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OtherAUTONOMIC PHARMACOLOGY

Pharmacological and Immunocytochemical Characterization of Subtypes of Alpha-1 Adrenoceptors in Dog Aorta

A. M. Low, H. Lu-Chao, Y. F. Wang, R. D. Brown, C. Y. Kwan and E. E. Daniel
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 894-901;
A. M. Low
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H. Lu-Chao
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Y. F. Wang
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R. D. Brown
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C. Y. Kwan
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E. E. Daniel
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Abstract

In this study, the effects of nine alpha-1 adrenoceptor antagonists [prazosin, WB 4101 (WB), chloroethylclonidine (CEC), 5-methylurapidil (5-MU), BMY 7378 (BMY), MDL 73005EF (MDL73), MDL 72832 (MDL72), RS 17053 (RS) and SK&F 105854 (SKF)] were studied on contractile responses to phenylephrine (PE) of the endothelium-denuded dog aorta in vitro. All antagonists, except CEC, 5-MU and RS, produced concentration-dependent competitive inhibition of contractile responses of the aorta to PE. The rightward shift of the concentration-response curves of PE yielded constant pKBvalues with increasing antagonist concentrations in most cases allowing a single pooled value to be determined: for prazosin, a pKBof 8.99 ± 0.11 (n = 20,KB of 1.03 nM); for WB, a pKB of 8.75 ± 0.08 (n = 23,KB of 1.76 nM); for BMY, a pKBof 7.21 ± 0.13 (n = 13,KB of 62 nM); for MDL72, a pKBof 7.95 ± 0.15 (n = 12,KB of 11.2 nM); and for SK&F 105854, a pKB of 5.82 ± 0.08 (n = 15,KB of 1.52 μM). For MDL73, pKBvalues decreased with antagonist concentration: 7.88 ± 0.06 at 10 nM, 7.56 ± 0.28 at 100 nM and 6.92 ± 0.18 at 1000 nM, which suggests the presence of more than one receptor subtype. CEC (10 and 100 μM) almost completely inhibited responses to PE; lower concentrations had no significant effect. 5-MU (10–300 nM) and RS (3–300 nM) were ineffective antagonists in this tissue. Because WB, a highly selective alpha-1D andalpha-1A adrenoceptor subtypes inhibitor, blocked PE responses (with less affinity than foralpha-1A adrenoceptors), and 5-MU and RS, which are selective blockers for alpha-1A adrenoceptor, were ineffective, we conclude that alpha-1A adrenoceptors are absent in the dog aorta. The effects of the less selective MDL72 were inconsistent with actions at alpha-1B oralpha-1D adrenoceptors. Although WB shifted the PE concentration-response curve to the right, the abilities of BMY, MDL73 and SKF to inhibit competitively PE contraction were of lower affinity compared with expectations for interaction with alpha-1D adrenoceptors; they are not the predominant subtype. The complete inhibition of PE responses by CEC suggests that the dog aorta contains the alpha-1B adrenoceptor subtype. In immunocytochemical studies of the expression of alpha-1B adrenoceptor, all cells apparently expressed this protein. Moreover, Western blot studies of the microsomal fractions confirmed the presence ofalpha-1B adrenoceptors. In the dog aorta, the alpha-1 adrenoceptors predominantly resemblealpha-1B rather than alpha-1D adrenoceptors as reported in the rat aorta.

Footnotes

  • Send reprint requests to: E.E. Daniel, PhD, Professor Emeritus, Room 4N51, Department of Biomedical Sciences, McMaster University, Hamilton ON L8N 3Z5, Canada.

  • ↵1 Supported by the Heart and Stroke Foundation of Ontario.

  • ↵2 Recipient of the Career Investigator award of the Heart and Stroke Foundation of Ontario.

  • Abbreviations:
    BMY
    BMY 7378 or {8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl)- 8-azaspirol[4,5]decane-7,9-dione
    Bmax
    maximum concentration of bound ligand per mg membrane protein
    CEC
    chloroethylclonidine
    DMA
    dog mesenteric artery
    EC50
    concentration for 50% maximum response
    IC50
    50% inhibitory concentration
    KB
    calculated antagonist dissociation constant in functional studies
    KD
    dissociation constant in saturation ligand binding studies
    Ki
    dissociation constant in competition ligand binding studies
    MDL72
    MDL 72832, {8-[4-(1,4-benzodioxan-2-ylmethylamino)butyl]-8-azaspirol[4,5]decane-7,9-dione HCl
    MDL73
    MDL 73005EF, {8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspirol[4,5]decane-7,9-dione HCl
    MIC2
    microsomal fraction used for binding
    RS
    RS-17053 or N-[2-(-cyclopropyl methoxy phenoxy) ethyl]-5-chloro-α, α-dimethyl-1H-indole-3-ethanamine HCl
    SKF
    SK&F 105854 or 7-chloro-2-bromo-3,4,5,6-tetrahydro-4-methylfurol[4,3,2-ef]-3 benzapine
    WB
    WB 4101 or 2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane
    5-MU
    5-methylurapidil
    PE
    phenylephrine
    • Received August 21, 1997.
    • Accepted January 30, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherAUTONOMIC PHARMACOLOGY

Pharmacological and Immunocytochemical Characterization of Subtypes of Alpha-1 Adrenoceptors in Dog Aorta

A. M. Low, H. Lu-Chao, Y. F. Wang, R. D. Brown, C. Y. Kwan and E. E. Daniel
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 894-901;

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Pharmacological and Immunocytochemical Characterization of Subtypes of Alpha-1 Adrenoceptors in Dog Aorta

A. M. Low, H. Lu-Chao, Y. F. Wang, R. D. Brown, C. Y. Kwan and E. E. Daniel
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 894-901;
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