@article {Dhaliwal334, author = {Jasdeep S. Dhaliwal and Adeleke M. Badejo, Jr. and David B. Casey and Subramanyam N. Murthy and Philip J. Kadowitz}, title = {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}, volume = {330}, number = {1}, pages = {334--341}, year = {2009}, doi = {10.1124/jpet.109.151449}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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-11α,9α-epoxymethanoprostaglandin F2α], hypoxia, or Nω-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.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/330/1/334}, eprint = {https://jpet.aspetjournals.org/content/330/1/334.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }