Inhibition of KV and KCa channels antagonizes NO-induced relaxation in pulmonary artery

Jian Wang, Lewis J. Rubin, Jason Yuan

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Endogenous nitric oxide (NO) may contribute to the maintenance of normal pulmonary vasomotor tone, and inhaled NO is used to treat patients with pulmonary hypertension. Because pulmonary vascular tone is regulated by intracellular free Ca2+ concentration and membrane potential, which are controlled by the K+ channel activity in pulmonary artery (PA) smooth muscle cells, we sought to determine whether K+ channels are involved in NO-induced relaxation and, if so, which types of K+ channels are responsible. Authentic NO (∼0.3 μM) and sodium nitroprusside (SNP, 10 μM) both produced significant relaxation in isolated PA rings precontracted by increasing extracellular K+ concentration. Further elevation of the K+ concentration from 20 to 60 mM resulted in a significant increase in contraction but caused a marked decline in SNP-and NO-mediated PArelaxation. The dependence of SNP- and NO-induced relaxation on transmembrane K+ gradient suggests that K+ efflux through K+ channels is involved in these effects. Furthermore, 4-aminopyridine (4-AP, 5-10 mM), which blocks voltage-gated K+ channels (KV), and charybdotoxin (200 nM), which blocks Ca2+-activated K+ channels (KCa), both significantly inhibited NO- and SNP-induced PA relaxation. The ATP-sensitive K+ channel blocker glibenclamide, however, had no effect on the relaxation response. The blocking of guanylate cyclase diminished, but did not abolish, the NO-induced relaxation, whereas 4-AP further decreased the NO-induced relaxant response in the presence of the guanylate cyclase inhibitor LY-83583. These data suggest that activation of both KV channels and KCa channels by guanosine 3′,5′-cyclic monophosphate-dependent and -independent pathways is a mechanism, at least in part, by which NO induces PA relaxation.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume41
Issue number2
StatePublished - Feb 1997
Externally publishedYes

Fingerprint

Pulmonary Artery
Nitric Oxide
Single Nucleotide Polymorphism
Guanylate Cyclase
6-anilino-5,8-quinolinedione
Charybdotoxin
Voltage-Gated Potassium Channels
Calcium-Activated Potassium Channels
Lung
4-Aminopyridine
Guanosine
Glyburide
Nitroprusside
Pulmonary Hypertension
Membrane Potentials
Smooth Muscle Myocytes
Blood Vessels
Adenosine Triphosphate
Maintenance

Keywords

  • 4-aminopyridine
  • Calcium-activated potassium channels
  • Charybdotoxin
  • Glibenclamide
  • Guanosine 3′,5′-cyclic monophosphate
  • Nitric oxide
  • Nitroprusside
  • Voltage-gated potassium channels

ASJC Scopus subject areas

  • Physiology

Cite this

Inhibition of KV and KCa channels antagonizes NO-induced relaxation in pulmonary artery. / Wang, Jian; Rubin, Lewis J.; Yuan, Jason.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 41, No. 2, 02.1997.

