Evidence for a receptor mediated action of norepinephrine distinct from alpha- and beta-adrenoceptors

Abstract

The mode of action of (-) norepinephrine (NE) and UK-14,304-18 has been investigated using the cholinergically-evoked 'twitch' response of the electrically stimulated guinea-pig ileum. St 587 and benextramine were employed as antagonists. St 587 acted as a competitive antagonist toward UK-14,304-18, yielding an apparent pA2 value of 7.3. In contrast, St 587 failed to act competitively toward NE. Similarly, benextramine (1 X 10(-5) mol/l) blocked the inhibitory responses to UK-14,304-18 but was considerably less active toward NE. Remaining responses to NE after benextramine were not antagonized by St 587, even at a concentration of 3 X 10(-5) mol/l. It is postulated that NE acts to inhibit the 'twitch' response be evoking two different receptor-mediated events: 1. agonism at the alpha 2-adrenoceptor and 2. agonism at a site which is distinct from the alpha- and beta-subtypes. In the concentrations studied, UK-14,304-18, St 587 and benextramine are postulated to lack affinity for the proposed site. The effect of NE and UK-14,304-18 was also investigated on the contractile responses to exogenously applied histamine. These experiments were done in the presence of muscarinic cholinergic and adrenoceptor blockade. NE inhibited responses to histamine but UK-14,304-18 was inactive. Furthermore, the inhibitory action of NE was stereoselective with the (-) form being 25 times more potent than the (+) enantiomer. These findings suggest the presence of a receptor site for NE which is distinct from cholinergic mechanisms and established alpha and beta-adrenoceptors.

Agonist and antagonist characterization of a putative adrenoceptor with distinct pharmacological properties from the α‐ and β‐subtypes

“…However, it is suggested that the response is receptor-mediated because of (1) the concentrationdependence of the response; (2) the recognition of optical isomers of isoprenaline (this study) and noradrenaline (Bond et al, 1986b); (3) blockade of the putative receptor by nadolol. The presence of an undefined adrenoceptor in the guinea-pig ileum is evident from the failure of propranolol and nadolol to interact competitively with f-adrenoceptor agonists even though aadrenoceptors were saturated with phentolamine (3pM) and equilibrium conditions prevailed (depletion of endogenous monoamines with reserpine and the addition of ascorbic acid, cocaine, and corticosterone to the Krebs solution).…”

α.‐Adrenoceptor modulation of the efferent function of capsaicin‐sensitive sensory neurones in guinea‐pig isolated atria

“…Indeed the results of the present study appear to be very similar to those obtained in the guinea-pig ileum where the twitch response induced by electrical field stimulation is inhibited by NA and by the m2-agonists, clonidine and UK-14,304-18. Only the effect of the imidazolines however is completely antagonized by M2-blockers, while noradrenaline shows a 'remaining effect' which is insensitive to a(X-, a2or P-adrenoceptor blockers (Bond et al, 1986a;b). Those effects of NA insensitive to aand P-blockade are consistently observed in other cardiac preparations, such as rabbit papillary muscle (Schumann, 1980), rat atria (Williamson & Broadley, 1989) and chick atria (Tayo, 1984).…”

“…Thus, as well as in the cardiac adrenergic terminals of several animal species (Kobinger & Pichler, 1980;Docherty, 1983;Ledda & Mantelli, 1984 (Neylon & Summers, 1985;Harrison et al, 1991) including those of rat submandibular gland tissue slices and rat brain slices (Turner et al, 1984;Nasseri & Minneman 1987 . Only the effect of the imidazolines however is completely antagonized by M2-blockers, while noradrenaline shows a 'remaining effect' which is insensitive to a(X-, a2-or P-adrenoceptor blockers (Bond et al, 1986a;b). Those effects of NA insensitive to a-and P-blockade are consistently observed in other cardiac preparations, such as rabbit papillary muscle (Schumann, 1980), rat atria (Williamson & Broadley, 1989) and chick atria (Tayo, 1984).…”