LAUSR

Abstract Protein kinase G (PKG) I&agr; mediates the cyclic guanosine monophosphate‐mediated vasodilatory effects induced by NO. Endothelium‐derived hyperpolarizing factors (EDHFs), like H2O2 can activate PKGI&agr; in a cyclic guanosine monophosphate‐independent manner, but whether this is true for all EDHFs (e.g., S‐nitrosothiols) is unknown. Here, we investigated the contribution of PKGI&agr; to bradykinin‐, H2O2‐, L‐S‐nitrosocysteine‐, and light‐induced relaxation in porcine coronary arteries, making use of the fact that thioredoxin reductase inhibition with auranofin or 1‐chloro‐2,4‐dinitrobenzene potentiates PKGI&agr;. Thioredoxin reductase inhibition potentiated bradykinin and H2O2, but not L‐S‐nitrosocysteine or light. The relaxations by the latter 2 and bradykinin, but not those by H2O2, were prevented by the soluble guanylyl cyclase (sGC) inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one. Yet, after S‐nitrosothiol depletion with ethacrynic acid, thioredoxin reductase inhibition also potentiated light‐induced relaxation, and this was prevented by the Na+‐K+ ATPase inhibitor ouabain. This indicates that photorelaxation depends on sGC activation by S‐nitrosothiols, while only after S‐nitrosothiol depletion oxidized PKGI&agr; comes into play, and acts via Na+‐K+ ATPase. In conclusion, both bradykinin‐ and light‐induced relaxation of porcine coronary arteries depend, at least partially, on oxidized PKGI&agr;, and this does not involve sGC. H2O2 also acts via oxidized PKGI&agr; in an sGC‐independent manner. Yet, S‐nitrosothiol‐induced relaxation is PKGI&agr;‐independent. Clearly, PKG activation does not contribute universally to all EDHF responses, and targeting PKGI&agr; may only mimick EDHF under certain conditions. It is therefore unlikely that PKGI&agr; activators will be universal vasodilators.