Nitric oxide‐induced adenosine inhibition of hippocampal synaptic transmission depends on adenosine kinase inhibition and is cyclic GMP independent

Abstract

Adenosine is an important inhibitory neuromodulator that regulates neuronal excitability. Several studies have shown that nitric oxide induces release of adenosine. Here we investigated the mechanism of this release. We studied the effects of nitric oxide on evoked field excitatory postsynaptic potentials (fEPSPs) recorded in the CA1 area of rat hippocampal slices. The nitric oxide donor 1,1-diethyl-2-hydroxy-2-nitroso-hydrazine sodium (DEA/NO; 100 microm) depressed the fEPSP by 77.6 +/- 4.1%. This effect was abolished by the adenosine A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 400 nm), indicating that the nitric oxide effect was mediated by adenosine accumulation. The DEA/NO effect was unaltered by the 5'-ectonucleotidase inhibitor alpha,beta-methylene-adenosine 5'-diphosphate (AMP-CP; 100 microm), indicating that extracellular adenosine did not derive from ATP or cAMP release. The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one (ODQ; 5 microm) did not affect nitric oxide depression of the fEPSPs, indicating that nitric oxide-mediated adenosine release was not mediated through a cGMP signaling cascade. This conclusion was confirmed by the observation that 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate (8-pCPT-cGMP; 1 mm) reversibly depressed the fEPSP by 24.9 +/- 4.5%, but this effect was not blocked by adenosine antagonists. Adenosine kinase inhibitor 5-iodotubercidin (ITU; 7 microm) occluded the nitric oxide effects by 74%, suggesting that inhibition of adenosine kinase activity contributes to adenosine release. In conclusion, exogenous nitric oxide evokes adenosine release by a cGMP-independent pathway. Intracellular cGMP elevation partially inhibits the fEPSP but not through adenosine release. Although a direct block of adenosine kinase by nitric oxide can not be excluded, the depression of adenosine kinase activity may be due to inhibition by its own substrate adenosine.

Nitric oxide modulates the discharge rate of basal forebrain neurons

“…It also explains the stronger inhibitory effect of the higher concentration (1 vs. 0.5 mM) which, respectively, could lead to release of higher concentration of adenosine. Adenosine's role in inhibitory action of NO was previously observed in hippocampal slice preparations, where focal excitatory post-synaptic potentials (fEPSP) were reduced during treatment by NO donors (Broome et al 1994;Arrigoni and Rosenberg 2006b). The inhibitory effect of NO was removed by blocking A1 adenosine receptors (Arrigoni and Rosenberg 2006b).…”

“…Adenosine's role in inhibitory action of NO was previously observed in hippocampal slice preparations, where focal excitatory post-synaptic potentials (fEPSP) were reduced during treatment by NO donors (Broome et al 1994;Arrigoni and Rosenberg 2006b). The inhibitory effect of NO was removed by blocking A1 adenosine receptors (Arrigoni and Rosenberg 2006b). In the present study, we observed neurons with only partial recovery of the discharge rate after blocking of A1 adenosine receptors.…”

Modulation of cGMP accumulation by adenosine A1 receptors at the hippocampus: Influence of cGMP levels and gender

“…In addition, the adenosine A 1 receptor selective antagonist DPCPX, blocked the inhibitory effect of a NO donor and zaprinast on hippocampal synaptic transmission (Broome et al, 1994), suggesting an involvement of adenosine A 1 receptor. Later, it was shown that both NO donor and zaprinast increase the release of adenosine -an effect not mediated by cGMP -a finding explaining the adenosine A 1 receptor-dependent inhibitory action of NO donors and zaprinast on neurotransmission (Arrigoni and Rosenberg, 2006). An indirect evidence of adenosine A 1 receptor action on cGMP levels at the nervous system came from a recent study, where the inhibitory effect of peripheral adenosine A 1 receptor on inflammatory hypernociception was blocked by sGC and PKG inhibitors, suggesting a cGMP-mediated effect of the adenosine A 1 receptor (Lima et al, 2010); however a direct effect of adenosine A 1 receptor on cGMP levels was not evaluated.…”

Adenosine Kinase: Exploitation for Therapeutic Gain

“…Several studies have shown that nitric oxide (NO) induces the release of adenosine. Mechanistic studies performed on cultured neurons or hippocampal slices suggest that NO raises adenosine through inhibition of ADK (Rosenberg et al, 2000;Arrigoni and Rosenberg, 2006). However, it was not resolved whether inhibition of ADK was a direct effect of NO or an indirect effect caused by substrate inhibition.…”

“…Several studies have shown that pharmacological inhibition of ADK reduced lipopolysaccharide (LPS)-induced NO production and the induction of inducible NO synthase, most likely via an A 2 R-dependent mechanism Petrov et al, 2005). On the other hand, as discussed above, NO triggers a rise in adenosine and subsequent inhibition of ADK by substrate inhibition (Rosenberg et al, 2000;Arrigoni and Rosenberg, 2006). This interrelationship between adenosine and NO homeostasis could be a self-limiting mechanism to terminate NO-dependent signaling.…”