Relationship of nonspecific antiarrhythmic and negative inotropic activity with physicochemical parameters of propranolol analogs

Abstract

In an attempt to separate the nonspecific antiarrhythmic activity of propranolol from its negative inotropic effects, analogues containing hydrophilic and lipophilic substituents on the nitrogen and on the naphthyl ring were prepared and tested in an isolated tissue preparation. Though it had been predicted that analogues containing a very hydrophilic group on the nitrogen would have the highest antiarrhythmic/negative inotropic effect ratio, it was found that both effects increased identically when the lipophilicity of either the nitrogen or ring substituent was increased.

Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in ΔKPQ Scn5a murine hearts modelling human long QT 3 syndrome

“…Additional local anaesthetic actions of propranolol, Na + channel blockade, leading to reductions in APD have previously been observed in cardiac tissue ( Davis & Temte 1968 , Pruett et al 1980 , Matthews & Baker 1982 ). Indeed, Matthews & Baker (1982) concluded that concentrations of propranolol required to produce a 50% blockade of Na + channels closely correlated with concentrations required to exert antiarrhythmic effects on isolated rabbit atria ( Rauls & Baker 1979 ). Additionally, at the clinical level, Duff et al (1983) reported that suppression of ventricular arrhythmias in 40% of patients necessitates a plasma propranolol concentration in excess of that producing substantial β-receptor blockade.…”

“…Accordingly, it made endocardial and epicardial monophasic action potential (MAP) recordings from the left ventricle of isolated, intact Langendorff-perfused ΔKPQ Scn5a ( Scn5a +/Δ) and wild type (WT) hearts, exposed to a range of propranolol concentrations. Propranolol is well known to exert potent Na + channel blockade occurring independently of its β-adrenoceptor blocking actions, thought important in its antiarrhythmic action ( Rauls & Baker 1979 , Matthews & Baker 1982 ). Propranolol concentrations used (0.1 and 1 μ m ) were based on values known to cause electrophysiological effects in clinical dose–response studies ( Duff et al 1983 ).…”

Targeting the β‐adrenergic receptor in the clinical management of congenital long QT syndrome

“…Independent of β-adrenoceptor blockade, propranolol has Na + channel blocking effects. 128,129 Thus, propranolol acting on the myocardium will block the Na V 1.5 channel causing a decrease in the amplitude of phase 0 depolarization of the AP, as well as a decrease in the Na + window/late Na + current. Therefore, in the endocardium, these effects will cause an abbreviation in the APD.…”

Partition and distribution coefficients of aryloxypropanolamine β-adrenoceptor antagonists

“…The aryloxypropanolamines are the most widely represented chemical class within the group of the P-adrenergic blocking drugs. It is known that their cardiac activity is correlated with their lipophilic character and a number of studies have appeared in the literature dealing with this argument (Hellenbrecht et al 1974;Rauls & Baker 1979;Cruickshank 1980;Harada et a1 198 I;Gortner & Hellenbrecht 1988). The lipophilicity of these drugs has also been shown to have a role in some of their biochemical actions (Street & Walsh 1984), as well as in their binding to tissues (Dax & Partilla 1982;Ijzerman et al 1985Ijzerman et al , 1987Bree et al 1986).…”