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

1 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. 2 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 tan adenylate cyclase activator), was equipotent in vessels from eNOS WT and KO animals. 3 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. 4 The NOS inhibitor N-G-nitro-L-arginine methyl ester (r-NAME; 3 x 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. 5 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.