Modulation of vascular cyclic nucleotide phosphodiesterases by cyclic GMP: role in vasodilatation.

Vascular smooth muscle contraction is modulated by an increase in cyclic guanosine monophosphate (cyclic GMP) subsequent to nitric oxide production by endothelial cells. The participation in this vasodilatation of specific cyclic adenosine monophosphate (cyclic AMP) phosphodiesterase (PDE) forms differentially sensitive to cyclic GMP is unclear. Chromatographic separation and pharmacological characterization show that the specific cyclic AMP PDE of endothelial cells is of the PDE IV subtype, known to be insensitive to cyclic GMP, whereas cyclic AMP PDEs of vascular smooth muscle are both cyclic GMP-sensitive and -insensitive (subtypes PDE III and PDE IV, respectively). The role of these PDE forms in the modulation of vascular contraction was investigated in rat aorta with and without endothelium by using specific inhibitors of PDE III and PDE IV as relaxing agents. PDE III inhibitors (milrinone, CI 930, SK&F 94120 and LY 195115) similarly relax rat aorta with and without endothelium and their potencies are not modified by NG-monomethyl-L-arginine (L-NMMA, 300 microM) or L-arginine (1 mM). However, PDE IV inhibitors (rolipram and denbufylline) only induce relaxation of aorta with endothelium, this relaxation being reversed by addition of L-NMMA and restored by addition of L-arginine. Relaxation studies performed with PDE IV inhibitors in the presence of low concentration of agents that increase cyclic AMP or cyclic GMP, clearly show that PDE IV inhibitor potencies are markedly increased by cyclic GMP elevating agents, by PDE III inhibitors and by the presence of functional endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)