The L-arginine-NO pathway and cyclic GMP in the vessel wall

Nitric oxide (NO) formation from L-arginine and subsequent activation of a soluble guanylate cyclase accounts for the effect of the endothelium derived relaxing factor (EDRF). Cyclic GMP produced in smooth muscle cells induces relaxation through a mechanism which involves cyclic GMP kinase, but has not yet been entirely elucidated. Experiments with specific inhibitors of the different cyclic nucleotide phosphodiesterases (PDEs) suggest that a cyclic GMP-inhibited PDE which selectively hydrolyzes cyclic AMP, called PDE III, might also be involved in the relaxing mechanism of cyclic GMP. In arteries removed from endotoxemic rats or exposed to E. coli endotoxin, an extra-endothelial production of NO or a NO-like relaxing factor is induced in smooth muscle cells. Evidence that this phenomenon may be important in endotoxin shock is provided by experiments in which vascular reactivity is restored to control level by inhibitors of NO production in endotoxemic rats. These findings show that the L-arginine-NO pathway and cyclic GMP play a major role in regulating vascular contractility in physiological and pathological conditions.