Article date: July 1994
By: Sylvin Ouedraogo, Martin Tschöpl, Jean‐Claude Stoclet, Bernard Bucher, in Volume 112, Issue 3, pages 867-872
The effects of membrane permeable analogues of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP), and of the NO donor, 3‐morpholinosydnonimine‐N‐ethylcarbamide (SIN‐1) were investigated on [3H]‐noradrenaline release and neurogenic vasoconstriction in electrical field stimulated rat tail arteries.
Two 8‐substituted analogues of cyclic GMP (8‐bromoguanosine 3′:5′‐cyclic monophosphate; 8‐bromo‐cyclic GMP and 8‐(4‐chlorophenylthio)‐guanosine 3′:5′‐cyclic monophosphate; 8‐pCPT‐cyclic GMP) concentration‐dependently enhanced stimulation‐induced [3H]‐noradrenaline release. These prejunctional effects were antagonized by the cyclic AMP‐dependent protein kinase (PKA) inhibitor N‐[2‐((3‐(4‐bromophenyl)‐2‐propenyl)‐amino)‐ethyl]‐5 isoquinolinesulphonamide dihydrochloride (H‐89; 100 nm) but not by the cyclic GMP‐dependent protein kinase (PKG) inhibitors, Rp‐8‐bromoguanosine 3′:5′‐cyclic monophosphorothioate (Rp‐8‐bromo‐cyclic GMPS; 10 μm) or Rp‐8‐(4‐chlorophenylthio)‐guanosine 3′:5′‐cyclic monophosphorothioate (Rp‐8‐pCPT‐cyclic GMPS; 10 μm).
β‐Phenyl‐1,N2‐ethenoguanosine 3′:5′‐cyclic monophosphate (PET‐cyclic GMP) had no effect on stimulation‐induced [3H]‐noradrenaline release but concentration‐dependently decreased the stimulation‐induced vasoconstriction.
The two 8‐substituted cyclic GMP derivatives, PET‐cyclic GMP and SIN‐1, both decreased stimulation‐induced vasoconstriction. In addition, SIN‐1 relaxed rat tail arteries precontracted with phenylephrine (1 μm). The SIN‐1 concentration‐relaxation curve was shifted in parallel manner to the right by Rp‐8‐bromo‐cyclic GMPS (10 μm) and Rp‐8‐pCPT‐cyclic GMPS (10 μm) with no change in the maximum effect, showing that the relaxation was mediated by a cyclic GMP/PKG‐dependent mechanism.
It is concluded that PKA activation is involved in the noradrenaline release enhancing effect of the two 8‐substituted cyclic GMP analogues, whereas a cyclic GMP/PKG‐operated pathway accounts for the inhibitory effects of the cyclic GMP and its analogues on vascular smooth muscle contraction.
The effects of membrane permeable analogues of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP), and of the NO donor, 3‐morpholinosydnonimine‐N‐ethylcarbamide (SIN‐1) were investigated on [3H]‐noradrenaline release and neurogenic vasoconstriction in electrical field stimulated rat tail arteries.
Two 8‐substituted analogues of cyclic GMP (8‐bromoguanosine 3′:5′‐cyclic monophosphate; 8‐bromo‐cyclic GMP and 8‐(4‐chlorophenylthio)‐guanosine 3′:5′‐cyclic monophosphate; 8‐pCPT‐cyclic GMP) concentration‐dependently enhanced stimulation‐induced [3H]‐noradrenaline release. These prejunctional effects were antagonized by the cyclic AMP‐dependent protein kinase (PKA) inhibitor N‐[2‐((3‐(4‐bromophenyl)‐2‐propenyl)‐amino)‐ethyl]‐5 isoquinolinesulphonamide dihydrochloride (H‐89; 100 nm) but not by the cyclic GMP‐dependent protein kinase (PKG) inhibitors, Rp‐8‐bromoguanosine 3′:5′‐cyclic monophosphorothioate (Rp‐8‐bromo‐cyclic GMPS; 10 μm) or Rp‐8‐(4‐chlorophenylthio)‐guanosine 3′:5′‐cyclic monophosphorothioate (Rp‐8‐pCPT‐cyclic GMPS; 10 μm).
β‐Phenyl‐1,N2‐ethenoguanosine 3′:5′‐cyclic monophosphate (PET‐cyclic GMP) had no effect on stimulation‐induced [3H]‐noradrenaline release but concentration‐dependently decreased the stimulation‐induced vasoconstriction.
The two 8‐substituted cyclic GMP derivatives, PET‐cyclic GMP and SIN‐1, both decreased stimulation‐induced vasoconstriction. In addition, SIN‐1 relaxed rat tail arteries precontracted with phenylephrine (1 μm). The SIN‐1 concentration‐relaxation curve was shifted in parallel manner to the right by Rp‐8‐bromo‐cyclic GMPS (10 μm) and Rp‐8‐pCPT‐cyclic GMPS (10 μm) with no change in the maximum effect, showing that the relaxation was mediated by a cyclic GMP/PKG‐dependent mechanism.
It is concluded that PKA activation is involved in the noradrenaline release enhancing effect of the two 8‐substituted cyclic GMP analogues, whereas a cyclic GMP/PKG‐operated pathway accounts for the inhibitory effects of the cyclic GMP and its analogues on vascular smooth muscle contraction.
DOI: 10.1111/j.1476-5381.1994.tb13160.x
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