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, L. A. Shimoda, B. J. Undem, J. T. Sylvester, J. S.K. Sham

Research output: Contribution to journalArticlepeer-review

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)
Pages (from-to)A342
JournalFASEB Journal
Volume11
Issue number3
StatePublished - Dec 1 1997

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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