BAY 41-2272 inhibits the development of chronic hypoxic pulmonary hypertension in rats.
The present study investigated whether BAY 41-2272(5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine), a novel pyrazolopyridine that activates guanylyl cyclase and sensitizes the enzyme towards nitric oxide (NO), inhibits the development of pulmonary hypertension. BAY 41-2272 (1 or 10 mg/kg/day) was administered intraperitoneally, and sildenafil (25 mg/kg/day), an inhibitor phosphodiesterase type 5, was given in the drinking water to rats kept under chronic hypobaric hypoxia for two weeks. Right ventricular systolic pressure and hypertrophy, degree of muscularization and relaxation of pulmonary arteries were measured, and immunoblotting was performed. Chronic hypoxia increased right ventricular systolic pressure and expression of soluble guanylyl cyclase and phosphorylated vasodilator-stimulated phosphoprotein (VASP-P(ser239)). BAY 41-2272 prevented hypoxia-induced increase in right ventricular systolic pressure and right ventricular hypertrophy to the same extent as sildenafil. Only sildenafil significantly decreased hypoxia-induced muscularization of pulmonary arteries. Expressed relative to soluble guanylyl cyclase expression, VASP-P(ser239) was increased in lungs from rats treated with BAY 41-2272. Acutely BAY 41-2272 caused pulmonary as well as systemic vasodilatation. In the chronic setting systemic blood pressure was not different to baseline at trough after intraperitoneally administered BAY 41-2272. BAY 41-2272 vasorelaxation in isolated pulmonary resistance arteries was inhibited by an inhibitor of guanylyl cyclase, ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxaline-1-one), and of Na(+)-K(+)-ATPase, ouabain. In conclusion, in an adult rat model of chronic hypoxic pulmonary hypertension, BAY 41-2272 to a similar degree as sildenafil prevents pulmonary hypertension. Thus, BAY 41-2272 may provide a novel therapeutic compound for treating chronic hypoxic pulmonary hypertension.
Thorsen
Lise Bech
LB
Department of Pharmacology, Faculty of Health Sciences, Aarhus University, Aarhus C, Denmark.
Eskildsen-Helmond
Yvonne
Y
Zibrandtsen
Helle
H
Stasch
Johannes-Peter
JP
Simonsen
Ulf
U
Laursen
Britt Elmedal
BE
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D011687:Purines / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D011725:Pyridines / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D013450:Sulfones; D014665:Vasodilator Agents; D000098662:Vasodilator-Stimulated Phosphoprotein; D000068677:Sildenafil Citrate; D006162:Guanylate Cyclase