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

Brian Fouty, Padmini Komalavilas, Masashi Muramatsu, Alan Cohen, Ivan F. McMurtry, Thomas M. Lincoln, David M. Rodman

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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)
Pages (from-to)H672-H678
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number2 43-2
StatePublished - Feb 1998
Externally publishedYes


  • Hypoxic pulmonary vasoconstriction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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