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

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)
Pages (from-to)H672-H678
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume274
Issue number2 43-2
DOIs
StatePublished - Feb 1998

Keywords

  • Hypoxic pulmonary vasoconstriction

ASJC Scopus subject areas

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

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