Characterization of an α1D‐adrenoceptor mediating the contractile response of rat aorta to noradrenaline
BA Kenny, DH Chalmers, PC Philpott… - British journal of …, 1995 - Wiley Online Library
BA Kenny, DH Chalmers, PC Philpott, AM Naylor
British journal of pharmacology, 1995•Wiley Online Library1 The affinities of a number of α1‐adrenoceptor antagonists were determined by
displacement of [3H]‐prazosin binding from cloned human α1A‐adrenoceptors (previously
designated cloned α1c subtype), α1B α1D and rat α1D‐adrenoceptors, stably expressed in
rat‐1 fibroblasts. Functional affinity estimates for these compounds were also determined
from noradrenaline‐mediated contractions of rat aorta. 2 BMY 7378 displayed high affinity
for cloned human α1D‐adrenoceptors (pKi= 8.2±0.10) and was selective over α1A (pAi …
displacement of [3H]‐prazosin binding from cloned human α1A‐adrenoceptors (previously
designated cloned α1c subtype), α1B α1D and rat α1D‐adrenoceptors, stably expressed in
rat‐1 fibroblasts. Functional affinity estimates for these compounds were also determined
from noradrenaline‐mediated contractions of rat aorta. 2 BMY 7378 displayed high affinity
for cloned human α1D‐adrenoceptors (pKi= 8.2±0.10) and was selective over α1A (pAi …
- 1The affinities of a number of α1 ‐adrenoceptor antagonists were determined by displacement of [3H]‐prazosin binding from cloned human α1A‐adrenoceptors (previously designated cloned α1c subtype), α1B α1D and rat α1D‐adrenoceptors, stably expressed in rat‐1 fibroblasts. Functional affinity estimates for these compounds were also determined from noradrenaline‐mediated contractions of rat aorta.
- 2BMY 7378 displayed high affinity for cloned human α1D‐adrenoceptors (pKi = 8.2 ±0.10) and was selective over α1A (pAi = 6.2 ±0.10) and α1B subtypes (6.7 ± 0.11). WB 4101, benoxathian and phentolamine displayed high affinity for α1A and α1D adrenoceptors compared to the α1B subtype. Spiperone displayed high affinity and selectivity for α1B adrenoceptors (pKi 8.8 ±0.16). 5‐Methyl‐urapidil was selective for cloned α1A adrenoceptors.
- 3Comparative binding affinities (pKi for compounds at cloned human and rat1D adrenoceptors were almost identical (r = 0.99, slope =1.08).
- 4Prazosin, doxazosin and 5‐methyl‐urapidil were potent, competitive antagonists of noradrenaline‐mediated contractions of rat aorta (pA2 values of 9.8, 8.8 and 7.8 respectively). The selective α1D antagonist BMY 7378 was also a potent antagonist on rat aorta (pKB = 8.3±0.1) but the interaction of this compound was not consistent with competitive antagonism at a single population of receptors.
- 5Functional affinities for compounds determined against noradrenaline‐mediated contractions of rat aorta correlated well with binding affinities at cloned α1D‐adrenoceptors (r = 0.96), but not with α1A (r = 0.61) or α1B (r = 0.46) subtypes.
- 6Noradrenaline‐mediated contractions of rat aorta were sensitive to the alkylating effects of chlorethylclonidine (CEC). CEC (10 μm) caused a small rightward shift in the noradrenaline concentration‐response curve. CEC at 100 μm caused a further shift and suppression of the maximum response to noradrenaline.
- 7The results of this study suggest that noradrenaline predominantly, but not exclusively, mediates contraction of rat aorta through the activation of an α1D‐adrenoceptor.
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