Agonist interaction with alkylation-sensitive and -resistant alpha-1 adrenoceptor subtypes

M. T. Piascik, B. T. Butler, T. A. Pruitt, J. W. Kusiak

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28 Scopus citations


The interaction of agonists with alpha-1 receptor subtypes sensitive and resistant to alkylation by a prazosin analog {1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo[2.2.2]octa-2,5- diene-z-carbonyl)-piperazine; SZL-49} has been examined. In rat aortic rings, SZL-49 (0.1-10 nM) shifted the dose-response curves for norepinephrine and phenylephrine to the right. The curves were biphasic, consisting of high and low affinity components. At >10 nM, the curves became monophasic. After SZL-49 treatment, the response to norepinephrine was partially antagonized by diltiazem. Chlorethylclonidine (1-100 μM) also produced biphasic dose-response curves. Phenylephrine bound to high and low affinity sites labeled by [3H]prazosin, and the high affinity site was eliminated by SZL-49. SZL-49 (i.p.) shifted the pressor dose-response curve for phenylephrine to the right but did not decrease the maximal response. Chlorethylclonidine was much less potent than SZL-49 at shifting the pressor dose-response curve. Pertussis toxin, 50 μg/kg i.v., shifted the phenylephrine pressor dose-response curve in control and SZL-49-treated animals. SZL-49 inhibited norepinephrine-induced inositol phosphate formation, whereas chlorethylclonidine had no effect on inositol phosphate formation. These data show: 1) both in vitro and in vivo, alpha-1 receptor subtypes sensitive and resistant to alkylation by SZL-49 can mediate the full response of agonists; 2) these subtypes exhibit high and low affinity for agonists; 3) responses mediated by either subtype are partially dependent on calcium channel activity and a pertussis toxin-sensitive G-protein; 4) the SZL-49 sensitive site is able to enhance the formation of inositol phosphates.

Original languageEnglish
Pages (from-to)982-991
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 1990

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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