Large-conductance calcium-activated K+ channels, rather than KATP channels, mediate the inhibitory effects of nitric oxide on mouse lymphatic pumping

Hae Jin Kim, Min Li, Colin G. Nichols, Michael J. Davis

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background and Purpose: KATP channels are negative regulators of lymphatic vessel excitability and contractility and are proposed to be targets for immune cell products that inhibit lymph transport. Previous studies in rat and guinea pig mesenteric lymphatics found that NO-mediated inhibition of lymphatic contraction was prevented or reversed by the KATP channel inhibitor, glibenclamide. We revisited this hypothesis using mouse lymphatic vessels and KATP channel knockout mice. Experimental Approach: Mouse popliteal lymphatics were isolated, and contractility was assessed using pressure myography. K+ channel expression was determined by PCR analysis of FACS-purified lymphatic smooth muscle cells. Key Results: The NO-producing agonist, ACh, and the NO donor, NONOate, both produced dose-dependent inhibition of spontaneous lymphatic contractions that were blocked by the soluble GC inhibitor, ODQ, or the PKG inhibitor, Rp-8-Br-PET-cGMPS. Surprisingly, the inhibitory effects of both were preserved in Kir6.1−/− vessels, suggesting that KATP channels did not mediate NO-induced responses. We hypothesized a role for BK channels, given their prominence in arterial smooth muscle. Indeed, BK channels were expressed in mouse lymphatic smooth muscle and NS11021 (a BK channel activator) caused dilation and reduced contraction frequency, whereas iberiotoxin and penitrem A (BK channel inhibitors) produced right-ward shifts in NONOate concentration–response curves. Conclusion and Implications: Inhibition of mouse lymphatic contractions by NO primarily involves activation of BK channels, rather than KATP channels. Thus, BK channels are a potential target for therapeutic reversal of lymph pump inhibition by NO generated by immune cell activation of iNOS in chronic lymphoedema.

Original languageEnglish
Pages (from-to)4119-4136
Number of pages18
JournalBritish Journal of Pharmacology
Volume178
Issue number20
DOIs
StatePublished - Oct 2021

Keywords

  • ACh
  • K6.1 channels
  • NONOate
  • SUR2
  • apamin
  • iberiotoxin
  • lymphatic muscle

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