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 language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 274 |
| Issue number | 2 |
| State | Published - 1998 |
| Externally published | Yes |
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Keywords
- Hypoxic pulmonary vasoconstriction
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Protein kinase G is not essential to NO-cGMP modulation of basal tone in rat pulmonary circulation
AU - Fouty, B.
AU - Komalavilas, P.
AU - Muramatsu, M.
AU - Cohen, A.
AU - McMurtry, I. F.
AU - Lincoln, T. M.
AU - Rodman, D. M.
PY - 1998
Y1 - 1998
N2 - 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.
AB - 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.
KW - Hypoxic pulmonary vasoconstriction
UR - http://www.scopus.com/inward/record.url?scp=0031915824&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031915824&partnerID=8YFLogxK
M3 - Article
C2 - 9486273
AN - SCOPUS:0031915824
VL - 274
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 0363-6135
IS - 2
ER -