Involvement of cGMP-dependent protein kinase in the relaxation of ovine pulmonary arteries to cGMP and cAMP.
Agonist-induced smooth muscle relaxation occurs following an increase in intracellular concentrations of cGMP or cAMP. However, the role of protein kinase G (PKG) and/or protein kinase A (PKA) in cGMP- or cAMP-mediated pulmonary vasodilation is not clearly elucidated. In this study, we examined the relaxation responses of isolated pulmonary arteries of lambs (age = 10 +/- 1 days), preconstricted with endothelin-1, to increasing concentrations of 8-bromo-cGMP (8-BrcGMP) or 8-BrcAMP (cell-permeable analogs), in the presence or absence of Rp-8-beta-phenyl-1,N(2)-etheno-bromoguanosine cyclic monosphordthioate (Rp-8-PET-BrcGMPS) or KT-5720, selective inhibitors of PKG and PKA, respectively. When examined for specificity, Rp-8-Br-PET-cGMPS abolished PKG, but not PKA, activity in pulmonary arterial extracts, whereas KT-5720 inhibited PKA activity only. 8-BrcGMP-induced relaxation was inhibited by the PKG inhibitor only, whereas 8-BrcAMP-induced relaxation was inhibited by both inhibitors. A nearly fourfold higher concentration of cAMP than cGMP was required to relax arteries by 50% and to activate PKG by 50%. Our results demonstrate that relaxation of pulmonary arteries is more sensitive to cGMP than cAMP and that PKG plays an important role in both cGMP- and cAMP-mediated relaxation.
Dhanakoti
S N
SN
Department of Pediatrics, Harbor-UCLA Medical Center, School of Medicine, University of California, Los Angeles, Torrance, California 90509, USA. dhanakoti@humc.edu
Gao
Y
Y
Nguyen
M Q
MQ
Raj
J U
JU
D000818:Animals; D002227:Carbazoles; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology; D012756:Sheep; D013873:Thionucleotides / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013873:Thionucleotides; C098740:8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate; C057416:KT 5720; D000242:Cyclic AMP; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP