Role of L‐type voltage dependent calcium and large conductance potassium channels in adenosine A1 receptor mediated vasoconstriction through Cyp4a

Abstract

Adenosine A1 receptor (A1AR) induces vasoconstriction possibly via arachidonic acid‐derived metabolite, 20‐HETE by Cyp4a. 20‐ HETE is important in the regulation of vascular tone. We hypothesize that A1AR‐mediated vasoconstriction depends on Cyp4a through activation of L‐type voltage dependent calcium channels (L‐VDCC) and inhibition of large conductance potassium (BK) channels. Using WT and A1KO mouse aortae, responses for AR agonists were obtained with inhibitors of Cyp4a (HET0016, 10−5M), L‐VDCC (nifedipine, 10−6M) and BK activator (NS1619, 10−5M). Immunoblots suggest higher Cyp4a levels in WT than A1KO (p<0.05) aortae. CCPA (A1AR agonist, 10−7M) elicited contraction was significantly blunted with HET0016 (−7.9 ± 1.9% vs. −32.5 ± 1.7%, p<0.05) and nifedipine (−11.5 ± 5.9% vs. −32.5 ± 1.7%, p<0.05) in WT and with no effect in A1KO. NECA (AR agonist, 10−7M) induced relaxation was unaltered in control and NS1619 treated WT. NS1619 enhanced NECA elicited relaxation (32.4 ± 4.2% vs. −1.7 ± 4.2%, p<0.05) in A1KO. 20‐HETE (10−7M) induced contraction was higher in WT than A1KO (−33.4 ± 2.9% vs. −23.9 ± 2.4%, p<0.05) that was significantly abated by nifedipine and NS1619 in WT and A1KO. This is the first evidence suggesting that A1AR mediates vasoconstriction via 20‐ HETE by activating L‐VDCC and inhibiting BK channels which may have important implications in cardiovascular disorders. (HL027339, HL094447, HL071802)