title: Inhibition of phosphodiesterase-1 attenuates cold-induced pulmonary hypertension.
abstract: Chronic exposure to cold caused pulmonary arterial hypertension (cold-induced pulmonary hypertension [CIPH]) and increased phosphodiesterase-1C (PDE-1C) expression in pulmonary arteries (PAs) in rats. The purpose of this study is to investigate a hypothesis that inhibition of PDE-1 would decrease inflammatory infiltrates and superoxide production leading to attenuation of CIPH. Three groups of male rats were exposed to moderate cold (5±1°C) continuously, whereas 3 groups were maintained at room temperature (23.5±1°C, warm; 6 rats/group). After 8-week exposure to cold, 3 groups in each temperature condition received continuous intravenous infusion of 8-isobutyl-methylxanthine (8-IBMX) (PDE-1 inhibitor), apocynin (NADPH oxidase inhibitor) or vehicle, respectively, for 1 week. Cold exposure significantly increased right-ventricular systolic pressure compared with warm groups (33.8±3.2 versus 18.6±0.3 mm Hg), indicating that animals developed CIPH. Notably, treatment with 8-IBMX significantly attenuated the cold-induced increase in right ventricular pressure (23.5±1.8 mm Hg). Cold exposure also caused right-ventricular hypertrophy, whereas 8-IBMX reversed cold-induced right ventricular hypertrophy. Cold exposure increased PDE-1C protein expression, macrophage infiltration, NADPH oxidase activity, and superoxide production in PAs and resulted in PA remodeling. 8-IBMX abolished cold-induced upregulation of PDE-1C in PAs. Interestingly, inhibition of PDE-1 eliminated cold-induced macrophage infiltration, NADPH oxidase activation, and superoxide production in PAs and reversed PA remodeling. Inhibition of NADPH oxidase by apocynin abolished cold-induced superoxide production and attenuated CIPH and PA remodeling. In conclusion, inhibition of PDE-1 attenuated CIPH and reversed cold-induced PA remodeling by suppressing macrophage infiltration and superoxide production, suggesting that upregulation of PDE-1C expression may be involved in the pathogenesis of CIPH.
authors: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126-0901, USA.
authors: Patrick
authors: P
authors: Crosswhite
authors: Zhongjie
authors: Z
authors: Sun
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000627:therapeutic use; D000098:Acetophenones / Q000627:therapeutic use; D000818:Animals; D003080:Cold Temperature / Q000009:adverse effects*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D008171:Lung Diseases / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D013481:Superoxides; C056165:acetovanillone; D019255:NADPH Oxidases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517274:Pde1C protein, rat; D015056:1-Methyl-3-isobutylxanthine