Effects Of A Glucagon Like Peptide-1 Agonist And Rho-Kinase Inhibitor On Pulmonary And Right Ventricle Function In Pulmonary Hypertensive Rats With And Without Insulin Resistance

Objective: Insulin resistance is now recognized as an important factor in the development of pulmonary hypertension (PH). Increased activation of RhoA/Rho-kinase (ROCK) inhibits the protective actions of endothelial nitric oxide (NO) synthase (eNOS) signaling in diabetes and PH. Glucagon like peptide-1 (GLP-1) agonists were shown to reverse these pathological changes. We investigated how liraglutide (GLP-1 agonist) and fasudil (ROCK inhibitor) treatments affect the progression of pulmonary and right ventricle (RV) dysfunction in PH rats with insulin resistance. Design and method: SU5416 (20 mg/kg) was administered to male Wistar and prediabetic Goto-Kakizaki (GK) rats followed by 3 weeks of chronic hypoxia (SuHx) or normoxia exposure. Osmotic pumps delivered a continuous infusion of liraglutide (1 mg/kg/d) or fasudil (100 mg/kg/d) for the final 3 weeks in some SuHx rats. Synchrotron microangiography of the left lung was performed in vivo. Results: During chronic hypoxia 30% mortality occurred due to RV failure associated with thrombosis in GK rats. Systolic RV pressure was 74 mm Hg and 128 mm Hg in GK and Wistar SuHx rats respectively. Prediabetes exacerbated pulmonary arteriole-artery rarefaction (two-fold occlusion increase) and pulmonary vasoconstriction, with acetylcholine (ACh)-mediated constriction at 3 weeks and loss of NO donor mediated dilation at 6 weeks SuHx. Wistar SuHx maintained ACh-mediated dilation in resistance vessels despite pronounced overall vasoconstriction of all branching orders. Neither strain differed in ROCK1/2 protein expression. Notably, liraglutide and fasudil improved pulmonary vasodilation, but only liraglutide halted vascular remodeling. Fasudil increased phosphorylation of eNOS at Ser1177 in the RV of GK SuHx. Liraglutide reduced RV systolic pressure and Fulton indices, while fasudil elevated RV pressure to 104 mm Hg in the GK SuHx. Conclusions: Reduced NO bioavailability contributes to exacerbated pulmonary arterial rarefaction and depressed RV contractility associated with prediabetes in SuHx rats. GLP-1 agonist treatment did not ameliorate endothelin-1/ROCK- mediated suppression of eNOS phosphorylation in the RV as observed with fasudil. While liraglutide intervention prevented pulmonary microvessel occlusion, inhibition of both ROCK1/2 isoforms with fasudil increased occlusion formation suggesting that ROCK1 might act to inhibit pulmonary microvessel muscularization.