Sildenafil improves the beneficial haemodynamic effects of intravenous nitrite infusion during acute pulmonary embolism.
Acute pulmonary embolism produces acute pulmonary hypertension, which can be counteracted by activating the nitric oxide-cyclic guanosine 3',5'-monophosphate (cGMP) pathway. While previous studies have shown that sildenafil (an inhibitor of cGMP-specific phosphodiesterase type 5) or nitrite (a storage molecule for nitric oxide) produces beneficial effects during acute pulmonary embolism, no previous study has examined whether the combination of these drugs can produce additive effects. Here, we expand previous findings and examine whether sildenafil enhances the beneficial haemodynamic effects produced by a low-dose infusion of nitrite in a dog model of acute pulmonary embolism. Haemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with saline (n = 4), and in embolized dogs (intravenous injections of microspheres) that received nitrite (6.75 micromol/kg intravenously over 15 min. followed by 0.28 micromol/kg/min.) and sildenafil (0.25 mg/kg over 30 min.; n = 8), or nitrite followed by saline (n = 8), or saline followed by sildenafil (n = 7), or only saline (n = 8). Plasma thiobarbituric acid-reactive substances (TBARS) concentrations were determined using a fluorometric method. Acute pulmonary embolism increased pulmonary artery pressure by approximately 24 mmHg. While the infusion of nitrite or sildenafil infusions reversed this increase by approximately 42% (both P < 0.05), the combined infusion of both drugs reversed this increase by approximately 58% (P < 0.05). Similar effects were seen on the pulmonary vascular resistance index. Nitrite or sildenafil alone produced no significant hypotension. However, the combined infusion of both drugs caused transient hypotension (P < 0.05). Both drugs, either alone or combined, blunted the increase in TBARS concentrations caused by acute pulmonary embolism (all P < 0.05). These results suggest that sildenafil improves the beneficial haemodynamic effects of nitrite during acute pulmonary embolism.
Dias-Junior
Carlos A
CA
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Montenegro
Marcelo F
MF
Florencio
Barbara C
BC
Tanus-Santos
Jose E
JE
D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000503:physiopathology / Q000517:prevention & control; D007262:Infusions, Intravenous; D008054:Lipid Peroxides / Q000097:blood; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011655:Pulmonary Embolism / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use; D012119:Respiration / Q000187:drug effects; D000068677:Sildenafil Citrate; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000627:therapeutic use*; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use*; D014655:Vascular Resistance / Q000187:drug effects
D008054:Lipid Peroxides; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D012977:Sodium Nitrite