Richard J. Gorczynski

Pharmacology of ASL-8052, a novel beta-adrenergic receptor antagonist with an ultrashort duration of action.

Summary ASL-8052, a novel β-adrenergic receptor antagonist, was studied in isolated guinea pig cardiac and tracheal tissues, in isolated frog sciatic nerves, and in anesthetized dogs. The compound was a moderately potent β-adrenoceptor antagonist in right atria (pA2 6.96) but was much less active in tracheal tissues (pA2 5.33), indicating cardioselective properties. ASL-8052 possessed a small degree of intrinsic sympathomimetic action in isolated guinea pig right atria and caused direct cardiac depression only at concentrations 1,000-fold higher than its cardiac pA2. Significant local anesthetic action in frog sciatic nerve occurred at extremely high concentrations of ASL-8052 (>0.1 M). In anesthetized dogs, ASL-8052 produced steady-state levels of β-blockade within 10 min during a 3-h intravenous infusion. In contrast, propranolol produced increasing levels of blockade throughout most of the infusion period. Recovery from β-blockade occurred rapidly following termination of ASL-8052 infusion (80% recovery in approximately 12 min), whereas very little recovery occurred following cessation of propranolol infusion. Intravenous infusion of ASL-8052 produced dose-dependent blockade of cardiac responses to isoproterenol but only minimally decreased hind limb vascular responses to isoproterenol. The resuts indicate that ASL-8052 is a novel cardioselective β-blocker with an ultrashort duration of action.

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.

β-Adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol

The beta-adrenoreceptor antagonist properties of ASL-8123, the primary metabolite of esmolol, were determined in vitro and in vivo. ASL-8123 demonstrated weak competitive beta-adrenoreceptor blocking activity in isolated guinea pig right atria with a pA2 of 3.73 +/- 0.07; no agonist-like activity was observed in this tissue at concentrations of ASL-8123 from 3 X 10(-5) to 1 X 10(-2) M. In anesthetized dogs, ASL-8123 was infused at increasing dosages from 0.2-25.6 mg/kg/min, each dose rate maintained for 20 min. The compound produced a slight decrease in heart rate of 15-22 beats/min at cumulative doses of 508-1,020 mg/kg and decreased diastolic blood pressure by 14-47 mm Hg at cumulative doses of 252-1,020 mg/kg. ASL-8123 dose-dependently inhibited the heart rate and diastolic blood pressure responses to isoproterenol (0.5 micrograms/kg i.v.). Blood levels of ASL-8123 were linearly correlated with inhibition of the heart rate response to isoproterenol (r = 0.95-0.99 for each dog, n = 6). The blood level of ASL-8123 that produced a 50% inhibition of isoproterenol-induced tachycardia averaged 293 +/- 65 micrograms/ml. Recovery from beta-adrenoreceptor blockade after terminating the infusion of ASL-8123 occurred slowly, decreasing from 81% at the end of the infusion to 55% 60 min later, and was paralleled by a slow decrease in blood levels of ASL-8123. Thus, ASL-8123 is a weak beta-adrenoreceptor antagonist which is approximately 1,600-1,900 times less potent than its parent, esmolol.

Beta-blocking and hemodynamic effects of ASL-8052.

The hemodynamic and cardiac beta-blocking effects of ASL-8052 (esmolol), an ultrashort-acting beta-blocker, were examined in pentobarbital-anesthetized dogs. The compound produced dose-dependent reductions in heart rate, left ventricular dP/dt, right ventricular contractile force, and diastolic arterial blood pressure in dogs with intact autonomic function. ASL-8052 was devoid of any hemodynamic effects in ganglion-blocked animals. Responses to isoproterenol (except for diastolic blood pressure) were blocked by ASL-8052 in qualitatively similar fashion in both groups of animals. The compound reduced the rate-pressure product and decreased diastolic coronary blood flow. The reactive hyperemic response to a 10-s occlusion of the left circumflex coronary artery was not modified by ASL-8052. Heart rate and contractile force dose-response curves to isoproterenol were equally shifted to the right in a dose-dependent, parallel fashion by constant infusion of ASL-8052. During infusion of large doses in reserpinized dogs, the compound decreased heart rate, contractility, and arterial blood pressure, while left ventricular end-diastolic pressure increased. No intrinsic sympathomimetic effect was observed. Tachycardia induced by either stimulation of the right ansa subclavia or intravenous injection of isoproterenol was blocked to an equivalent degree by ASL-8052. These data indicate that ASL-8052 produces hemodynamic effects that are characteristic of and explained by beta-adrenergic receptor blockade. However, direct cardiac depression is observed at extremely high doses.

