Selective Blockade of Adrenoceptive Beta Receptors in the Heart

Abstract

On the basis of a study of the activity of five sympathomimetic amines, Ahlquist in 1948 classified adrenoceptive receptors into two main types, which he designated alpha and beta. This classification has been vindicated by the development of drugs which specifically block the effects of stimulation of one type of receptor but not the other. Classical adrenergic blocking drugs such as phenoxybenzamine, dibenamine, phentolamine, tolazoline and dihydroergotamine block the effects of stimulation of alpha receptors but not beta receptors (Nickerson, 1949;Levy & Ahlquist, 1961 ;Moran & Perkins, 1961). These drugs are now described as adrenergic alpha receptor blocking agents. Recently several compounds have been described which block beta receptors but not alpha receptors. These, adrenergic beta receptor blocking agents, include dichloroisoprenaline (Powell & Slater, 1958) (Shanks, Wood, Dornhorst &Clark, 1966) and H 56/28 (Johnsson, Norrby, Solvell &Ablad, 1966). Structurally these compounds are closely related to each other and may be considered as derivatives of isoprenaline; in each case the side chain is identical with that of isoprenaline, or as in the last three compounds differs by the addition of an -OCH2 group. The blocking activity of these compounds is similar qualitatively, in that they block all beta receptors, but differs quantitatively. Another group of compounds, which block some but not all beta receptors, has recently emerged. These compounds include N-isopropylmethoxamine (Levy, 1964) which blocks beta receptors in the rat uterus; N tertiary butylmethoxamine (Levy, 1966a), and dimethyl isopropylmethoxamine (Levy, 1966b) which block beta receptors in the rat uterus, canine intestine and peripheral blood vessels. None of these compounds blocks the cardiac inotropic or chronotropic actions of catecholamines. Structurally these compounds are characterized by having a methyl group attached to the alpha carbon atom of the side chain. These observations suggest that beta receptors are not a homogenous group and may be capable of division into sub-groups. This hypothesis is further substantiated by the present paper in which

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).…”

Transformation of Adrenergic Receptors in the Myocardium

“…of new e-adrenergi c blocking agents that can selectively inhibit peripheral (VanDeripe and Moran, 1965;Levy, 1967) or cardiac responses (Dunlop and Shanks, 1968). Selective stimulation rather than selective block served as a basis for a subdivision of s-adrenergi c receptors by Lands et Al.…”

Effects of lignocaine and propranolol on experimental cardiac arrhythmias

“…Although ventricular arrhythmias induced by sympathomimetic amines and by coronary artery ligation in animals have been widely used in the evaluation of ,8-adrenoceptor blocking drugs (Dunlop & Shanks, 1968; Barrett & Cullum, 1968;Lucchesi & Iwami, 1968), the antiarrhythmic properties of lignocaine have not been previously studied by these methods. However, the electrophysiological effect of lignocaine on isolated canine Purkinje fibres and ventricular muscle have been studied in detail (Davis & Temte, 1969;Bigger & Mandel, 1970a, b).…”