Nitric oxide‐sensitive guanylyl cyclase is the only nitric oxide receptor mediating platelet inhibition

See also Gordge MP. Nitric oxide: a one‐trick pony? This issue, pp 1340–2. Summary. Background: The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade is involved in the precise regulation of platelet responses. NO released from the endothelium is known to activate NO‐sensitive guanylyl cyclase (NO‐GC) in platelets. By the generation of cGMP and subsequent activation of cGMP‐dependent protein kinase (PKG), NO‐GC mediates the reduction of the intracellular calcium and inhibits platelet adhesion and aggregation. However, NO has been postulated to influence these platelet functions also via cGMP‐independent mechanisms. Objective: We studied the effect of NO on platelets lacking NO‐sensitive guanylyl cyclase with regards to aggregation, adhesion, calcium mobilization and bleeding time. Methods and results: Here, we show that NO signaling leading to inhibition of agonist‐induced platelet aggregation is totally abrogated in platelets from mice deficient in NO‐GC (GCKO). Even at millimolar concentrations none of the several different NO donors inhibited collagen‐induced aggregation of GCKO platelets. In addition, NO neither affected adenosine 5′‐diphosphate (ADP)‐induced adhesion nor thrombin‐induced calcium release in GCKO platelets. Although the NO‐induced cGMP signal transduction was totally abrogated cyclic adenosine monophosphate (cAMP) signaling was still functional; however, cGMP/cAMP crosstalk was disturbed on the level of phosphodiesterase type 3 (PDE3). These in vitro data are completed by a reduced bleeding time indicating the lack of NO effect in vivo. Conclusions: We conclude that NO‐GC is the only NO receptor in murine platelets mediating the inhibition of calcium release, adhesion and aggregation: lack of the enzyme leads to disturbance of primary hemostasis.