Reciprocal regulation of cGMP-mediated vasorelaxation by soluble and particulate guanylate cyclases

Nitric oxide (NO) and atrial natriuretic peptides (ANP) activate soluble (s GC) and particulate guanylate cyclase (pGC), respectively, and play importa nt roles in the maintenance of cardiovascular homeostasis. However, little is known about potential interactions between these two cGMP-generating pat hways. Here we demonstrate that sGC and pGC cooperatively regulate cGMP-med iated relaxation in human and murine vascular tissue. In human vessels, the potency of spermine-NONOate (SPER-NO) and ANP was increased after inhibiti on of endogenous NO synthesis and decreased by prior exposure to glyceryl t rinitrate (GTN). Aortas from endothelial NO synthase (eNOS) knockout (KO) m ice were more sensitive to ANP than tissues from wild-type (WT) animals. Ho wever, in aortas from WT mice, the potency of ANP was increased after pretr eatment with NOS or sGC inhibitor. Vessels from eNOS KO animals were less s ensitive to ANP after GTN pretreatment, an effect that was reversed in the presence of an sGC inhibitor. cGMP production in response to SPER-NO and AN P was significantly greater in vessels from eNOS KO animals compared with W T animals. This cooperative interaction between NO and ANP may have importa nt implications for human pathophysiologies involving deficiency in either mediator and the clinical use of nitrovasodilators.