Characterization of α1-adrenoceptor-mediated contraction in the mouse thoracic aorta

doi:10.1016/S0014-2999(01)01134-7

European Journal of Pharmacology

Volume 424, Issue 2, 20 July 2001, Pages 131-140

https://doi.org/10.1016/S0014-2999(01)01134-7 Get rights and content

Abstract

In the mouse thoracic aorta, noradrenaline, adrenaline, phenylephrine and methoxamine behaved as full agonists. The pA₂ values for 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione dihydrochloride (BMY 7378) against each agonist were in good agreement with the generally accepted affinity value of α_1D-adrenoceptors. 5-Methylurapidil, 2-[2,6-dimethoxyphenoxyethyl]aminomethyl-1,4-benzodioxane hydrochloride (WB 4101) and prazosin inhibited the contraction in response to noradrenaline. A significant correlation was obtained between the antagonist affinities in mouse thoracic aorta and those of native α_1D-adrenoceptors in rat thoracic aorta or with those of cloned α_1d-adrenoceptors, but not with those for either α_1a- or α_1b-adrenoceptors. Buspirone behaved as a partial agonist in mouse thoracic aorta, the contraction of which was antagonized by BMY 7378 with a pA₂ value (8.49) consistent with that found against noradrenaline (8.43). Clonidine acted as a partial agonist (pD₂=5.94). The pK_p value for clonidine against noradrenaline was similar to the pD₂ value for clonidine. The apparent pK_B value for BMY 7378 against clonidine was similar to the pA₂ value against other full agonists used in the present study. These results suggest that the α_1D-adrenoceptor subtype exists, and that the full agonists and the partial agonists evoke the contraction mediated through the α_1D-adrenoceptor in mouse thoracic aorta.

Introduction

Pharmacological and molecular cloning studies have established operational and structural heterogeneity among the α₁-adrenoceptors Minneman, 1988, Bylund et al., 1994, Ford et al., 1994. The α₁-adrenoceptor classification comprises three native subtypes, termed α_1A, α_1B and α_1D, and their cloned counterparts are now designated as α_1a, α_1b and α_1d Bylund et al., 1994, Ford et al., 1994, Hieble et al., 1995b. Various groups have shown that the α₁-adrenoceptor antagonist, prazosin, does not discriminate between these subtypes Ford et al., 1994, Hieble et al., 1995a, Hieble et al., 1995b, Michel et al., 1995. Functional pharmacological studies, however, have resulted in a subdivision of the α₁-adrenoceptors that is based on selectivity of prazosin. Muramatsu et al., 1990b, Muramatsu et al., 1995 proposed that the α₁-adrenoceptors can be pharmacologically divided into α_1H and α_1L subtypes with high (pA₂>9) and low (pA₂<9) affinity for prazosin, respectively. The α_1A-, α_1B- and α_1D-adrenoceptor subtypes are all included in the α_1H-adrenoceptor subtypes. There is a report that α_1L-adrenoceptor is a different conformation of α_1A-adrenoceptor (Ford et al., 1997).

The distribution of the various α₁-adrenoceptor subtypes is not homogeneous among the thoracic aorta of different animal species. For example, the contraction response seen in the thoracic aorta of the rat is mediated via the α_1D-adrenoceptor Saussy et al., 1994, Kenny et al., 1995, Testa et al., 1995, Eltze, 1996, whereas in the guinea pig, the thoracic aorta responses are said to be mediated via α_1L-adrenoceptors Muramatsu et al., 1990b, Yamamoto and Koike, 1999. On the other hand, α_1A- and α_1B- Suzuki et al., 1990, Oriowo and Ruffolo, 1992, Castillo et al., 1993, α_1B- and α_1L- Muramatsu et al., 1990a, Muramatsu et al., 1998, α_1D- and α_1L- Leonardi et al., 1997, Testa et al., 1997, Eltze et al., 1999 adrenoceptor-mediated contractions have been reported for rabbit aorta.

Targeted gene disruption has been used increasingly to elucidate the in vivo functions of several receptors, including some adrenoceptor subtypes Link et al., 1995, Susulic et al., 1995, MacMillan et al., 1996, Rohrer et al., 1996, Cavalli et al., 1997. The potential functional changes occurring in knockout mice might allow, on one hand, to assign distinct functions to the receptor that has been deleted, and on the other, to test the functional redundancy among receptor subtypes. However, there is little information about the distribution of the α₁-adrenoceptor subtype in the normal mouse.

BMY 7378 is the first selective antagonist at the α_1D-adrenoceptor subtype Saussy et al., 1994, Goetz et al., 1995. This agent is used with various tissues to detect the presence of the α_1D-adrenoceptor subtype. Recently, Hussain and Marshall, 1997, Hussain and Marshall, 2000 reported that the pA₂ value for BMY 7378 against phenylephrine was inconsistent with the pK_B value for BMY 7378 against methoxamine in the rat mesenteric artery in which there is an α_1D-adrenoceptor subtype mediating contraction.

