Objective Soluble guanylyl cyclase (sGC), the predominant receptor for nitric oxide (NO), exists in 2 active isoforms (α₂β₁ and α₁β₁). In vascular tissue sGCα₁β₁ is believed to be the most important. The aim of our study was to investigate the functional importance of the sGCα₁-subunit in vasorelaxation.

Methods Aortic and femoral artery segments from male and/or female sGCα₁^−/− mice and wild-type littermates were mounted in a small-vessel myograph for isometric tension recording. This was supplemented with biochemical measurements of the cGMP concentration and sGC enzyme activity.

Results The functional importance of sGCα₁β₁ was demonstrated by the significantly decreased relaxing effects of acetylcholine (ACh), sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine (SNAP), NO gas, YC-1, BAY 41-2272 and T-1032 in the sGCα₁^−/− mice of both genders. Moreover, the basal and SNP-stimulated cGMP levels and basal sGC activity were significantly lower in the sGCα₁^−/− mice. However, the relaxing effects of NO, BAY 41-2272 and YC-1 seen in blood vessels from sGCα₁^−/− mice indicate a role for an sGCα₁β₁-independent mechanism. The increase in sGC activity after addition of BAY 41-2272 and the inhibition of the ACh-, SNP-, SNAP- and NO gas-induced response by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) in the sGCα₁^−/− mice are observations suggesting that the sGCα₂β₁ isoform is also functionally active. However, the insignificant increase in cGMP in response to SNP and the non-upregulated sGCα₂ expression level in the sGCα₁^−/− mice suggest rather the involvement of (an) sGC-independent mechanism(s).

Conclusions We conclude that sGCα₁β₁ is involved in the vasorelaxation induced by NO-dependent and NO-independent sGC activators in both genders. However, the remaining relaxation seen in the sGCα₁^−/− mice suggests that besides sGCα₁β₁ also the minor isoform sGCα₂β₁ and/or (an) sGC-independent mechanism(s) play(s) a substantial role.