Effects of cyclic AMP and analogues on neurogenic transmission in the rat tail artery

Abstract

1 The effects of two 8-substituted analogues of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were compared with those of forskolin and isoprenaline on [3H]-noradrenaline release and vasoconstriction induced by electrical field stimulation (24 pulses at 0.4 Hz, 200 mA, 0.3 ms duration) in the rat tail artery, in the absence and in the presence of protein kinase inhibitors.2 8-Bromo-adenosine 3':5'-cyclic monophosphate (8-bromo-cyclic AMP, 10-300 tiM), 8-(4-chlorophenylthio)-adenosine 3':5' cyclic monophosphate (8-pCPT-cycic AMP, 3-300 pM), forskolin (0.3-10 tiM) and isoprenaline (1 nM-I1LM) all concentration-dependently enhanced stimulation-induced [3H]-noradrenaline release. The effect of cyclic AMP analogues was larger (2.5 fold at 300 flM) than those of cyclic AMP elevating drugs (1.6 fold at 10 M for forskolin and 1.5 fold at 30 nM for isoprenaline). 3 At concentrations active at the prejunctional level, the four drugs had differential effects on stimulation-induced vasoconstriction, which was enhanced by the two cyclic AMP analogues, decreased by forskolin and not significantly altered by isoprenaline. By contrast they were unaffected by the cyclic GMP-dependent protein kinase (PKG) inhibitor, 8-bromo-guanosine 3':5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-bromo-cyclic GMPS; 10WM). At the same concentrations the PKA inhibitor attenuated only the nerve-induced vasoconstrictor responses obtained in the presence of 8-bromo-cyclic AMP, whereas the PKG inhibitor did not modify that obtained in the presence of 8-bromo-cycic AMP or forskolin.5 Exposure to the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (1 jM) enhanced nerve-evoked [3H]-noradrenaline release, and this effect was decreased by the PKC inhibitor, 2-[1-(3-dimethylaminopropyl)-indol-3-yl]-3-(-indol-3-yl)-maleimide (GF 109203X; 100 nM). However, the latter drug did not modify the enhancing effect of 8-bromo-cyclic AMP on [3H]-noradrenaline release. 6 It is concluded that activation of cyclic AMP-dependent protein kinase is involved in the enhancing effect of cyclic AMP-elevating compounds on prejunctional release of noradrenaline. In addition the results provide no clear-cut evidence for a vasodilator role of PKA.

Stimulatory effect of paeoniflorin on the release of noradrenaline from ileal synaptosomes of guinea-pig in-vitro

“…Moreover, Rp-cAMP, an inhibitor of adenosine 3« ,5« -monophosphate-dependent protein kinase A (Wang et al 1991), suppressed the noradrenaline-releasing action of paeoni¯orin ( Figure 4) within a concentration range eOE ective at blocking the action of cyclic AMP (Murthy et al 1995). It has been documented that cyclic AMP is involved in the release of neurotransmitter (Ouedraogo et al 1994). The results we obtained are consistent with this and show that paeoni¯orin induced a calcium-dependent and cyclic-AMP-related release of noradrenaline from noradrenergic terminals of guinea-pig ileum.…”

Inhibition of cyclic GMP‐dependent protein kinase‐mediated effects by (Rp)‐8‐bromo‐PET‐cyclic GMPS

“…The selectivity towards PKG is also confirmed in the present functional studies. Activation of PKA has been implicated in the enhancing effect of cyclic AMP-elevating compounds on prejunctional release of noradrenaline (Ouedraogo et al, 1994a) and in the present study, forskolin induced a concentration-dependent vasodilator effect on preconstricted arteries. Both effects which are assumed to operate via activation of PKA (reviewed by Beebe & Corbin, 1986) are unaffected by (Rp)-8-bromo-PET-cycic GMPS at a concentration which produced an inhibition of effects involving the cyclic GMP/ PKG-operated pathway.…”

Effects of cyclic GMP and analogues on neurogenic transmission in the rat tail artery

“…The effects of the two 8-substituted analogues of cyclic GMP on stimulation-induced noradrenaline release were inhibited by the selective PKA inhibitor H-89 (Chijiwa et al, 1990), suggesting an involvement of PKA. In the same experimental model H-89 significantly attenuates the enhancement of electrically-evoked release of [3H]-noradrenaline by forskolin, isoprenaline and 8-bromo-cyclic AMP (Ouedraogo et al, 1994). The cyclic GMP analogue PET-cyclic GMP, which had no effect on transmitter release is 10 to 20 times less potent in activating PKA than 8-bromo-cyclic GMP and 8-pCPT-cyclic GMP (Francis et al, 1988).…”