogue of changrolin, an antiarrhythmic agent used in the Peoples Republic of China. Since changrolin and other antiarrhythmic agents exert parasympatholytic activity which may limit their clinical usefulness, it was of interest to examine the parasympatholytic effects of ACC‐9358. For comparative purposes we also studied the parasympatholytic activity of disopyramide. 2 In guinea‐pig isolated ileal strips, disopyramide, 3–30 μM, and ACC‐9358, 100–300 μM, competitively antagonized carbachol‐induced contractions with pA2 values of 5.78 and 4.17, respectively. 3 In guinea‐pig isolated right atria, disopyramide 3–30 μM, competitively antagonized methacholine‐induced slowing of spontaneous beating with a pA2 value of 5.99 whereas ACC‐9358, 3–300 μM, produced no significant muscarinic blockade in this preparation. 4 Disopyramide (1.9–15 mg kg−1, i.v.), but not ACC‐9358 (7.5‐1.5 mg kg−1, i.v.), significantly increased rat pupil diameter in vivo. 5 Disopyramide and ACC‐9358 blocked vagal‐induced reductions in heart rate in dogs anaesthetized with pentobarbitone. ED50 values were approximately 0.65 and 11.25 mg kg−1, respectively. 6 We conclude that ACC‐9358 possesses significantly less parasympatholytic activity than disopyramide.

Antiarrhythmic activity of flestolol, a novel ultra-short-acting β-adrenoceptor antagonist, in the dog

The antiarrhythmic activity of flestolol, an ultra-short acting beta-adrenergic blocker lacking appreciable local anesthetic activity, was examined in several different canine ventricular arrhythmia models. Flestolol, at steady state infusions of 1-1,000 micrograms/kg per min, was generally ineffective in reversing either ouabain-induced or delayed ischemia-induced (24 h Harris dog) ventricular tachycardia. However, flestolol (1, 10 and 100 micrograms/kg per min) produced a dose-dependent decrease in l-norepinephrine (5 micrograms/kg i.v.)-induced ventricular tachycardia in the 5-6 day old Harris dog; the effect of 100 micrograms/kg per min flestolol, 94% suppression of norepinephrine-induced ventricular tachycardia, was completely reversed 60 min after termination of flestolol infusion. In pentobarbital-anesthetized open-chest dogs with pretreatment heart rates greater than or equal to 145 beats/min, flestolol (10 micrograms/kg per min) reduced the incidence of ventricular fibrillation resulting from abrupt coronary artery occlusion compared to placebo-treated controls (15% or 2/13 vs. 70% or 7/10, respectively). These results demonstrate that flestolol has an antiarrhythmic profile consistent with its lack of local anesthetic activity and its ultra-short duration of beta-blockade.