A xanthine‐based KMUP‐1 with cyclic GMP enhancing and K + channels opening activities in rat aortic smooth muscle

KMUP‐1 (1, 3, 5 mg kg −1 , i.v.), a xanthine derivative, produced dose‐dependent sustained hypotensive and short‐acting bradycardiac effects in anaesthetized rats. This hypotensive effect was inhibited by pretreatment with glibenclamide (5 mg kg −1 , i.v.). In endothelium‐intact or denuded aortic rings preconstricted with phenylephrine, KMUP‐1 caused a concentration‐dependent relaxation. This relaxation was reduced by endothelium removal, the presence of NOS inhibitor L ‐NAME (100 μ M ) and sGC inhibitors methylene blue (10 μ M ) and ODQ (1 μ M ). The vasorelaxant effects of KMUP‐1 was attenuated by pretreatment with various K + channel blockers TEA (10 m M ), glibenclamide (1 μ M ), 4‐AP (100 μ M ), apamin (1 μ M ) and charybdotoxin (ChTX, 0.1 μ M ). Increased extracellular potassium levels (30 – 80 m M ) caused a concentration‐related reduction of KMUP‐1‐induced vasorelaxations. Preincubation with KMUP‐1 (1, 10, 100 n M ) increased the ACh‐induced maximal vasorelaxations mediated by endogenous NO release, and enhanced the potency of exogenous NO‐donor SNP. The vasorelaxant responses of KMUP‐1 (0.01, 0.05, 0.1 μ M ) together with a PDE inhibitor IBMX (0.5 μ M ) had an additive action. Additionally, KMUP‐1 (100 μ M ) affected cyclic GMP metabolism since it inhibited the activity of PDE in human platelets. KMUP‐1 induced a dose‐related increase in intracellular cyclic GMP levels in rat A10 vascular smooth muscle (VSM) cells, but not cyclic AMP. The increase in cyclic GMP content of KMUP‐1 (0.1 – 100 μ M ) was almost completely abolished in the presence of methylene blue (10 μ M ), ODQ (10 μ M ), and L ‐NAME (100 μ M ). In conclusion, these results indicate that KMUP‐1 possesses the following merits: (1) stimulation of NO/sGC/cyclic GMP pathway and subsequent elevation of cyclic GMP, (2) K + channels opening, and (3) inhibition of PDE or cyclic GMP breakdown. Increased cyclic GMP display a prominent role in KMUP‐1‐induced VSM relaxations.British Journal of Pharmacology (2001) 134 , 265–274; doi: 10.1038/sj.bjp.0704231