The cardiac -adrenergic receptor blocking actions of propranolol and its stereoisomers

Abstract

THE introduction o£ the beta-adrensrgic receptor blocking ageaC, dichloroisoproterenol (DCI), by Powell and Slater l provided the coat coapelling evidence in support of the dwl adrensrgic receptor hypothesis of Ahlquist 2 .Numerous other beta -receptor antagonists have since been introduced, including pronethalol 3 and propranolol 4' S . The competitive equilibrium nature of the adrenargic blockade produced by these agents suggests that that while they probablq possess affinity for the bate-adrenergic receptor site, they are without "intrinsic activity" as beta-receptor stimulants or agonists 6 . Ariens has suggested that the side-chain alcoholic hgdrozyl group is one of the major determinants of affinity between beta-sympathominetics lThe racemic mi.zture of propranolol will be referred to as propranolol, or as dl-propranolol . The dextrorotatory and levorotatory isomers will be referred to as d-propranolol and 1-propranolol, or as daztto-propranolol and levo-propranoloZ, respectively .

Cardiovascular Beta-Adrenergic Receptor Blocking Activities of 1-(7-Indenyloxy)-3-Isopropyl-Aminopropane-2-Ol Hydrochloride (Yb-2) and Its Optical Isomers

“…It seems that Y13-2, like propranolol, exhibits no cardioselectivity which has been claimed in the studies on practolol (13)(14)(15) YB-2 and its optical isomers in the doses required to inhibit the positive inotropic and chronotropic responses to isoproterenol and cardiac sympathetic nerve stimulations failed to alter the inotropic response to calcium chloride. The finding appears to be simi lar to the result obtained from the study on isoproterenol-antagonism of propranolol and its optical isomers (18).…”

“…Whitsitt and Lucchesi observed no significant difference in the doses of propranolol required to antagonize the pharmacological and neurogenic beta-adrenergic stimulations in both isolated rabbit atria and anesthetized dogs (18). In the present study, a similar tendency was observed not only in the doses of propranolol but in those of YB-2 and its optical isomers in both isolated guinea pig atria and anesthetized dogs.…”

“…Whitsitt and Lucchesi reported that in both isolated rabbit atria and dog hearts the positive inotropic effects of beta-adrenergic stimulations were antagonized in a lower concentration of propranolol than that required to antagonize the positive chronotropic effects (18). Singh and Vaughan Williams also reported a similar result with d and 1…”

“…Tachikawa and Takenaka reported 1-YB-2 to be 200 times more active than the d-isomer in antago nizing the positive inotropic response to isoproterenol in isolated guinea pig atria (4). In isolated rabbit atria, the 1-isomer of propranolol was 1.7-1.9 times more potent than the racemate and 60-80 times more potent than the d-isomer in blocking isoproterenol-induced inotropic and chronotropic effects (18). Burrett estimated that d-propranolol was 50 times less active than dl-propranolol to isoproterenol-induced responses in heart rate, cardiac contractile force and blood pressure in anesthetized dogs, although the dose-re sponse curves were not parallel (19).…”

Antiarrhythmic activity of dextro- and levoisomers of 5-methyl-8-(2-hydroxy-3-T-butylaminopropoxy) coumarin hydrochloride (bucumolol), a .BETA.-adrenergic blocking agent, on aconitineinduced atrial and ouabain-induced ventricular arrhythmias in dogs.

“…Howe and Shanks (19) reported that racemic propranolol and its optical isomers were equally effective in abolishing ouabain-induced arrhythmia, while the ]-isomer was a little more effective. Lucchesi et al (20), and Whitsitt and Lucchesi (21) found that both i and d-isomer of either propranolol or pronethalol were capable of suppressing ectopic ventricular automaticity induced by ouabain, and such suggests that there is no special relation between fl-blocking action and prevention of ouabain-induced arrhythmia. Somani and others demonstrated that local anesthetic action was essential for antiarrhythmic activity of j3-blocking agents (22,23 Tse and Han also found that ouabain enhanced the action of catecholamine on the auto maticity of Purkinje fibers causing ventricular arrhythmia (32).…”