Transformation of Adrenergic Receptors in the Myocardium

Abstract

·ABSTRACTThe present series of experiments provided evidence that the generally accepted distinction between a-and s-adrenergic receptors is not immutable. In frog hearts and rat atria 3H-phenoxybenzamine (3H-POB ) blocked inotropic responses to catecholamines only at temperatures below l7 0 C and potentiated responses ab ove 23 0 C, and considerably more radioactivity was bound to the myocardium at lower temperatures. The converse was true for l4C-propranolol, and the potency of a-and s-adrenergic agonists was shawn to parallel the effectiveness of the blocking agents. Alkylation of a-adrenergic receptors by POB at l4 0 c prevented the appearance of s-adrenergic receptors when the temperature was subsequently raised ta 24 o C.Phentolamine prevented block by 3H-POB and considerably reduced its binding ta the myocardium at low but not at high temperatures. After exposure ta unlabelled POB in the presence of phentolamine at low temperature and thorough washing, exposure to 3H-POB produced a IIpositive label" of the adrenergic receptors, which was localized in a 20,000 9 (ll mitochondrial ll ) and in a IIsoluble protein" fraction. Pretreatment of rats with 6-hydroxydopamine, but not with reserpine, prevented the appearance of oe-adrenergic receptor charac.teristics in left atria at low temperatures; this indicated that adrenergic innervation, but probably not stores of neurotransmitter, is necessary to allow transformation of the receptors. It is suggested that a-and S-adrenergic receptors may be different allosteric conformations of the same molecule.

alpha-Adrenergic reduction of cyclic adenosine monophosphate concentrations in rat myocardium.

“…It has been suggested that the /3-and aadrenergic receptors are very closely related and may even represent two allosteric configurations of a single active site. 36 In line with this notion, results of some studies have been interpreted as showing transformation of f3-to aadrenergic receptors. 36 Perhaps, in our study, when /3-adrenergic receptors were stimulated by isoproterenol, aadrenergic receptors became inaccessible to phenylephrine.…”

“…36 In line with this notion, results of some studies have been interpreted as showing transformation of f3-to aadrenergic receptors. 36 Perhaps, in our study, when /3-adrenergic receptors were stimulated by isoproterenol, aadrenergic receptors became inaccessible to phenylephrine. Such a phenomenon could also explain the lack of potentiation of epinephrine augmentation of cyclic AMP levels by phentolamine.…”

Temperature‐induced interconversion of alpha‐and beta‐adrenoceptors in the frog heart.

“…(1952), and had a specific activity of 33-13 mc/m-mole. Its physicochemical and pharmacological properties were identical to those of an authentic sample of POB-HCl (Smith Kline & French), and it was shown to be radiochemically pure (Yong & Nickerson, 1973 Determination of retained radioactivity. Hearts were freeze-dried and weighed.…”

“…Phentolamine, a reversible competitive a-adrenoceptor antagonist, was selected for the protection experiments because it has been reported not to affect tissue uptake sites for noradrenaline (Hertting, Axelrod & Whitby, 1961) or to interact with other catecholamine binding sites (Yong & Nickerson, 1973), and thus appeared to be more specific for the a-adrenoceptor than an agonist. (Fig.…”

“…This was interpreted as evidence for a single type of adrenoceptor whose characteristics are governed by the metabolic state of the tissue (Kunos & Szentivanyi, 1968). However, an alternative explanation is that there are separate and independent 'pools' of o-and fi-adrenoceptors with different sensitivities to temperature (Buckley & Jordan, 1970 (Kunos, Yong & Nickerson, 1973).…”