Functional role of the soluble guanylyl cyclase α1 subunit in vascular smooth muscle relaxation

Objective: Soluble guanylyl cyclase (sGC), the predominant receptor for nitric oxide (NO), exists in 2 active isofon-nS (alpha(2)beta(1) and alpha(1)beta(1)). In vascular tissue sGC alpha(1)beta(1), is believed to be the most important. The aim of our study was to investigate the functional importance of the sGC alpha(1)-subunit in vasorelaxation. Methods: Aortic and femoral artery segments from male and/or female sGC alpha(-/-)(1) 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 sGC alpha(1)beta(1) 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 sGC alpha(-/-)(1) mice of both genders. Moreover, the basal and SNP-stimulated cGMP levels and basal sGC activity were significantly lower in the sGC alpha(-/-)(1) mice. However, the relaxing effects of NO, BAY 41-2272 and YC-1 seen in blood vessels from sGC alpha(-/-)(1) mice indicate a role for an sGC alpha(1) 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 IH-[1,2,4]oxadiazolo[4,3-a]quinoxalin-l-one (ODQ) in the sGC alpha(-/-)(1) mice are observations suggesting that the sGC alpha(2)beta(1) isoform is also functionally active. However, the insignificant increase in cGMP in response to SNP and the non-upregulated sGC alpha(2) expression level in the sGCu alpha(-/-)(1) mice suggest rather the involvement of (an) sGC-independent mechanism(s). Conclusions: We conclude that sGCu alpha(1)beta(1) is involved in the vasorelaxation induced by NO-dependent and NO-independent sGC activators in both genders. However, the remaining relaxation seen in the sGC alpha(-/-)(1) mice suggests that besides sGC alpha(1)beta(1) also the minor isoform sGC alpha(2)beta(1) and/or (an) sGC-independent mechanism(s) play(s) a substantial role. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.