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

Abstract

1. The subtype of α₁-adrenoceptor mediating contractions to phenylephrine of the rat thoracic aorta, mesenteric artery and pulmonary artery were investigated by use of antagonists which show selectivity between the cloned α₁-adrenoceptor subtypes in binding studies.

2. Cumulative concentration-contraction curves for phenylephrine were competitively antagonized in the rat thoracic aorta by prazosin (pA₂ 9.9), WB4101 (pA₂ 9.6), 5-methylurapidil (pA₂ 8.1), benoxathian (pA₂ 9.2) and indoramin (pA₂ 7.4). These compounds were also competitive antagonists in the mesenteric and pulmonary arteries (except for 5-methylurapidil in the pulmonary artery), (prazosin pA₂ 9.9 and 9.7; WB4101 pA₂ 9.8 and 9.6; 5-methylurapidil pA₂ 7.9 and pK_B estimate 8.0; benoxathian pA₂ 8.8 and 9.3; indoramin pA₂ 7.2 and 7.5, respectively).

3. RS 17053 was not a competitive antagonist in any blood vessel as Schild plot slopes were greater than unity. The pK_B estimates for RS 17053 were 7.1 in aorta, 7.0 in the mesenteric artery and 7.7 in the pulmonary artery.

4. The α_1D-subtype selective antagonist BMY 7378 appeared to be non-competitive with shallow Schild plot slopes. The data were better fitted with two lines in all tissues, with Schild plot slopes that were no longer different from unity, except in the pulmonary artery. The higher affinity site for BMY 7378 in the aorta had a pA₂ of 9.0, while it was 8.8 and 8.9 in the mesenteric and pulmonary arteries, respectively.

5. MDL73005EF acted in a non-competitive manner in all three blood vessels, with shallow Schild plot slopes. The pK_B estimates for MDL73005EF were 8.4 in aorta, 7.5 in the mesenteric artery and 8.0 in the pulmonary artery.

6. In all three blood vessels the functionally determined antagonist affinity estimates correlated best with published pK_i values for their displacement of [³H]-prazosin binding on membranes expressing cloned α_1d-adrenoceptors compared with α_1a- or α_1b-adrenoceptors. The antagonist affinity estimates in the aorta, mesenteric and pulmonary arteries correlated highly with their previously published pA₂ values in rat aorta (α_1D) and less well with those for α_1A- and α_1B-adrenoceptors mediating contraction of the rat epididymal vas deferens and rat spleen, respectively.

7. The results of this study suggest that the contraction to phenylephrine of the rat thoracic aorta, mesenteric artery and pulmonary artery are mediated in part via the α_1D-subtype of adrenoceptor. The data for both BMY 7378 and MDL73005EF in all three blood vessels are consistent with receptor heterogeneity. However, the identity of the second site is unclear.

Full Text

The Full Text of this article is available as a PDF (424.4 KB).