TY - JOUR
T1 - Interactions of adenosine, prostaglandins and nitric oxide in hypoxia-induced vasodilatation: in vivo and in vitro studies
AU - Ray, Clare
AU - Abbas, MR
AU - Coney, Andrew
AU - Marshall, Janice
PY - 2002/10/1
Y1 - 2002/10/1
N2 - Adenosine, prostaglandins (PG) and nitric oxide (NO) have all been implicated in hypoxia-evoked vasodilatation. We investigated whether their actions are interdependent. In anaesthetised rats, the PG synthesis inhibitors diclofenac or indomethacin reduced muscle vasodilatation evoked by systemic hypoxia or adenosine, but not that evoked by iloprost, a stable analogue of prostacyclin (PGI(2)), or by an NO donor. After diclofenac, the A(1) receptor agonist CCPA evoked no vasodilatation: we previously showed that A(1), but not A(2A), receptors mediate the hypoxia-induced muscle vasodilatation. Further, in freshly excised rat aorta, adenosine evoked a release of NO, detected with an NO-sensitive electrode, that was abolished by NO synthesis inhibition, or endothelium removal, and reduced by similar to50 % by the A(1) antagonist DPCPX, the remainder being attenuated by the A(2A) antagonist ZM241385. Diclofenac reduced adenosine-evoked NO release by similar to50 % under control conditions, abolished that evoked in the presence of ZM241385, but did not affect that evoked in the presence of DPCPX. Adenosine-evoked NO release was also abolished by the adenyl cyclase inhibitor 2',5'-dideoxyadenosine, while dose-dependent NO release was evoked by iloprost. Finally, stimulation of A(1), but not A(2A), receptors caused a release of PGI(2) from rat aorta, assessed by radioimmunoassay of its stable metabolite, 6-keto PGF(1alpha), that was abolished by diclofenac. These results suggest that during systemic hypoxia, adenosine acts on endothelial A(1) receptors to increase PG synthesis, thereby generating cAMP, which increases the synthesis and release of NO and causes muscle vasodilatation. This pathway maybe important in other situations involving these autocoids.
AB - Adenosine, prostaglandins (PG) and nitric oxide (NO) have all been implicated in hypoxia-evoked vasodilatation. We investigated whether their actions are interdependent. In anaesthetised rats, the PG synthesis inhibitors diclofenac or indomethacin reduced muscle vasodilatation evoked by systemic hypoxia or adenosine, but not that evoked by iloprost, a stable analogue of prostacyclin (PGI(2)), or by an NO donor. After diclofenac, the A(1) receptor agonist CCPA evoked no vasodilatation: we previously showed that A(1), but not A(2A), receptors mediate the hypoxia-induced muscle vasodilatation. Further, in freshly excised rat aorta, adenosine evoked a release of NO, detected with an NO-sensitive electrode, that was abolished by NO synthesis inhibition, or endothelium removal, and reduced by similar to50 % by the A(1) antagonist DPCPX, the remainder being attenuated by the A(2A) antagonist ZM241385. Diclofenac reduced adenosine-evoked NO release by similar to50 % under control conditions, abolished that evoked in the presence of ZM241385, but did not affect that evoked in the presence of DPCPX. Adenosine-evoked NO release was also abolished by the adenyl cyclase inhibitor 2',5'-dideoxyadenosine, while dose-dependent NO release was evoked by iloprost. Finally, stimulation of A(1), but not A(2A), receptors caused a release of PGI(2) from rat aorta, assessed by radioimmunoassay of its stable metabolite, 6-keto PGF(1alpha), that was abolished by diclofenac. These results suggest that during systemic hypoxia, adenosine acts on endothelial A(1) receptors to increase PG synthesis, thereby generating cAMP, which increases the synthesis and release of NO and causes muscle vasodilatation. This pathway maybe important in other situations involving these autocoids.
UR - http://www.scopus.com/inward/record.url?scp=0036794517&partnerID=8YFLogxK
U2 - 10.1113/jphysiol.2002.023440
DO - 10.1113/jphysiol.2002.023440
M3 - Article
C2 - 12356892
SN - 1469-7793
VL - 544
SP - 195
EP - 209
JO - The Journal of Physiology
JF - The Journal of Physiology
IS - 1
ER -