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Cardiovascular Research Advance Access first published online on January 6, 2009
This version [Corrected Proof] published online on January 23, 2009
Cardiovascular Research, doi:10.1093/cvr/cvn359
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Tirofiban increases soluble guanylate cyclase in rat vascular walls: pharmacological and pathophysiological consequences

María P. Ruiz-Torres1,*, Mercedes Griera1, Aránzazu Chamorro1, María L. Díez-Marqués1, Diego Rodríguez-Puyol2,3,4 and Manuel Rodríguez-Puyol1

1 Physiology Department, Universidad de Alcala, Campus Universitario s/n, Alcalá de Henares, 28871 Madrid, Spain
2 Medicine Department, Universidad de Alcala, Alcalá de Henares, Madrid, Spain
3 Research Unit, ‘Príncipe de Asturias’ Hospital, Alcalá de Henares, Madrid, Spain
4 Nephrology Section, ‘Príncipe de Asturias’ Hospital, Alcalá de Henares, Madrid, Spain

* Corresponding author. Tel: +34 91 8854519; fax: +34 91 8854590. E-mail address: mpiedad.ruiz{at}uah.es

Aims: Our aim was to evaluate whether tirofiban, which mimics the structure of arginine-glycine-aspartic acid (RGD) peptides, up-regulates soluble guanylate cyclase β1 subunit (sGC-β1) expression in vascular smooth muscle cells (VSMCs) and in aorta from rats, and to investigate the pharmacological and pathophysiological consequences of this up-regulation.

Methods and results: Wistar, Wistar Kyoto, and spontaneously hypertensive rats (SHRs) were used. sGC-β1 content was assessed by immunoblotting. Arterial pressure was recorded using a tail-cuff sphygmomanometer. Sodium nitroprusside (SNP) and isosorbide dinitrate (IDN) were used as nitric oxide (NO) donors. Tirofiban increased the sGC-β1 content in VSMCs and in aortic walls from rats after 6 h of treatment. Rats treated with tirofiban experienced a more pronounced decrease in their arterial pressure after acute SNP treatment than vehicle-treated rats. Isolated rat aortic rings incubated with tirofiban showed a higher relaxing response to SNP than control rings as well as an increased sGC-β1 content and SNP-induced cyclic guanosine monophosphate synthesis. Animals receiving IDN for 1 week showed decreased sGC-β1 in aortic walls and did not respond to SNP treatment with changes in arterial pressure. Tirofiban restored the decreased sGC-β1 content in IDN-treated rats and promoted a decreased arterial pressure in response to SNP administration. SHRs showed reduced sGC-β1 levels, and tirofiban increased these levels and led to a higher response to SNP.

Conclusion: Tirofiban increased the sGC-β1 content in contractile cells and aortic walls of rats, enhancing the response to SNP and reversing the NO donor tachyphylaxis.

KEYWORDS Nitric oxide; Nitric oxide donors; RGD motifs; Soluble guanylate cyclase; Arterial pressure; Integrin

Time for primary review: 17 days


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