Regional heterogeneity in EDHF‐mediated relaxation in the rat mesenteric vascular bed: role of small‐ and intermediate conductance calcium‐activated K+ channels

Abstract

Background Calcium-activated K+-channels (KCa) are important regulators of vasomotor tone. Activation of these endothelial KCa channels result in smooth muscle hyperpolarization and relaxation. The relative contribution of the EDHF-mediated relaxation differs depending on the vessel type and size. It is unknown whether these KCa channels are differentially distributed along the same vascular bed and hence have different roles in mediating the EDHF response. We therefore assessed the role of small- (SKCa) and intermediate- (IKCa) conductance KCa channels in mediating EDHF-induced relaxations in both 4th and 1st-order side branches of the rat superior mesenteric artery (MrA). Methods and Results 2-mm segments of each MrA were mounted in the wire-myograph, incubated with L-NAME (100 μM) and indomethacin (INDO, 10 μM) and pre-contracted with phenylephrine (10 μM). Cumulative concentration-response curves to ACh (10−9–10−5 M) were performed in the absence or presence of the selective SKCa channel antagonist apamin (0.5 μM) or the selective IKCa channel antagonist TRAM-34 (10 μM). Maximal ACh-induced relaxations in the presence of both L-NAME and INDO were similar in both artery types (Emax 76±4% in 4th-order versus 75±7% in 1st-order MrA). Apamin almost completely abolished these relaxations in 4th-order MrA (Emax 2±2 %), but only partially blocked relaxations in 1st-order MrA (Emax 36±8%). TRAM-34 caused a significantly greater inhibition of the ACh-induced EDHF-mediated relaxation in 4th-order MrA compared to 1st-order MrA (Emax 26±7% versus 57±8%, respectively). Conclusion Our data demonstrate regional heterogeneity in SKCa and IKCa function, and stress the importance of KCa channels in smaller resistance-sized arteries, where the role of EDHF is more pronounced.