α1‐Adrenoceptor subtypes involved in vasoconstrictor responses to exogenous and neurally released noradrenaline in rat femoral resistance arteries

• Published in: British journal of pharmacology 2004-03, Vol.141 (6), p.915-924
• Main Authors: Zacharia, Joseph, Hillier, Chris, MacDonald, Allan
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; electrical field stimulation; Medical sciences; noradrenaline; Pharmacology. Drug treatments; rat femoral artery; resistance artery; α1A‐adrenoceptor; α1B‐adrenoceptor; α1D‐adrenoceptor; α1‐adrenoceptor subtypes; α1‐Adrenoceptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705690

The α1‐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 (α1A‐selective), BMY 7378 (α1D‐selective) and the alkylating agent chloroethylclonidine (preferential for α1B‐). Prazosin and 5‐methyl‐urapidil produced rightward shifts of the exogenous noradrenaline concentration – response curve (CRC) with pA2 values of 9.2 and 9.1 respectively, in agreement with the presence of α1A‐adrenoceptors. BMY 7378 (1 μM) shifted the noradrenaline CRC with an apparent pKB of 6.7, in agreement with the presence of α1A‐, but not α1D‐, adrenoceptors. Chloroethylclonidine at 1 μM had no effect and at 10 μM produced only a small reduction (c. 20%) in the maximum response to noradrenaline, indicating little, if any, contribution from α1B‐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 α1‐adrenoceptor stimulation. Prazosin and 5‐methyl‐urapidil inhibited EFS‐mediated responses with pIC50s of 9.3 and 8.2, respectively, consistent with the α1A‐adrenoceptor being the predominant subtype. Responses to EFS at 10–30 Hz were relatively insensitive to BMY 7378 (pIC50, 6.5–6.7), while responses to 5 Hz were inhibited with a significantly higher pIC50 of 8.02, suggesting the contribution of α1D‐adrenoceptors. Chloroethylclonidine had no effect on responses to EFS, ruling out the contribution of an α1B‐subtype. In the presence of cocaine, the predominant subtype involved in responses to EFS was the α1A‐adrenoceptor, with a contribution from α1D‐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 α1D‐adrenoceptor component may be uncovered in the presence of cocaine. The present study has shown a predominant role of the α1A‐adrenoceptor in contractions due to exogenous noradrenaline and to neurally released noradrenaline in rat femoral resistance arteries. α1D‐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) 14