Analysis of alpha 1L-adrenoceptor pharmacology in rat small mesenteric artery

Br J Pharmacol. 1999 Jun;127(3):661-70. doi: 10.1038/sj.bjp.0702598.

Abstract

1. To illuminate the controversy on alpha 1A- or alpha 1L-adrenoceptor involvement in noradrenaline-mediated contractions of rat small mesenteric artery (SMA), we have studied the effects of subtype-selective alpha 1-adrenoceptor agonists and antagonists under different experimental conditions. 2. The agonist potency order in rat SMA was: A61603 >> SKF89748-A > cirazoline > noradrenaline > ST-587 > methoxamine. Prazosin antagonized all agonists with a low potency (pA2: 8.29-8.80) indicating the involvement of alpha 1L-rather than alpha 1A-adrenoceptors. 3. The putative alpha 1L-adrenoceptor antagonist JTH-601, but not the alpha 1B-adrenoceptor antagonist chloroethylclonidine (10 microM) antagonized noradrenaline-induced contractions of SMA. The potency of the selective alpha 1D-adrenoceptor antagonist BMY 7378 against noradrenaline (pA2 = 6.16 +/- 0.13) and of the selective alpha 1A-adrenoceptor antagonist RS-17053 against noradrenaline (pKB = 8.35 +/- 0.10) and against the selective alpha 1A-adrenoceptor agonist A-61603 (pKB = 8.40 +/- 0.09) were too low to account for alpha 1D- and alpha 1A-adrenoceptor involvement. 4. The potency of RS-17053 (pKB/pA2's = 7.72-8.46) was not affected by lowering temperature, changing experimental protocol or inducing myogenic tone via KCl or U46619. 5. Selective protection of a putative alpha 1A-adrenoceptor population against the irreversible action of phenoxybenzamine also failed to increase the potency of RS-17053 (pA2 = 8.25 +/- 0.06 against A61603). 6. Combined concentration-ratio analysis demonstrated that tamsulosin, which does not discriminate between alpha 1A- and alpha 1L-adrenoceptors, and RS-17053 competed for binding at the same site in the SMA. 7. In summary, data obtained in our experiments in rat SMA indicate that the alpha 1-adrenoceptor mediating noradrenaline-induced contraction displays a distinct alpha 1L-adrenoceptor pharmacology. This study does not provide evidence for the hypothesis that alpha 1L-adrenoceptors represent an affinity state of the alpha 1A-adrenoceptor in functional assays. Furthermore, there is no co-existing alpha 1A-adrenoceptor in the SMA.

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
  • Adrenergic alpha-1 Receptor Agonists*
  • Adrenergic alpha-1 Receptor Antagonists*
  • Adrenergic alpha-Agonists / pharmacology*
  • Adrenergic alpha-Antagonists / pharmacology*
  • Animals
  • Clonidine / analogs & derivatives
  • Clonidine / pharmacology
  • Cresols / pharmacology
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Indoles / pharmacology
  • Male
  • Mesenteric Arteries / drug effects*
  • Mesenteric Arteries / physiology
  • Norepinephrine / pharmacology
  • Piperazines / pharmacology
  • Potassium / pharmacology
  • Prazosin / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha-1 / physiology
  • Sulfonamides / pharmacology
  • Tamsulosin
  • Tetrahydronaphthalenes / pharmacology

Substances

  • A 61603
  • Adra1a protein, rat
  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Cresols
  • Imidazoles
  • Indoles
  • Piperazines
  • RS 17053
  • Receptors, Adrenergic, alpha-1
  • Sulfonamides
  • Tetrahydronaphthalenes
  • chlorethylclonidine
  • JTH 601
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Tamsulosin
  • BMY 7378
  • Clonidine
  • Potassium
  • Norepinephrine
  • Prazosin