Brouckaert, Peter

Buys, Emmanuel

Nimmegeers, Sofie

Sips, Patrick

Van de Voorde, Johan

BMC Pharmacology

Ghent University Academic Bibliography

NO-MEDIATED VASCULAR SMOOTH MUSCLE RELAXATION IN SGC1 KNOCK-OUT MICE Nimmegeers1 S., Sips2 P., Buys2 E., Brouckaert2 P., Van de Voorde1 J. 1Department of Physiology and Physiopathology 2Department of Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology, Ghent University, Ghent, 9000, Belgium Soluble guanylyl cyclase (sGC) is composed of one  and one  subunit, each existing in 2 isoforms (1/2 and 1/2). The aim of our study was to investigate the functional importance of the sGC1-subunit in several sGC-mediated vasorelaxations. Therefore, we studied blood vessels from mice lacking the sGC1 subunit. From mice of both genders, segments of the thoracic aorta and femoral artery were mounted in a small vessel myograph for isometric tension recording. Concentration-response curves were established on acetylcholine (ACh) (1 nM–10 M), sodium nitroprusside (SNP) (1 nM–10 M), NO gas (1 M–100 M), BAY 41-2272 (1 nM–10 M), and levcromakalim (Lev) (1 M–100 M) in control conditions and/or in the presence of ODQ. The relaxing influence of endogenous NO (released from the endothelium in response to ACh), exogenous NO (delivered by the NO-donor SNP and NO gas) and BAY 41-2272 (an NO-independent sGC-activator) was significantly reduced in the arteries of the sGC1 knock-out mice. However, preparations from sGC1 knock-out mice still showed a substantial relaxation in response to exogenous NO and BAY 41-2272. The sGC-inhibitor ODQ strongly diminished the remaining effect of exogenous NO. The sGC1 knock-out mice and their wild type littermates showed a similar response to the KATP-channel opener Lev, indicating that the reduced NO- and BAY 41-2272-induced responses are not aspecific. All observations were similar in both sexes. Taken together, these findings indicate that the sGC11 isoform is involved in the vasorelaxing effect of both endogenous and exogenous NO. However, the substantial relaxation response to exogenous NO still observed in the sGC1 knock-out mice suggests the contribution of the sGC21 isoform or other ODQ sensitive mechanism.The vasorelaxing effect of BAY 41-2272 in the sGC1 knock-out mice, indicates that both sGC isoforms are present in the blood vessels studied.  

NO-mediated vascular smooth muscle relaxation in sGCα1 knock-out mice

Sofie Nimmegeers

Patrick Sips

Emmanuel Buys

Peter Brouckaert

Johan Van de Voorde

Springer - Publisher Connector

BioMed Central
Page 1 of 1
(page number not for citation purposes)
BMC Pharmacology
Open AccessPoster presentation
NO-mediated vascular smooth muscle relaxation in sGCα1 
knock-out mice
Sofie Nimmegeers*1, Patrick Sips2, Emmanuel Buys2, Peter Brouckaert2 and 
Johan Van de Voorde1
Address: 1Department of Physiology and Physiopathology, Ghent University, Ghent, Belgium and 2Departement of Molecular Biomedical 
Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Ghent, Belgium
Email: Sofie Nimmegeers* - sofie.nimmegeers@UGent.be
* Corresponding author    
Background
Nitric oxide (NO) is the active metabolite responsible for
the relaxing influence of several endogenous and exoge-
nous 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 vasorelaxa-
tions 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 nitroprus-
side (SNP) (1 nM – 10 µM) and levcromakalim (Lev)(1
µM – 100 µM) in control conditions and/or in the pres-
ence of ODQ.
Results
The relaxing influences of both endogenous NO (released
from the endothelium in response to ACh) and the exog-
enous 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-acti-
vator 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 differ-
ent, indicating the specificity of the impairment of the
sGC-related responses. All observations were similar in
both sexes.
Conclusion
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.
from 2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications
Potsdam, Germany, 10–12 June, 2005
Published: 16 June 2005
BMC Pharmacology 2005, 5(Suppl 1):P41 doi:10.1186/1471-2210-5-S1-P41
<supplement> <title> <p>2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts</note> </supplement>


NO-mediated vascular smooth muscle relaxation in sGCα1 knock-out mice Sofie Nimmegeers1, Patrick Sips2, Emmanuel Buys2, Peter Brouckaert2 and Johan Van de Voorde1 1  Department of Physiology and Physiopathology, Ghent University, Ghent, Belgium 2  Departement of Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and Ghent University, Ghent, Belgium Background 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. Results 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. Conclusion 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. 

https://biblio.ugent.be/publication/1151871/file/1221646

NO-mediated vascular smooth muscle relaxation in sGCα1 knock-out mice

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