Investigation of α 1 ‐adrenoceptor subtypes mediating vasoconstriction in rabbit cutaneous resistance arteries

1 Cutaneous resistance arteries (c.r.a.) (internal diameter=240.94±5.42 μm, n =67/25 (number arteries/number animals)) from New Zealand white rabbits were mounted in wire myographs and a normalization procedure followed. 2 Cumulative concentration‐response curves (CCRCs) were constructed for the α‐adrenoceptor agonists noradrenaline (NA), (R)A61603 and phenylephrine (PE) in the presence of cocaine (3 μ M ), propranolol (1 μ M ) and corticosterone (10 μ M ). The effects of competitive α 1 ‐adrenoceptor antagonists, prazosin, WB4101, 5‐methyl‐urapidil, HV723, BMY7378 and the irreversible α 1B selective compound chloroethylclonidine (CEC) were examined versus the potency and maximum response of the c.r.a.s to noradrenaline. 3 The high potency of A‐61603 relative to PE has been shown to differentiate both functional and binding site α 1A ‐ or α 1B ‐adrenoceptors from α 1D ‐adrenoceptors: A‐61603 was 944 times more potent than phenylephrine (at EC 50 ) suggesting the presence of a functional α 1A or α 1B as opposed to an α 1D ‐subtype. 4 Exposure to chloroethylclonidine (CEC; 100 μ M ) decreased the maximum response to noradrenaline but did not significantly change noradrenaline sensitivity indicating that a substantial part of noradrenaline‐induced vasoconstriction in rabbit cutaneous arteries is CEC‐insensitive. 5 The potencies of prazosin (pA 2 =9.14) and WB4101 (pA 2 =9.30) indicate the involvement of prazosin‐sensitive functional α 1 ‐adrenoceptors. The slopes of corresponding Schild plots for prazosin and WB4101 did not include negative unity which implies the possible involvement of more than one functional α 1 ‐adrenoceptor subtype in noradrenaline‐induced vasoconstriction in rabbit cutaneous resistance arteries. In contrast to this, in the case of 5‐methyl‐urapidil and HV723, the Schild plot slope parameters were not significantly different from negative unity over the range of concentrations used; the low pA 2 value for 5‐methylurapidil (7.27) suggests the non‐involvement of an α 1A ‐ or an α 1D ‐adrenoceptor; the low pA 2 value for HV723 (8.47) was similar to that against responses postulated as α 1L . 6 We conclude that rabbit cutaneous resistance arteries express a prazosin‐sensitive functional α 1 ‐adrenoceptor resembling the α 1B and another low affinity site for prazosin which on the basis of the functional antagonism produced by HV723 most closely resembles the α 1L ‐adrenoceptor; the low pA2 value for HV723 (8.47) is similar to that against responses postulated as α 1L .British Journal of Pharmacology (1997) 122 , 825–832; doi: 10.1038/sj.bjp.0701451