Protein kinase G is not essential to NO-cGMP modulation of basal tone in rat pulmonary circulation

B. Fouty, P. Komalavilas, M. Muramatsu, A. Cohen, I. F. McMurtry, T. M. Lincoln, D. M. Rodman

Research output: Contribution to journalArticle

Abstract

Nitric oxide (NO) is important in modulating increased pulmonary vascular tone. Whereas in other systems it is believed that the action of NO is mediated through guanosine 3',5'-cyclic monophosphate (cGMP) and protein kinase G (PKG), the validity of this pathway in the pulmonary circulation has not been established. Using isolated salt-perfused normotensive and hypertensive rat lungs, we studied the effects of the soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and the PKG inhibitors, KT5823, Rp-8-pCPT-cGMPS, and |N-[2-(methylamino)ethyl]-5- isoquinolinesulfonamide| (H-8), on pulmonary vascular resistance. In isolated normotensive lungs, ODQ-mediated inhibition of soluble guanylyl cyclase augmented hypoxic pulmonary vasoconstriction, whereas the PKG inhibitors had no effect. Despite the marked differences in the physiological effect, ODQ and Rp-8-pCPT-cGMPS inhibited PKG activity to a similar degree as determined by a back-phosphorylation assay showing decreased PKG-mediated phosphorylation of serine 1755 on the D-myo-inositol 1,4,5-trisphosphate receptor. In hypertensive lungs, inhibition of soluble guanylyl cyclase by ODQ increased perfusion pressure by 101 ± 20% (P <0.05), an increase similar to that seen with inhibition of NO synthase (NOS), confirming an essential role for cGMP. In contrast, KT5823, Rp-8-pCPT-cGMPS, and H-8 (used in doses 5- to 100-fold in excess of their reported inhibitory concentrations for PKG) caused only a small increase in baseline perfusion pressure (14 ± 2%, P = not significant from vehicle control). Effectiveness of PKG inhibition in the hypertensive lungs was also confirmed with the back- phosphorylation assay. These studies suggest that whereas NO-mediated modulation of vascular tone in the normotensive and hypertensive pulmonary circulation is dependent on cGMP formation, activation of PKG may not be essential.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume274
Issue number2
StatePublished - 1998
Externally publishedYes

Fingerprint

Cyclic GMP-Dependent Protein Kinases
Pulmonary Circulation
Nitric Oxide
Lung
Phosphorylation
Protein Kinase Inhibitors
Blood Vessels
Perfusion
Inositol 1,4,5-Trisphosphate Receptors
Pressure
Inositol 1,4,5-Trisphosphate
Cyclic GMP
Vasoconstriction
Nitric Oxide Synthase
Vascular Resistance
Serine
Salts

Keywords

  • Hypoxic pulmonary vasoconstriction

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Fouty, B., Komalavilas, P., Muramatsu, M., Cohen, A., McMurtry, I. F., Lincoln, T. M., & Rodman, D. M. (1998). Protein kinase G is not essential to NO-cGMP modulation of basal tone in rat pulmonary circulation. American Journal of Physiology - Heart and Circulatory Physiology, 274(2).

Protein kinase G is not essential to NO-cGMP modulation of basal tone in rat pulmonary circulation. / Fouty, B.; Komalavilas, P.; Muramatsu, M.; Cohen, A.; McMurtry, I. F.; Lincoln, T. M.; Rodman, D. M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 274, No. 2, 1998.

Research output: Contribution to journalArticle

Fouty, B, Komalavilas, P, Muramatsu, M, Cohen, A, McMurtry, IF, Lincoln, TM & Rodman, DM 1998, 'Protein kinase G is not essential to NO-cGMP modulation of basal tone in rat pulmonary circulation', American Journal of Physiology - Heart and Circulatory Physiology, vol. 274, no. 2.
Fouty, B. ; Komalavilas, P. ; Muramatsu, M. ; Cohen, A. ; McMurtry, I. F. ; Lincoln, T. M. ; Rodman, D. M. / Protein kinase G is not essential to NO-cGMP modulation of basal tone in rat pulmonary circulation. In: American Journal of Physiology - Heart and Circulatory Physiology. 1998 ; Vol. 274, No. 2.
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AU - Rodman, D. M.

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