ATP‐sensitive K + channels in smooth muscle cells of guinea‐pig mesenteric lymphatics: role in nitric oxide and β ‐adrenoceptor agonist‐induced hyperpolarizations

1 Intracellular microelectrode recordings were performed to investigate the membrane K + conductances involved in smooth muscle hyperpolarization of lymphatic vessels in the guinea‐pig mesentery. 2 Nitric oxide (NO), released either by the endothelium after acetylcholine (ACh; 10 μ M ) stimulation or by sodium nitroprusside (SNP; 50–100 μ M ), hyperpolarized lymphatic smooth muscle. These responses were inhibited with the guanylyl cyclase inhibitor 1H‐[1,2,4]oxadiazole [4,3‐a]quinoxalin‐1‐one (ODQ, 10 μ M ). 3 ACh and SNP‐induced hyperpolarizations were inhibited (by about 90%) upon application of the ATP‐sensitive K + (K ATP ) channel blocker, glibenclamide (10 μ M ), or with 4‐aminopyridine (2.5 m M ), but were not affected by the Ca 2+ ‐activated K + channels blocker, penitrem A (100 n M ). 4 Hyperpolarization caused by the K + channel opener, cromakalim (0.1–10 μ M ), isoprenaline (0.1 μ M ) or forskolin (0.5 μ M ) were all significantly blocked by glibenclamide. 5 Hyperpolarization evoked by ACh and SNP were inhibited with N‐[2‐(p‐bromociannamylamino)‐ethyl]‐5‐isoquinolinesulfonamide‐dichloride (H89, 10 μ M ), suggesting the involvement of cyclic AMP dependent protein kinase (PKA). 6 These results suggest that K ATP channels play a central role in lymphatic smooth muscle hyperpolarization evoked by a NO‐induced increase in cyclic GMP synthesis, as well as by β‐adrenoceptor‐mediated production of cyclic AMP. Interestingly, both pathways lead to K ATP channels opening through the activation of PKA.British Journal of Pharmacology (1998) 125 , 17–22; doi: 10.1038/sj.bjp.0702026