Cardiovascular pharmacology of ACC-9089: a novel, ultra-short-acting, β-adrenergic receptor antagonist

The β-adrenergic receptor blocking properties of ACC-9089 were studied in isolated cardiac and tracheal tissues from guinea pigs and in anesthetized dogs. The compound was a potent, nonselective P-blocker in isolated tissues (atrial pA2 8.01; tracheal pA2 8.16). ACC-9089 was without intrinsic sympathomimetic action and caused direct cardiac depression only at concentrations that were four orders of magnitude higher than its pA2. In anesthetized dogs, ACC-9089 produced steady-state β-blockade within 20 min of initiation of 3-h intravenous infusions. Recovery from β-blockade occurred rapidly following termination of infusion (80% recovery in 17 μ 2 min after 1.2 u.g/kg/min). Intravenous infusion of ACC-9089 caused dose-dependent inhibition of heart rate responses to sympathetic nerve stimulation and inhibition of isoproterenol-induced decreases in perfusion pressure in a perfused hindlimb preparation. The compound (a) did not produce α-blockade; (b) had no direct effect on hindlimb vascular resistance; and (c) did not alter hemodynamic variables in catecholamine-depleted dogs. The results indicate that ACC-9089 is a novel, ultra-short-acting β-blocker that does not possess direct cardiovascular effects beyond those expected as a result of β-blockade.

Controlled β-receptor blockade with flestolol: a novel ultrashort-acting β-blocker

Summary: The pharmacological properties of an ultrashort- acting β-receptor blocking agent, flestolol, were evaluated in rabbits. Infusion of graded doses (1–100 µg/kg/min, i.v.) into conscious rabbits produced dose-dependent bradycardia without any significant effect on mean arterial pressure. A desired level of heart rate could be obtained by either increasing or decreasing the dose infused. Such titration could be done by changing the dose of flestolol at 20-min intervals. Infusion of 31 µg/kg/ min of flestolol into reserpinized, conscious rabbits had no effect on mean arterial pressure or heart rate but produced significant inhibition of isoproterenol-induced hypotension and tachycardia. This dose had no effect on the chronotropic and vascular effects of norepinephrine (NE), angiotensin II, adenosine, or acetylcholine. In these rabbits, flestolol was >10-fold as active as esmolol, another ultrashort-acting β-blocking agent, in inhibiting the responses to isoproterenol. In rabbits under pentobarbital anesthesia, infusion of flestolol (3.1, 10, and 31 (µg/kg/min) produced dose-dependent β-receptor blockade. On termination of a 70-min infusion, recovery of the responses to isoproterenol occurred within 30 min. In a separate series of experiments, the effects of infusion of flestolol (10 µg/kg/min) into the portal vein were compared with the effects of infusion of the same dose of flestolol into the femoral vein of anesthetized rabbits. Infusion into the femoral vein produced bradycardia and inhibited the hypotensive as well as cardioaccelerator effects of isoproterenol. Infusion into the portal vein was devoid of either effect, suggesting extensive inactivation by the liver. The results of this study show that flestolol is a specific β-receptor blocking agent with a very short duration of action. Such properties permit rapid titration of the dose to achieve desired level of β-receptor blockade.

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.

Participation of the autonomic nervous system in the cardiovascular effects of milrinone

The cardiodynamic activity of intravenously administered milrinone was examined in alpha-chloralose anesthetized dogs. Two groups of dogs were used, one pretreated with hexamethonium to block autonomic reflexes, and a second group which received no pretreatment. In the untreated group milrinone produced dose-dependent increases in +dP/dt and heart rate while decreasing both systolic and diastolic blood pressure and left ventricular end diastolic pressure (LVEDP). After treatment with hexamethonium basal heart rate was significantly increased, whereas reflex changes in heart rate in response to i.v. norepinephrine or nitroglycerin were ablated. Systolic, but not diastolic blood pressure was also markedly reduced by hexamethonium. In the presence of hexamethonium responses to milrinone were qualitatively similar to milrinone responses in the absence of hexamethonium. However, the dose-response curves for milrinone were shifted dextrally for changes in +dP/dt and LVEDP, whereas the dose-response curve for blood pressure was shifted sinistrally. Thus, it appears that the autonomic nervous system enhances the effect of milrinone on +dP/dt and LVEDP, but attenuates its effect on blood pressure.