NO-mediated vascular smooth muscle relaxation in sGCα1 knock-out mice
© BioMed Central Ltd 2005
Published: 16 June 2005
Nitric oxide (NO) is the active metabolite responsible for the relaxing influence of several endogenous and exogenous vasodilators. The predominant intracellular receptor for NO is soluble guanylyl cyclase (sGC), that consists of an α and a β subunit, each existing in 2 isoforms (α1/α2 and β1/β2). The α1β1 isoform is most abundantly expressed and widely distributed. We investigated the functional importance of the α1-subunit in vasorelaxations induced by endogenous NO and exogenous NO-donors.
Materials and Methods
Segments of the thoracic aorta and femoral artery from female and male homozygous sGCα1-/- mice and wild type littermates were mounted in a small vessel myograph for isometric tension recording. Concentration-response curves were established with acetylcholine (ACh) (1 nM – 10 μM), BAY 41-2272 (1 nM – 10 μM), sodium nitroprusside (SNP) (1 nM – 10 μM) and levcromakalim (Lev)(1 μM – 100 μM) in control conditions and/or in the presence of ODQ.
The relaxing influences of both endogenous NO (released from the endothelium in response to ACh) and the exogenous NO-donor SNP were significantly decreased in the femoral artery and aorta from sGCα1 knock-out mice. However, the impairment of the response to ACh was more pronounced than that of SNP. In the presence of the sGC-inhibitor ODQ, the difference in ACh- and SNP-induced response between the corresponding vessels from sGCα1 knock-out- and wild type mice was significantly reduced. The response to the NO-independent sGC-activator BAY 41-2272 was also significantly diminished in blood vessels from sGCα1 knock-out mice. Relaxations in response to the KATP-channel opener Lev were not different, indicating the specificity of the impairment of the sGC-related responses. All observations were similar in both sexes.
The results indicate the involvement an sGC isoform with the α1 subunit in vascular relaxations induced by both endogenous and exogenous NO. However, the substantial relaxation remaining in sGCα1 knock-out mice suggests the contribution of (an) additional pathway(s) in NO-induced relaxations. Also BAY 41-2272 exerts its effect at least in part through activation of an sGC isoform with the α1subunit.