Clonidine-induced tension changes in guinea pig thoracic aorta: roles of α1L-adrenoceptors, L-type voltage-dependent Ca2+ channels, and K+ channels

We pharmacologically analyzed clonidine-induced tension changes in endothelium-denuded guinea pig thoracic aorta (GP-TA). Clonidine alone produced little change in basal tension; however, in the presence of tetraethylammonium (TEA) or Ba²⁺, it elicited a pronounced contraction that was almost completely abolished by verapamil. In contrast, phenylephrine alone evoked a robust contraction, which was also further enhanced in the presence of Ba²⁺; this Ba²⁺-potentiated component was nearly abolished by verapamil. The Ba²⁺-enhanced clonidine-evoked contraction was insensitive to the α₂-adrenoceptor (AR) antagonist idazoxan but was competitively inhibited by the α₁-AR antagonists prazosin and tamsulosin, yielding pA₂ values of 8.26 and 9.92, respectively. Clonidine competitively inhibited phenylephrine-induced contraction, with a pA₂ value of 5.67 in the presence of verapamil. Moreover, clonidine suppressed the sustained component of the phenylephrine response; this inhibition was attenuated by Ba²⁺ but remained unchanged in the presence of verapamil. These findings indicate that, in GP-TA, clonidine acts as a biased and partial agonist primarily at α_1L-ARs, promoting Ca²⁺ influx through L-type voltage-dependent Ca²⁺ channels (VDCCs). These L-type VDCC-mediated responses are negatively regulated by Ba²⁺-sensitive K⁺ channels. In addition, clonidine itself appears to directly or indirectly activate Ba²⁺-sensitive K⁺ channels, thereby suppressing the α_1L-AR-L-type VDCC functional coupling.