Detail of "19216-56-9"

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Prazosin selectively antagonizes norepinephrine contractions at low-affinity, non-alpha adrenoceptor sites (extraceptors) in arterial muscle

Prazosin selectively antagonizes norepinephrine contractions at low-affinity, non-alpha adrenoceptor sites (extraceptors) in arterial muscle. Laher, I.; Nishmura, S.; Bevan, J. A. (Dep. Pharmacol., Univ. Vermont, Burlington, VT 05405, USA). J. Pharmacol. Exp. Ther., 239(3), 846-52 (English) 1986. CODEN: JPETAB. ISSN: 0022-3565. DOCUMENT TYPE: Journal CA Section: 2 (Mammalian Hormones) The characteristics of a low-affinity site activated by norepinephrine (NE) [51-41-2], which is demonstrable in arterial smooth muscle pretreated with phenoxybenzamine (PBZ) to alkylate most alpha adrenoceptors, were studied. Treatment with PBZ resulted in biphasic dose-response curves to NE. The initial phase assocd. with concns. of NE up to 10-5 M was due to its action in tissues where alpha adrenoceptors have been reduced to a no. that would not support a max. contraction. The 2nd phase occurred with higher doses of NE. This latter PBZ-resistant phase or contraction, which can represent >60% of the control maximal response, probably occurs at low-affinity sites for the NE extraceptors distinct from alpha adrenoceptors in arterial smooth muscle. These residual responses to NE after PBZ treatment were (1) inhibited selectively by prazosin [19216-56-9] and (2) protected by prazosin from further inhibition by addnl. doses of PBZ. Effects due to prazosin at low-affinity sites were obsd. only with doses in excess of those required to competitively inhibit responses through alpha adrenoceptors in smooth muscle. The response to NE occurring through PBZ-resistant adrenoceptors was not dependent on the presence of the endothelium. This low-affinity site for NE was also evident after alkylation of alpha adrenoceptors with other irreversibly acting antagonists (e.g., benextramine and dibenamine). These observations are discussed in relation to the suggestion for a new adrenoceptor, the gamma-adrenoceptor. Differences and similarities of the extraceptor with this proposed adrenoceptor are discussed. Both sites have a high threshold to NE, and both may be influenced by prazosin. However, there are differences in their reported distribution within the arterial tree. Apparently, low-affinity sites for NE (e.g., extraceptors) exist in arterial smooth muscle. These sites are resistant to alpha adrenoceptor antagonists. Prazosin in doses greater than those required to competitively inhibit alpha adrenoceptor-mediated contractions is able to inhibit responses occurring through activation of the low-affinity site for NE.

Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta

Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta. Alosachie, Iyad; Godfraind, Theophile (Lab. Pharmacodyn. Gen. Pharmacol., Univ. Cathol. Louvain, Brussels B-1200, Belg.). Br. J. Pharmacol., 89(3), 525-32 (English) 1986. CODEN: BJPCBM. ISSN: 0007-1188. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The effect of endothelium on the adrenolytic action of prazosin [19216-56-9] was studied in the rat isolated aorta. Prazosin showed a non-competitive type of antagonism in prepns. with intact endothelium while in prepns. where endothelium had been removed, prazosin at concns. between 0.3 nM-10 nM acted as a competitive antagonist. Methylene blue, used to decrease tissue levels of cyclic GMP [7665-99-8] converted prazosin from a non-competitive antagonist into an apparently competitive antagonist in the presence of endothelium. Increasing tissue levels of cyclic GMP by incubation with 8-bromo-cyclic GMP converted prazosin from an apparently competitive antagonist into a non-competitive antagonist in the absence of endothelium. Anal. of concn.-response curves for noradrenaline in the presence and absence of endothelium showed that the affinity for noradrenaline was the same but the efficacy, measured by estg. the receptor reserve, was not; it was lower in the presence than in the absence of endothelium. Apparently, the change in the mode of antagonism of prazosin after endothelium removal could be related to an alteration in the efficacy of the agonist, brought about by a change in the tissue levels of cyclic GMP.