Abstract
In the dog saphenous vein (DSV), phenylephrine (PE) responses throughalpha-1 adrenoceptors receptors are antagonized by bothalpha-1 and alpha-2 receptor antagonists. Furthermore, pretreatment with chloroethylclonidine (CEC) eliminates prazosin binding but reduces rauwolscine binding by half (Daniel et al.,1996). In new functional experiments, the effects of preincubation with phenoxybenzamine (PBZ), an irreversible alphaadrenoceptor antagonist, on responses to PE and two selectivealpha-2 adrenoceptor agonists were evaluated. Also, the ability of prazosin or rauwolscine to prevent irreversible losses of responses to these agonists when coincubated with PBZ was determined. Preincubation in PBZ (10–300 nM) concentration dependently reduced PEEmax and the calculated fraction of residual receptors (q). Preincubation in PBZ (10–300 nM) increasedKB values for prazosin (30 and 100 nM) but did not alter the KB value for rauwolscine (50 nM) acting at the residual receptors from control values. Coincubation of PBZ with prazosin partially prevented these PBZ actions (Emax partly restored) on responses to PE, but coincubation of rauwolscine (≤1 μM) with PBZ, did not. Rauwolscine competitively inhibited responses to twoalpha-2 adrenoceptor agonists (Schild plot pA2 values near 9). Preincubation with PBZ concentrations of ≥300 nM caused >50% reduction in Emaxvalues of responses but did not alter the EC50 values for either agonist. Coincubation of rauwolscine with PBZ protected responses to alpha-2 agonists against PBZ (1 μM) effects. This study shows that PE initiates contractions at atypicalalpha-1 adrenoceptors represented by all sites of PE action. Rauwolscine antagonizes PE actions but does not protect against PBZ inactivation. Typical alpha-2 adrenoceptors are distinguished from the unusual alpha-1 adrenoceptors by their lesser sensitivity to PBZ and their protection by rauwolscine from PBZ.
Footnotes
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Send reprint requests to: E. E. Daniel, Doctor of Philosophy, Room 4N51, Department of Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada. E-mail:daniele{at}fhs.csu.mcmaster.ca
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↵1 This work was supported by the Heart and Stroke Foundation of Ontario.
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↵2 Present address: Department of Anesthesia, University of Toronto, Toronto, Ontario M5G 2C4, Canada.
- Abbreviations:
- DSV
- dog saphenous vein
- CEC
- chloroethylclonidine
- DMV
- dog mesenteric vein
- PBZ
- phenoxybenzamine
- PE
- phenylephrine
- B-HT 920
- [2-amino-6-allyl3,4,7,8-tetahydro-6H-thiazolo(5,4-d)azepine]dihydrochloride
- UK-14
- 304, [5-bromo-6-(imidazoline-2-ylamino-quinoxaline)]
- q
- residual receptor population
- Received July 8, 1998.
- Accepted August 12, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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