Dose-dependent beneficial hemodynamic effects of BAY 41-2272 in a canine model of acute pulmonary thromboembolism.
The current therapy of acute pulmonary embolism is focused on removing the mechanical obstruction of the pulmonary vessels. However, accumulating evidence suggests that pulmonary vasoconstriction drives many of the hemodynamic changes found in this condition. We examined the effects of stimulation of soluble guanylate cyclase with BAY 41-2272 (5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrim idin-4-ylamine) in an anesthetized dog model of acute pulmonary embolism. Hemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with vehicle (N=5), and in embolized dogs (intravenous injections of microspheres) that received BAY 41-2272 intravenously in doses of 0.03, 0.1, 0.3, and 1 mg/kg/h or vehicle (1 ml/kg/h of 1.13% ethanol in saline, volume/volume). Plasma cGMP and thiobarbituric acid reactive substances concentrations were determined using a commercial enzyme immunoassay and a fluorometric method, respectively. The infusion of BAY 41-2272 resulted in a decrease in pulmonary artery pressure by approximately 29%, and in pulmonary vascular resistance by approximately 46% of the respective increases induced by lung embolization (both P<0.05). While the higher doses of BAY 41-2272 produced no additional effects on the pulmonary circulation, they caused significant arterial hypotension and reduction in systemic vascular resistance (both P<0.05). Although BAY 41-2272 increased cGMP concentrations (P<0.05), it did not affect the hypoxemia and the increased oxidative stress caused by lung embolization. These results suggest that stimulation of soluble guanylate cyclase with low (but not high) doses of BAY 41-2272 produces selective pulmonary vasodilation during acute pulmonary embolism. The dose-dependent systemic effects produced by BAY 41-2272, however, may limit its usefulness in larger doses.
Cau
Stefany B A
SB
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP, 14049-900, Brazil.
Dias-Junior
Carlos A
CA
Montenegro
Marcelo F
MF
de Nucci
Gilberto
G
Antunes
Edson
E
Tanus-Santos
Jose E
JE
D000208:Acute Disease; D000818:Animals; D006152:Cyclic GMP / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006162:Guanylate Cyclase / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D008054:Lipid Peroxides / Q000097:blood; D008297:Male; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D008054:Lipid Peroxides; D011720:Pyrazoles; D011725:Pyridines; D006162:Guanylate Cyclase; D006152:Cyclic GMP