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

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Abstract
1. Cutaneous resistance arteries (c.r.a.) (internal diameter=240.94+/-5.42 microm, 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 alpha-adrenoceptor agonists noradrenaline (NA), (R)A61603 and phenylephrine (PE) in the presence of cocaine (3 microM), propranolol (1 microM) and corticosterone (10 microM). The effects of competitive alpha1-adrenoceptor antagonists, prazosin, WB4101, 5-methyl-urapidil, HV723, BMY7378 and the irreversible alpha1B 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 alpha1A- or alpha1B-adrenoceptors from alpha1D-adrenoceptors: A-61603 was 944 times more potent than phenylephrine (at EC50) suggesting the presence of a functional alpha1A or alpha1B as opposed to an alpha1D-subtype. 4. Exposure to chloroethylclonidine (CEC; 100 microM) 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 alpha1-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 alpha1-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 alpha1A- or an alpha1D-adrenoceptor; the low pA2 value for HV723 (8.47) was similar to that against responses postulated as alpha1L. 6. We conclude that rabbit cutaneous resistance arteries express a prazosin-sensitive functional alpha1-adrenoceptor resembling the alpha1B and another low affinity site for prazosin which on the basis of the functional antagonism produced by HV723 most closely resembles the alpha1L-adrenoceptor; the low pA2 value for HV723 (8.47) is similar to that against responses postulated as alpha1L.