Research output: Contribution to journalArticle

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abstract = "Endogenous nitric oxide (NO) may contribute to the maintenance of normal pulmonary vasomotor tone, and inhaled NO is used to treat patients with pulmonary hypertension. Because pulmonary vascular tone is regulated by intracellular free Ca2+ concentration and membrane potential, which are controlled by the K+ channel activity in pulmonary artery (PA) smooth muscle cells, we sought to determine whether K+ channels are involved in NO-induced relaxation and, if so, which types of K+ channels are responsible. Authentic NO (∼0.3 μM) and sodium nitroprusside (SNP, 10 μM) both produced significant relaxation in isolated PA rings precontracted by increasing extracellular K+ concentration. Further elevation of the K+ concentration from 20 to 60 mM resulted in a significant increase in contraction but caused a marked decline in SNP-and NO-mediated PArelaxation. The dependence of SNP- and NO-induced relaxation on transmembrane K+ gradient suggests that K+ efflux through K+ channels is involved in these effects. Furthermore, 4-aminopyridine (4-AP, 5-10 mM), which blocks voltage-gated K+ channels (KV), and charybdotoxin (200 nM), which blocks Ca2+-activated K+ channels (KCa), both significantly inhibited NO- and SNP-induced PA relaxation. The ATP-sensitive K+ channel blocker glibenclamide, however, had no effect on the relaxation response. The blocking of guanylate cyclase diminished, but did not abolish, the NO-induced relaxation, whereas 4-AP further decreased the NO-induced relaxant response in the presence of the guanylate cyclase inhibitor LY-83583. These data suggest that activation of both KV channels and KCa channels by guanosine 3′,5′-cyclic monophosphate-dependent and -independent pathways is a mechanism, at least in part, by which NO induces PA relaxation.",
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N2 - Endogenous nitric oxide (NO) may contribute to the maintenance of normal pulmonary vasomotor tone, and inhaled NO is used to treat patients with pulmonary hypertension. Because pulmonary vascular tone is regulated by intracellular free Ca2+ concentration and membrane potential, which are controlled by the K+ channel activity in pulmonary artery (PA) smooth muscle cells, we sought to determine whether K+ channels are involved in NO-induced relaxation and, if so, which types of K+ channels are responsible. Authentic NO (∼0.3 μM) and sodium nitroprusside (SNP, 10 μM) both produced significant relaxation in isolated PA rings precontracted by increasing extracellular K+ concentration. Further elevation of the K+ concentration from 20 to 60 mM resulted in a significant increase in contraction but caused a marked decline in SNP-and NO-mediated PArelaxation. The dependence of SNP- and NO-induced relaxation on transmembrane K+ gradient suggests that K+ efflux through K+ channels is involved in these effects. Furthermore, 4-aminopyridine (4-AP, 5-10 mM), which blocks voltage-gated K+ channels (KV), and charybdotoxin (200 nM), which blocks Ca2+-activated K+ channels (KCa), both significantly inhibited NO- and SNP-induced PA relaxation. The ATP-sensitive K+ channel blocker glibenclamide, however, had no effect on the relaxation response. The blocking of guanylate cyclase diminished, but did not abolish, the NO-induced relaxation, whereas 4-AP further decreased the NO-induced relaxant response in the presence of the guanylate cyclase inhibitor LY-83583. These data suggest that activation of both KV channels and KCa channels by guanosine 3′,5′-cyclic monophosphate-dependent and -independent pathways is a mechanism, at least in part, by which NO induces PA relaxation.

AB - Endogenous nitric oxide (NO) may contribute to the maintenance of normal pulmonary vasomotor tone, and inhaled NO is used to treat patients with pulmonary hypertension. Because pulmonary vascular tone is regulated by intracellular free Ca2+ concentration and membrane potential, which are controlled by the K+ channel activity in pulmonary artery (PA) smooth muscle cells, we sought to determine whether K+ channels are involved in NO-induced relaxation and, if so, which types of K+ channels are responsible. Authentic NO (∼0.3 μM) and sodium nitroprusside (SNP, 10 μM) both produced significant relaxation in isolated PA rings precontracted by increasing extracellular K+ concentration. Further elevation of the K+ concentration from 20 to 60 mM resulted in a significant increase in contraction but caused a marked decline in SNP-and NO-mediated PArelaxation. The dependence of SNP- and NO-induced relaxation on transmembrane K+ gradient suggests that K+ efflux through K+ channels is involved in these effects. Furthermore, 4-aminopyridine (4-AP, 5-10 mM), which blocks voltage-gated K+ channels (KV), and charybdotoxin (200 nM), which blocks Ca2+-activated K+ channels (KCa), both significantly inhibited NO- and SNP-induced PA relaxation. The ATP-sensitive K+ channel blocker glibenclamide, however, had no effect on the relaxation response. The blocking of guanylate cyclase diminished, but did not abolish, the NO-induced relaxation, whereas 4-AP further decreased the NO-induced relaxant response in the presence of the guanylate cyclase inhibitor LY-83583. These data suggest that activation of both KV channels and KCa channels by guanosine 3′,5′-cyclic monophosphate-dependent and -independent pathways is a mechanism, at least in part, by which NO induces PA relaxation.

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