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

Abstract

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 mM) stimulation or by sodium nitroprusside (SNP; 50 ± 100 mM), 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 mM). 3 ACh and SNP-induced hyperpolarizations were inhibited (by about 90%) upon application of the ATP-sensitive K + (K ATP ) channel blocker, glibenclamide (10 mM), or with 4-aminopyridine (2.5 mM), but were not aected by the Ca 2+ -activated K + channels blocker, penitrem A (100 nM). 4 Hyperpolarization caused by the K + channel opener, cromakalim (0.1 ± 10 mM), isoprenaline (0.1 mM) or forskolin (0.5 mM) were all signi®cantly blocked by glibenclamide. 5 Hyperpolarization evoked by ACh and SNP were inhibited with N-[2-(p-bromociannamylamino)-ethyl]-5-isoquinolinesulfonamide-dichloride (H89, 10 mM), 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 badrenoceptor-mediated production of cyclic AMP. Interestingly, both pathways lead to K ATP channels opening through the activation of PKA.

The pro‐inflammatory cytokineTNF‐α inhibits lymphatic pumping via activation of theNF‐κB‐iNOSsignaling pathway

“…Previous studies have shown that sGC and K ATP channels are involved in both physiological and inflammation-induced regulation of mesenteric lymphatic pumping by NO [49,69]. Using a pharmacological approach, we confirm here that sGC and K ATP channel activity are also important elements in the chain of events leading to lymphatic pumping inhibition by TNF-α.…”

“…Using a pharmacological approach, we confirm here that sGC and K ATP channel activity are also important elements in the chain of events leading to lymphatic pumping inhibition by TNF-α. In light of previous findings [69,72], we can suggest that the opening of K ATP channels inhibits contractile activity by hyperpolarizing the lymphatic muscle. Our current finding that TNF-α treatment mainly affects lymphatic contraction frequency further corroborates an alteration of the pacemaking mechanism regulating this rhythmical activity [67,71,72].…”

Mechanisms of β-adrenergic receptor–mediated venodilation in humans

“…This contrasts to the situation in arterial vessels, where Ca ++ ‐dependent K + channels participate in isoproterenol‐induced relaxation 45 , 46 . Although ATP‐sensitive K + channels are found to participate in the vascular responses to isoproterenol at least in some species, 47 the selective ATP‐sensitive K + ‐channel blocker glyburide had no effect in this study. Thus in human hand veins in vivo these channels do not participate in isoproterenol‐induced venodilation.…”

Lymphatic Vessel Network Structure and Physiology

“…The mechanism is presumed to involve activation of soluble guanylate cyclase in the smooth muscle layer, which would accelerate cGMP production and activate protein kinase G (366, 567), as this pathway has been shown to decrease STDs in other contexts (1108, 1117, 1118). It is worth noting that in rats of advanced age (22 months old), the roles of eNOS and NO in the shear stress-induced relaxation of lymphatic vessels appears to be impaired due to chronic inflammation.…”