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Acta Physiologica Congress

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Acta Physiologica 2008; Volume 192, Supplement 662
Belgian Society for Fundamental and Clinical Physiology and Pharmacology, Autumn Meeting 2007
11/17/2007-11/17/2007
Katholieke Universiteit Leuven, Leuven, Belgium


VASCULAR SMOOTH MUSCLE RELAXATION IN SOLUBLE GUANYLYL CYCLASE 1 HIS 105 PHE MUTANT MICE
Abstract number: P-20

Nimmegeers1 S., Decaluwe1 K., Thoonen2 R., Brouckaert 2 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

The binding of nitric oxide (NO) on the heme group of soluble guanylyl cyclase (sGC) is known to induce important changes within the cardiovascular system such as smooth muscle relaxation, thereby controlling blood pressure and blood flow. The sGCa1b1 and sGCa2b1 heterodimer are reported to be physiologically active, in which the b1 subunit acts as dimerizing partner for both a subunits. As the histidine (His) residue at position 105 of the b1 subunit functions as axial ligand for the heme prosthetic group, substitution of His by phenylalanine (Phe) will abolish the heme-dependent activation of sGC. This is the case in the sGCb1ki/kimice from which aortic and femoral artery segments were isolated and mounted on a small vessel myograph for isometric tension recording. In comparison with the preparations isolated from the wild type littermates, the response to endogenous NO (released from the endothelium in response to acetylcholine (ACh)) and exogenous NO (from the NO-donor sodium nitroprusside (SNP)) were practically completely abolished in the preparations from the sGCb1ki/kimice. This confirms the exclusive functional importance of sGC as receptor for NO. The response to the NO-independent sGC-activator (BAY 41-2272) was also significantly reduced in the sGCb1ki/kimice, indicating that the heme group plays a role in the BAY 41-2272-induced activation of sGC. In conclusion, the completely attenuated NO-induced response in the sGCb1ki/kimice, demonstrates the importance of sGC as the sole target for NO in regulating vasodilatation. Furthermore, the remaining relaxing effect of BAY 41-2272 in the sGCb1ki/kimice, suggests that the heme-binding pocket is very important but not indispensable for the interaction of BAY 41-2272 with sGC.

To cite this abstract, please use the following information:
Acta Physiologica 2008; Volume 192, Supplement 662 :P-20

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