title: Tirofiban increases soluble guanylate cyclase in rat vascular walls: pharmacological and pathophysiological consequences.
abstract: OBJECTIVE
  Our aim was to evaluate whether tirofiban, which mimics the structure of arginine-glycine-aspartic acid (RGD) peptides, up-regulates soluble guanylate cyclase beta1 subunit (sGC-beta1) expression in vascular smooth muscle cells (VSMCs) and in aorta from rats, and to investigate the pharmacological and pathophysiological consequences of this up-regulation.
  
  
  RESULTS
  Wistar, Wistar Kyoto, and spontaneously hypertensive rats (SHRs) were used. sGC-beta1 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-beta1 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-beta1 content and SNP-induced cyclic guanosine monophosphate synthesis. Animals receiving IDN for 1 week showed decreased sGC-beta1 in aortic walls and did not respond to SNP treatment with changes in arterial pressure. Tirofiban restored the decreased sGC-beta1 content in IDN-treated rats and promoted a decreased arterial pressure in response to SNP administration. SHRs showed reduced sGC-beta1 levels, and tirofiban increased these levels and led to a higher response to SNP.
  
  
  CONCLUSIONS
  Tirofiban increased the sGC-beta1 content in contractile cells and aortic walls of rats, enhancing the response to SNP and reversing the NO donor tachyphylaxis.
authors.affiliation: Physiology Department, Universidad de Alcala, Campus Universitario s/n, Alcalá de Henares, 28871 Madrid, Spain. mpiedad.ruiz@uah.es
authors.forename: María P
authors.initials: MP
authors.lastname: Ruiz-Torres
authors.forename: Mercedes
authors.initials: M
authors.lastname: Griera
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Chamorro
authors.forename: María L
authors.initials: ML
authors.lastname: Díez-Marqués
authors.forename: Diego
authors.initials: D
authors.lastname: Rodríguez-Puyol
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Puyol
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013618:Tachyphylaxis; D013997:Time Factors; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D020030:Nitric Oxide Donors; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D009599:Nitroprusside; D014443:Tyrosine; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D000077466:Tirofiban; D007548:Isosorbide Dinitrate