Abstract
The characteristics of a low-affinity site activated by norepinephrine (NE), 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 associated with concentrations of NE up to 10(-5) M was due to its action in tissues where alpha adrenoceptors have been reduced to a number that would not support a maximum contraction. The second phase occurred with higher doses of NE. We postulate that this latter PBZ-resistant phase or contraction, which can represent more than 60% of the control maximal response, occurs at low-affinity sites for NE "extraceptors" distinct from alpha adrenoceptors in arterial smooth muscle. These residual responses to NE after PBZ treatment were inhibited selectively by prazosin and protected by prazosin from further inhibition by additional doses of PBZ. Effects due to prazosin at low-affinity sites were observed 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.(ABSTRACT TRUNCATED AT 250 WORDS)
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