Abstract
To determine the characteristics of the α1-adrenoceptor subtypes involved in adrenergic regulation of peripheral vascular resistance, contraction of canine subcutaneous resistance arteries was studied using wire myographs. The potencies of agonists and antagonists, chosen for their ability to discriminate between α1-adrenoceptor subtypes, were assessed in the presence of cocaine (3 μM), corticosterone (30 μM), and propranolol (1 μM). The rank order of agonist potency (pEC50 ± S.E.) was (R)-A-61603 (7.88 ± 0.1) > norepinephrine (6.41 ± 0.1) > phenylephrine (5.83 ± 0.1). The high sensitivity to (R)-A-61603 relative to phenylephrine is inconsistent with the presence of the α1D-adrenoceptor and most consistent with an α1A-adrenoceptor response. This is supported by the low affinity for the α1D-selective antagonist BMY 7378 (pKB 6.51 ± 0.47). The low pA2 values for prazosin (8.36) and HV723 (8.81), by definition, indicate the involvement of the putative α1L-adrenoceptor, a hypothesis supported by the pA2 values for WB4101 (8.42) and 5-methyl-urapidil (8.08). Pre-exposure to 1 μM CEC had little effect, whereas 100 μM CEC reduced the maximum contraction but not the sensitivity to norepinephrine. This low sensitivity to CEC argues against the presence of the α1B-adrenoceptor. We conclude that, by current definitions, an α1A-/α1L-adrenoceptor causes contraction of these vessels. This does not support the concept that selectivity for the α1A-adrenoceptor is the basis for the effectiveness of some α-blockers in some tissues, such as prostate, but not in other tissues such as blood vessels. Rather, the generally low potency of α-blockers in some tissues may be due to a tissue-specific property of the receptors.
Footnotes
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Send reprint requests to: Sally Anne Argyle, Division of Veterinary Pharmacology, Glasgow University Veterinary School, Bearsden, Glasgow, G61 1QH, Scotland, UK. E-mail:saa6k{at}udcf.gla.ac.uk
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↵1 This work was funded by a Glasgow University Scholarship and the Clinical Research Initiative in heart failure. The work was presented in part at the IUPHAR Congress 1998 (Argyle et al., 1998).
- Abbreviations:
- CEC
- chloroethylclonidine
- CCRC
- cumulative concentration-response curve
- NE
- norepinephrine
- PE
- phenylephrine
- Received December 7, 1999.
- Accepted June 21, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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