ИСТИНА

Introduction: Activation of vascular smooth muscle high conductance calcium-activated potassium (BK) channels largely mediates vasodilation during acute responses to nitric oxide (NO). In vivo, NO is often released continuously. Whether under these conditions the vasoactive effect of NO is also dominated by BK channels is unknown. Objectives: The hypothesis was tested that BK channels mediate the vasoactive effect of continuously present NO. Materials & Methods: Experiments were performed on rat tail and saphenous arteries using isometric myography, FURA-2 fluorimetry and the patch-clamp technique. Results: The α1-receptor-agonist methoxamine (MX) produced a concentration-dependent contraction. This contraction was increased considerably by the specific BK channel inhibitor iberiotoxin (IBTX), showing that it is limited by active BK channels. In the continuous presence of NO-donors (SNP, SNAP, DETA-NO) the MX-induced contraction was attenuated in a concentration-dependent manner, demonstrating their anti-contractile effect. In contrast to our hypothesis, this effect was strongly increased by IBTX. Further, in the presence of NO-donors MX-induced contractions were no longer limited by BK channels. The effects of SNP were abolished by hydroxycobalamin, a NO-scavenger; ODQ, a guanylate cyclase-inhibitor and Rp-8-Br-PET-cGMPs, a PKG-inhibitor. In addition, SNP attenuated the MX-induced increases in intracellular calcium in intact vessels without affecting calcium store content. Furthermore, SNP abolished the MXinduced stimulation of the BK current in isolated smooth muscle cells. Conclusion: Our study demonstrates that in rat arteries continuously present NO-donors exert an anti-contractile effect that is limited by deactivation of smooth muscle BK channels and involves a GC/PKG-mediated reduction of the intracellular calcium concentration.