α 1 ‐Adrenoceptor subtypes involved in vasoconstrictor responses to exogenous and neurally released noradrenaline in rat femoral resistance arteries

The α 1 ‐adrenoceptor subtypes involved in responses to exogenous and neurally released noradrenaline in rat femoral resistance arteries were characterised using a small vessel myograph, with antagonists prazosin (nonsubtype selective), 5‐methyl‐urapidil ( α 1A ‐selective), BMY 7378 ( α 1D ‐selective) and the alkylating agent chloroethylclonidine (preferential for α 1B ‐). Prazosin and 5‐methyl‐urapidil produced rightward shifts of the exogenous noradrenaline concentration – response curve (CRC) with p A 2 values of 9.2 and 9.1 respectively, in agreement with the presence of α 1A ‐adrenoceptors. BMY 7378 (1 μ M ) shifted the noradrenaline CRC with an apparent p K B of 6.7, in agreement with the presence of α 1A ‐, but not α 1D ‐, adrenoceptors. Chloroethylclonidine at 1 μ M had no effect and at 10 μ M produced only a small reduction (c. 20%) in the maximum response to noradrenaline, indicating little, if any, contribution from α 1B ‐adrenoceptors. Responses of the rat femoral resistance arteries to electrical field stimulation (EFS) at 5–30 Hz for 10 s and 0.05 ms pulse width were principally due to α 1 ‐adrenoceptor stimulation. Prazosin and 5‐methyl‐urapidil inhibited EFS‐mediated responses with pIC 50 s of 9.3 and 8.2, respectively, consistent with the α 1A ‐adrenoceptor being the predominant subtype. Responses to EFS at 10–30 Hz were relatively insensitive to BMY 7378 (pIC 50 , 6.5–6.7), while responses to 5 Hz were inhibited with a significantly higher pIC 50 of 8.02, suggesting the contribution of α 1D ‐adrenoceptors. Chloroethylclonidine had no effect on responses to EFS, ruling out the contribution of an α 1B ‐subtype. In the presence of cocaine, the predominant subtype involved in responses to EFS was the α 1A ‐adrenoceptor, with a contribution from α 1D ‐adrenoceptors at low frequency, as seen in the absence of cocaine. However, there was also a significant increase in the sensitivity to BMY 7378 at higher frequencies, suggesting that a further small α 1D ‐adrenoceptor component may be uncovered in the presence of cocaine. The present study has shown a predominant role of the α 1A ‐adrenoceptor in contractions due to exogenous noradrenaline and to neurally released noradrenaline in rat femoral resistance arteries. α 1D ‐Adrenoceptors are not involved in responses to exogenous noradrenaline but appear to be activated by neurally released noradrenaline at a low frequency of stimulation and at higher frequencies in the presence of neuronal‐uptake blockade.British Journal of Pharmacology (2004) 141 , 915–924. doi: 10.1038/sj.bjp.0705690