Vasorelaxant effect of propentofylline in isolated equine digital veins.
We evaluated the vasorelaxant effect of propentofylline (PPF), a methylxanthine derivative, and its mechanism of action in equine digital veins (EDVs). Cumulative concentration-response curves to PPF (1 nM-300 µM) were recorded in phenylephrine-precontracted EDV rings under different experimental conditions. PPF-induced relaxation was partially inhibited by endothelium removal, but was unaltered by CGS-15943 (an adenosine receptor antagonist; 3 µM). PPF-induced relaxation was partially inhibited in the presence of L-NAME (a nitric oxide (NO) synthase inhibitor; 100 µM), ODQ (an inhibitor of soluble guanylyl cyclase; 30 µM) or Rp-8-Br-PET-cGMP-S (a protein kinase G inhibitor; 3 µM). It was not modified by indomethacin (a non-selective cyclooxygenase (COX) inhibitor; 10 µM), and was slightly potentiated by H-89 (a protein kinase A inhibitor; 2 µM). In endothelium-intact EDVs, PPF-induced relaxation was associated with a 2.4- and 24.1-fold increase in the tissue cGMP and cAMP content respectively. PPF (100 μM) did not shift the concentration-response curve to phenylephrine (1 nM-300 µM) but reduced the maximal effect. To investigate whether PPF can affect cAMP- and cGMP-induced relaxations, relaxation curves to forskolin (an activator of adenylate cyclase) and to sodium nitroprusside (SNP, a NO donor) were recorded in EDV rings pretreated with PPF (100 µM). PPF only slightly potentiated the forskolin-induced relaxation without affecting the SNP-induced relaxation. We demonstrated that PPF-induced relaxation in EDVs is partially endothelium-dependent. The PPF-induced relaxation partially occurred via NO release and both cAMP and cGMP generation, through COX-independent mechanisms but could also result from the inhibition of cAMP-phosphodiesterase activity for the highest concentrations.
LUNAM Université Oniris, "UPSP 5304 de physiopathologie animale et de pharmacologie fonctionnelle", Atlanpole-La Chantrerie, BP 40706, Nantes F-44307, France.
Nasr
N
Kabbesh
Marc
M
Gogny
Gérard
G
Chatagnon
Jacques
J
Noireaud
Jean-Claude
JC
Desfontis
Mohamed Yassine
MY
Mallem
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D005552:Forelimb / Q000098:blood supply*; D006736:Horses; D066298:In Vitro Techniques; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014680:Veins / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology*
D018047:Receptors, Purinergic P1; D014665:Vasodilator Agents; D014970:Xanthines; D009599:Nitroprusside; D005576:Colforsin; D010656:Phenylephrine; C032114:propentofylline; D000242:Cyclic AMP; D006152:Cyclic GMP
EDVs; Endothelium; Nitric oxide; Propentofylline; Vasorelaxation