The biological properties of the optical isomers of propranolol and their effects on cardiac arrhythmias

Abstract

1. The optical isomers of propranolol have been compared for their f,-blocking and antiarrhythmic activities.2. In blocking the positive inotropic and chronotropic responses to isoprenaline, ( +)-propranolol had less than one hundredth the potency of (-)-propranolol. At dose levels of (+ )-propranolol which attenuated the responses to isoprenaline, there was a significant prolongation of the PR interval of the electrocardiogram. 3. The metabolic responses to isoprenaline in dogs (an increase in circulating glucose, lactate and free fatty acids) were all blocked by (-)-propranolol. (+ )-Propranolol had no effect on fatty acid mobilization but significantly reduced the increments in both lactate and glucose. 4. Both isomers of propranolol possessed similar depressant potency on isolated atrial muscle taken from guinea-pigs. 5. The isomers of propranolol exhibited similar local anaesthetic potencies on an isolated frog nerve preparation at a level approximately three times that of procaine. The racemic compound was significantly less potent than either isomer.6. Both isomers of propranolol were capable of preventing adrenaline-induced cardiac arrhythmias in cats anaesthetized with halothane, but the mean dose of (-)-propranolol was 0.09+0.02 mg/kg whereas that of (+)-propranolol was 4.2+1.2 mg/kg. At the effective dose level of (+)-propranolol there was a significant prolongation of the PR interval of the electrocardiogram. Blockade of arrhythmias with both isomers was surmountable by increasing the dose of adrenaline.7. Both isomers of propranolol were also capable of reversing ventricular tachycardia caused by ouabain in anaesthetized cats and dogs. The dose of ( -)-propranolol was significantly smaller than that of (+ )-propranolol in both species but much higher than that required to produce evidence of ,8-blockade. 8. The implications of these results are discussed.Pronethalol is a specific competitive antagonist of adrenoceptive f8-receptors and the (-) isomer has been shown to be 40 times as active as the (+) isomer

Antiarrhythmic Activity of 1-(7-Indenyloxy)-3-Isopropylaminopropane-2-ol Hydrochloride (YB-2) and its Optical Isomers

“…Thus, YB-2 and its optical isomers appear to have a similar potency ratio for anti arrhythmic activity as is the case with propranolol and its optical isomers (5,11,20,37).…”

“…Recently the association between antiarrhythmic activity against ouabain-induced cardiac disturbances and local anesthetic activity, and the dissociation between the for mer property and beta-receptor blockade have been questioned by several investigators (20,24,25). Burrett and Cullum (20) It has been also reported that an increased release of catecholamines from the heart and adrenal glands by the ad ministration of ouabain may be an important factor in this type of arrhythmia (33,34).…”

“…Burrett and Cullum (20) It has been also reported that an increased release of catecholamines from the heart and adrenal glands by the ad ministration of ouabain may be an important factor in this type of arrhythmia (33,34).…”

“…A potent local anesthetic activity which is a property common to pronethalol, pro pranolol or alprenolol, but not to sotalol or practolol, may have a causative relationship to be effective against ouabain-induced arrhythmias (1,3,4,(19)(20)(21)(22). In addition, the d-isomers of pronethalol, propranolol and alprenolol, and the diethylmethyl analogue of propranolol (ICI 46037), which have insignificant beta-receptor blocking activities, retain their potent local anesthetic activities and are also effective against ouabain-induced ar rhythmias (1,4,19,23).…”

An opposing role for the adrenals in the hypotensive effects of propranolol in the spontaneously hypertensive rat

“…This unspecific effect might have contributed to the strong bradycardia in addition to the ~3-adrenergic blocking activity. The /3-antagonistic property of d,l-propranolol, however, is due mainly to the 1-isomer, while the d-isomer of propranolol has only weak/~-antagonist activity, and both exhibit equivalent local anesthetic activity (Howe and Shanks, 1966;Barrett and Cullum, 1968).…”