Analysis of pulmonary vasodilator responses to SB-772077-B [4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine], a novel aminofurazan-based Rho kinase inhibitor.
The effects of SB-772077-B [4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine], an aminofurazan-based Rho kinase inhibitor, on the pulmonary vascular bed and on monocrotaline-induced pulmonary hypertension were investigated in the rat. The intravenous injections of SB-772077-B decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure were enhanced when pulmonary vascular resistance was increased by U46619 [9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha)], hypoxia, or N(omega)-nitro-L-arginine methyl ester. SB-772077-B was more potent than Y-27632 [trans-4-[(1R)-1-aminoethyl]-N-4-pyridinyl-cyclohexanecarboxamide dihydrochloride] or fasudil [5-(1,4-diazepane-1-sulfonyl)isoquinoline] in decreasing pulmonary and systemic arterial pressures. The results with SB-772077-B, fasudil, and Y-27632 suggest that Rho kinase is constitutively active and is involved in the regulation of baseline tone and vasoconstrictor responses. Chronic treatment with SB-772077-B attenuated the increase in pulmonary arterial pressure induced by monocrotaline. The intravenous injection of SB-772077-B decreased pulmonary and systemic arterial pressures in rats with monocrotaline-induced pulmonary hypertension. The decreases in pulmonary arterial pressure in response to SB-772077-B in monocrotaline-treated rats were smaller than responses in U46619-infused animals, and the analysis of responses suggests that approximately 60% of the pulmonary hypertensive response is mediated by a Rho kinase-sensitive mechanism. The observation that Rho kinase inhibitors decrease pulmonary arterial pressure when pulmonary vascular resistance is increased by interventions such as hypoxia, U46619, angiotensin II, nitric-oxide synthase inhibition, and Bay K 8644 [S-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl]phenyl)-3-pyridine carboxylic acid methyl ester] suggest that the vasodilatation is independent of the mechanisms used to increase intracellular calcium and promote vasoconstriction. The present results suggest that SB-772077-B would be beneficial in the treatment of pulmonary hypertensive disorders.
Dhaliwal
Jasdeep S
JS
Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Badejo
Adeleke M
AM
Casey
David B
DB
Murthy
Subramanyam N
SN
Kadowitz
Philip J
PJ
D000818:Animals; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C516970:4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine; D007093:Imidazoles; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; D054460:rho-Associated Kinases