Nitric oxide (NO) stimulates Ca2+-activated K+ (KCa) channels and causes relaxation via cGMP-dependent pathways in human and rat pulmonary arteries

L. H. Deng, B. R. Crenshaw, G. M. Booth, Larissa Shimoda, Bradley J Undem, J. T. Sylvester, James Sham

Research output: Contribution to journalArticle

Abstract

NO has been shown to cause vasorelaxation in pulmonary arteries and stimulate KCa channels in rat pulmonary arterial smooth muscle cells (PASMCs). The effects of NO are thought to be mediated by production of cGMP by soluble guanylyl cyclase; however, it has recently been reported that NO can also activate KCa channels in the absence of cGMP (Bolotina et al., Nature 368:850-853, 1994). In this study, we determined whether NO activates KCa channels in human PASMCs and, if so, whether this action involves cGMP-independent mechanisms Human PASMCs were isolated from intrapulmonary arteries 6-14 mm in diameter. PASMCs were superfused with modified Tyrode's solution and whole-cell voltage-clamped. Pipette solution contained (in mM): 35 KCl, 90 K-gluconate, 10 NaCl, 5 MgATP, 0.5 GTP, 10 HEPES, 10 EGTA, 3 CaCl2, pH 7.2, free [Ca2+] ≈65 nM. Outward K+ currents were activated by depolarizing pulses from -70 mV to potentials between -50 to +60 mV. The NO-donor, 3-morpholinosydnonimine (SIN-1, 10-6 M), caused large increases in outward K currents, which were completely blocked by charybdotoxin (100 nM), suggesting that NO activated KCa channels. The effect of SIN-1 on KCa currents was completely obliterated by the selective soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxidiazolol[4,3-a]quinoxalin-1-one (ODQ, 3 μM). In rings of the same arteries preconstricted with phenylephrine, SIN-1 (10-7-10-5 M) caused concentration-dependent relaxation, which was also abolished by ODQ (3 μM). Similar results were obtained in rat pulmonary arteries. These data suggest that NO stimulates KCa channels and causes vasorelaxation in human and rat pulmonary arteries through activation of soluble guanylyl cyclase rather than a cGMP-independent pathway.

Original languageEnglish (US)
JournalFASEB Journal
Volume11
Issue number3
StatePublished - 1997

Fingerprint

Calcium-Activated Potassium Channels
pulmonary artery
Pulmonary Artery
nitric oxide
Rats
Nitric Oxide
calcium
Smooth Muscle Myocytes
Muscle
Guanylate Cyclase
rats
guanylate cyclase
smooth muscle
myocytes
Molsidomine
lungs
Lung
Cells
vasodilation
Vasodilation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Nitric oxide (NO) stimulates Ca2+-activated K+ (KCa) channels and causes relaxation via cGMP-dependent pathways in human and rat pulmonary arteries. / Deng, L. H.; Crenshaw, B. R.; Booth, G. M.; Shimoda, Larissa; Undem, Bradley J; Sylvester, J. T.; Sham, James.

In: FASEB Journal, Vol. 11, No. 3, 1997.

Research output: Contribution to journalArticle

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abstract = "NO has been shown to cause vasorelaxation in pulmonary arteries and stimulate KCa channels in rat pulmonary arterial smooth muscle cells (PASMCs). The effects of NO are thought to be mediated by production of cGMP by soluble guanylyl cyclase; however, it has recently been reported that NO can also activate KCa channels in the absence of cGMP (Bolotina et al., Nature 368:850-853, 1994). In this study, we determined whether NO activates KCa channels in human PASMCs and, if so, whether this action involves cGMP-independent mechanisms Human PASMCs were isolated from intrapulmonary arteries 6-14 mm in diameter. PASMCs were superfused with modified Tyrode's solution and whole-cell voltage-clamped. Pipette solution contained (in mM): 35 KCl, 90 K-gluconate, 10 NaCl, 5 MgATP, 0.5 GTP, 10 HEPES, 10 EGTA, 3 CaCl2, pH 7.2, free [Ca2+] ≈65 nM. Outward K+ currents were activated by depolarizing pulses from -70 mV to potentials between -50 to +60 mV. The NO-donor, 3-morpholinosydnonimine (SIN-1, 10-6 M), caused large increases in outward K currents, which were completely blocked by charybdotoxin (100 nM), suggesting that NO activated KCa channels. The effect of SIN-1 on KCa currents was completely obliterated by the selective soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxidiazolol[4,3-a]quinoxalin-1-one (ODQ, 3 μM). In rings of the same arteries preconstricted with phenylephrine, SIN-1 (10-7-10-5 M) caused concentration-dependent relaxation, which was also abolished by ODQ (3 μM). Similar results were obtained in rat pulmonary arteries. These data suggest that NO stimulates KCa channels and causes vasorelaxation in human and rat pulmonary arteries through activation of soluble guanylyl cyclase rather than a cGMP-independent pathway.",
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T1 - Nitric oxide (NO) stimulates Ca2+-activated K+ (KCa) channels and causes relaxation via cGMP-dependent pathways in human and rat pulmonary arteries

AU - Deng, L. H.

AU - Crenshaw, B. R.

AU - Booth, G. M.

AU - Shimoda, Larissa

AU - Undem, Bradley J

AU - Sylvester, J. T.

AU - Sham, James

PY - 1997

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