Interactions of adenosine, prostaglandins and nitric oxide in hypoxia‐induced vasodilatation: in vivo and in vitro studies

Abstract

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 ~50 % by the A 1 antagonist DPCPX, the remainder being attenuated by the A 2A antagonist ZM241385. Diclofenac reduced adenosine-evoked NO release bỹ 50 % 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 1a , 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 may be important in other situations involving these autocoids.

Adenosine Contributes to Blood Flow Regulation in the Exercising Human Leg by Increasing Prostaglandin and Nitric Oxide Formation

“…Consistent with this observation, an in vitro study clearly demonstrated that prostaglandin inhibition reduced NO formation in response to adenosine stimulation. 14 This observation, which suggests that prostaglandins promote NO synthesis, is also supported by the greater reduction in vascular conductance with inhibition of prostaglandins compared with inhibition of NOS. Therefore, the present findings suggest that the vasodilator response to adenosine, to a large extent, is mediated by prostaglandins and NO and that part of the increased NO formation could be prostaglandin mediated ( Figure 5).…”

“…10 -13 Furthermore, in vitro data have suggested that prostaglandins could be involved as a second messenger of adenosine by stimulating NO production. 14 Single inhibition of NO 15,16 or prostaglandin [17][18][19] formation has little or no effect on exercising limb blood flow, but simultaneous inhibition of NO and prostaglandin formation lowers blood flow to exercising limbs by Ϸ30%, 19,20 suggesting that there is an interaction between the prostaglandin and NO systems. It remains unknown whether adenosine contributes to blood flow regulation via direct stimulation of smooth muscle cell P1 receptors and/or by stimulation of endothelial second messengers systems, eg, prostaglandins and NO.…”

Prostaglandins do not contribute to the nitric oxide-mediated compensatory vasodilation in hypoperfused exercising muscle

“…However, available evidence in humans suggests that PGs contribute to the rise in skeletal muscle blood flow following periods of limb ischemia (2,10,14,20). Moreover, COX inhibition has been shown to attenuate muscle vasodilation evoked by systemic hypoxia in rats (25). Therefore, it is plausible that the role of PGs in the regulation of muscle blood flow during exercise under conditions of reduced oxygen availability may be enhanced.…”

“…These findings are based on little to no change in muscle blood flow following PG synthesis inhibition. However, PGs have been reported to be involved in the regulation of skeletal muscle blood flow following periods of ischemia (2,10,14,20) and during systemic hypoxia (25). Therefore, it is possible that the PGs may become a more important vasodilator signal during exercise under conditions of reduced oxygen availability.…”

“…Thus, the aim of the current study was to investigate whether PGs contribute to the compensatory vasodilation observed during acute hypoperfusion in exercising human skeletal muscle. Because there is an interaction between the PG and nitric oxide (NO) systems (17,19,25,27), a secondary aim of the study was to examine this potential interaction during exercise with hypoperfusion. We hypothesized that PGs would contribute to the compensatory vasodilator response; however, the contribution would be enhanced in the absence of NO.…”