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Functional chracterization of alpha(1)-adrenoceptor subtypes in human skeletal muscle resistance arteries

Jarajapu, Y.P. and Coats, Paul and McGrath, John C. and Hillier, Chris and MacDonald, Allan (2001) Functional chracterization of alpha(1)-adrenoceptor subtypes in human skeletal muscle resistance arteries. British Journal of Pharmacology, 133 (5). pp. 679-686. ISSN 0007-1188

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Abstract

alpha (1)-adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non-selective) and A61603 (alpha (1A)-selective), the antagonists prazosin (non-selective), 5-methyl-urapidil (alpha (1A)-selective) and BMY7378 (alpha (1D)-selective) and the alkylating agent chloroethylclonidine (Dreferential for alpha (1B)). 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 pA(2) value of 9.18, consistent with the presence of alpha (1)-adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5-Methyl-urapidil competitively antagonized responses to noradrenaline with a pK(B) value of 8.48 and a Schild slope of 0.99, consistent with the presence of alpha (1A)-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 muM chloroethylclonidine suggesting the absence of alpha (1B)-adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 muM chloroethylclonidine, suggesting an effect of chloroethylcionidine at alpha (1A)-adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 muM) poorly shifted the potency of noradrenaline giving a pA(2) of 6.52. These results rule out the presence of the alu-subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the alpha (1A)-adrenoceptor subtype with a minor population of an unknown alpha (1)-adrenoceptor subtype.