Investigation of α₁-adrenoceptor subtypes mediating vasoconstriction in rabbit cutaneous resistance arteries

Abstract

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 μM), propranolol (1 μM) and corticosterone (10 μM). The effects of competitive α₁-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 EC₅₀) suggesting the presence of a functional α_1A or α_1B as opposed to an α_1D-subtype.

4. Exposure to chloroethylclonidine (CEC; 100 μM) 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 (pA₂=9.14) and WB4101 (pA₂=9.30) indicate the involvement of prazosin-sensitive functional α₁-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 α₁-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 pA₂ value for 5-methylurapidil (7.27) suggests the non-involvement of an α_1A- or an α_1D-adrenoceptor; the low pA₂ 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 α₁-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.

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