Therefore in the present study, we tried to determine (1) which α₁-adrenoceptor subtypes are involved in the mouse thoracic aorta and (2) whether the functional subtypes mediating adrenergic contraction are dependent on the agonists, by calculating the pA₂ values of some antagonists.

Section snippets

Mechanical responses

Male albino ddY mice (20–30 g) were killed by a blow on the head and the thoracic aorta was isolated and dissected free of excess fat and connective tissues. The intimal surface of the thoracic aorta was gently rubbed with a polyethylene tube to remove the endothelium. Functional loss of endothelial cells was confirmed by the loss of the relaxation response to acetylcholine (1 μM). The aorta was cut into 4-mm ring segments. Each ring segment was suspended in a 20-ml organ bath filled with a

Effect of agonists in the mouse thoracic aorta

In the mouse thoracic aorta, noradrenaline, adrenaline, phenylephrine and methoxamine evoked contraction in a concentration-dependent manner. Each agonist yielded the full agonistic action, the rank order of potency being noradrenaline=adrenaline>phenylephrine>methoxamine (Fig. 1). The pD₂ values and intrinsic activities for the agonists are summarized in Table 1.

Effect of BMY 7378 on the contraction induced by agonists

The responses to agonists (noradrenaline, adrenaline, phenylephrine and methoxamine) were antagonized by BMY 7378 in a

Discussion

We examined the effects of BMY 7378, the first selective α_1D-adrenoceptor antagonist Saussy et al., 1994, Goetz et al., 1995, on contractions induced by some agonists (noradrenaline, adrenaline, phenylephrine and methoxamine) in the mouse thoracic aorta. The four agonists used in the present study evoked contraction in a concentration-dependent manner, and intrinsic activities were not significantly different from one, suggesting full agonism (Table 1; Fig. 1). The rightward shifts of the

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Characterization of α1-adrenoceptor-mediated contraction in the mouse thoracic aorta

Abstract

Introduction

Section snippets

Mechanical responses

Effect of agonists in the mouse thoracic aorta

Effect of BMY 7378 on the contraction induced by agonists

Discussion

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

J. Biol. Chem.

Life Sci.

Eur. J. Pharmacol.

Jpn. J. Pharmacol.

Investigation of the subtypes of α1-adrenoceptor mediating contractions of rat aorta, vas deferens and spleen

Br. J. Pharmacol.

Some quantitative uses of drug antagonists

Br. J. Pharmacol.

Evidence for a functional α1A-(a1C-)adrenoceptor mediating contraction of the rat epididymal vas deferens and α1B-adrenoceptor mediating contraction of the rat spleen

Br. J. Pharmacol.

International union of pharmacology nomenclature of adrenoceptors

Pharmacol. Rev.

Decreased blood pressure response in mice deficient of the α1b-adrenergic receptor

Proc. Natl. Acad. Sci. U. S. A.

RS 17053(N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamine hydrochloride), a selective (1A-adrenoceptor antagonist, displays low affinity for functional α1-adrenoceptors in human prostate: implication for adrenoceptor classification

Mol. Pharmacol.

Pharmacological pleiotropism of the human recombinant α1A-adrenoceptor: implications for α1-adrenoceptor classification

Br. J. Pharmacol.

The α1-adrenoceptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned hyman α1c-subtype

Mol. Pharmacol.

Pharmacological evidence of distinct α1-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery

Br. J. Pharmacol.

α- and β-adrenoceptors: from gene to the clinic: 1. Molecular biology and adrenoceptor subclassification

J. Med. Chem.

Recommendation for nomenclature of α1-adrenoceptors; consensus update

Pharmacol. Rev.

Characterization of α1-adrenoceptor subtypes mediating contractions to phenylephrine in rat thoracic aorta, mesenteric artery and pulmonary artery

Br. J. Pharmacol.

The role of alpha 1-adrenoceptors in the clonidine-induced contraction and relaxation of rat aorta

Res. Commun. Mol. Pathol. Pharmacol.

The classification of drugs and drug receptors in isolated tissues

Pharmacol. Rev.

Characterization of α₁-adrenoceptor-mediated contraction in the mouse thoracic aorta

Investigation of the subtypes of α₁-adrenoceptor mediating contractions of rat aorta, vas deferens and spleen

Evidence for a functional α_1A-(a1C-)adrenoceptor mediating contraction of the rat epididymal vas deferens and α_1B-adrenoceptor mediating contraction of the rat spleen

Decreased blood pressure response in mice deficient of the α_1b-adrenergic receptor

RS 17053(N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamine hydrochloride), a selective (1A-adrenoceptor antagonist, displays low affinity for functional α₁-adrenoceptors in human prostate: implication for adrenoceptor classification

Pharmacological pleiotropism of the human recombinant α_1A-adrenoceptor: implications for α₁-adrenoceptor classification

The α₁-adrenoceptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned hyman α_1c-subtype

Pharmacological evidence of distinct α₁-adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery

Recommendation for nomenclature of α₁-adrenoceptors; consensus update

Characterization of α₁-adrenoceptor subtypes mediating contractions to phenylephrine in rat thoracic aorta, mesenteric artery and pulmonary artery