Autoregulation of nitric oxide‐soluble guanylate cyclase‐cyclic GMP signalling in mouse thoracic aorta

The sensitivity of the soluble guanylate cyclase (sGC)‐cyclic guanosine‐3′,5′‐monophosphate (cyclic GMP) system to nitric oxide (NO) was investigated in mouse aorta from wild type (WT) and NO synthase (NOS) knockout (KO) animals. The NO donor, spermine‐NONOate (SPER‐NO) was more potent in aortas from eNOS KO mice compared to WT (pEC 50 7.30±0.06 and 6.56±0.04, respectively; n =6; P <0.05). In contrast, the non‐NO based sGC activator, YC‐1 was equipotent in vessels from eNOS WT and KO mice. The sensitivity of aortas from nNOS and iNOS KO animals to SPER‐NO was unchanged. Forskolin (an adenylate cyclase activator), was equipotent in vessels from eNOS WT and KO animals. The cyclic GMP analogue, 8‐Br‐cGMP was equipotent in eNOS WT and KO mice (pEC 50 4.38±0.04 and 4.40±0.05, respectively; n =5; P >0.05). Zaprinast (10 −5   M ) a phosphodiesterase type V (PDE V) inhibitor, had no effect on the response to SPER‐NO in vessels from eNOS WT or KO mice. The NOS inhibitor N G ‐nitro‐ L ‐arginine methyl ester ( L ‐NAME; 3×10 −4   M ) increased the potency of SPER‐NO in aortas from WT mice (pEC 50 6.64±0.02 and 7.37±0.02 in the absence and presence of L ‐NAME, respectively; n =4; P <0.05). In summary, there is increased sensitivity of vessels from eNOS KO animals to NO. Cyclic AMP‐mediated dilatation is unchanged, consistent with a specific up‐regulation of sGC–cyclic GMP signalling. The functional activity of cyclic GMP‐dependent protein kinase (G‐kinase) and PDE V was also unchanged, suggesting that sGC is the site of up‐regulation. These alterations in the sensitivity of the sGC–cyclic GMP pathway might represent a mechanism for the dynamic regulation of NO bioactivity.British Journal of Pharmacology (1999) 128 , 1082–1088; doi: 10.1038/sj.bjp.0702874