Functional characterization of α1‐adrenoceptor subtypes in human skeletal muscle resistance arteries

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Abstract
α1‐adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non‐selective) and A61603 (α1A‐selective), the antagonists prazosin (non‐selective), 5‐methyl‐urapidil (α1A‐selective) and BMY7378 (α1D‐selective) and the alkylating agent chloroethylclonidine (preferential for α1B). Small arteries were obtained from the non‐ischaemic skeletal muscle of limbs amputated for critical limb ischaemia and isometric tension recorded using wire myography. Prazosin antagonized responses to noradrenaline with a pA2 value of 9.18, consistent with the presence of α1‐adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5‐Methyl‐urapidil competitively antagonized responses to noradrenaline with a pKB value of 8.48 and a Schild slope of 0.99, consistent with the presence of α1A‐adrenoceptors. In the presence of 300 nM 5‐methyl‐urapidil, noradrenaline exhibited biphasic concentration response curves, indicating the presence of a minor population of a 5‐methyl‐urapidil‐resistant subtype. Contractile responses to noradrenaline were not affected by 1 μM chloroethylclonidine suggesting the absence of α1B‐adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 μM chloroethylclonidine, suggesting an effect of chloroethylclonidine at α1A‐adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 μM) poorly shifted the potency of noradrenaline giving a pA2 of 6.52. These results rule out the presence of the α1D‐subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the α1A‐adrenoceptor subtype with a minor population of an unknown α1‐adrenoceptor subtype. British Journal of Pharmacology (2001) 133, 679–686; doi:10.1038/sj.bjp.0704130