Right ventricular overloading is attenuated in monocrotaline-induced pulmonary hypertension model rats with a disrupted Gpr143 gene, the gene that encodes the 3,4-l-dihydroxyphenyalanine (l-DOPA) receptor

• Published in: Journal of pharmacological sciences 2022-02, Vol.148 (2), p.214-220
• Main Authors: Nakano, Masayuki, Koga, Motokazu, Hashimoto, Tatsuo, Matsushita, Natsuki, Masukawa, Daiki, Mizuno, Yusuke, Uchimura, Hiraku, Niikura, Ryo, Miyazaki, Tomoyuki, Nakamura, Fumio, Zou, Suo, Shimizu, Takahiro, Saito, Motoaki, Tamura, Kouichi, Goto, Takahisa, Goshima, Yoshio
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Adrenergic receptor alpha1; Animals; Disease Models, Animal; GPR143; Heart Failure - etiology; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - genetics; Hypertrophy, Right Ventricular - etiology; In Vitro Techniques; l-DOPA; Male; Monocrotaline - adverse effects; Pulmonary artery; Pulmonary Artery - physiology; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1 - physiology; Receptors, G-Protein-Coupled - physiology; Receptors, Neurotransmitter - genetics; Systole; Vasoconstriction - drug effects; Vasoconstriction - genetics; Ventricular Dysfunction, Right - etiology; Ventricular Function, Right - genetics
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2021.11.008

Pulmonary hypertension (PH) is a severe and progressive disease that causes elevated right ventricular systolic pressure, right ventricular hypertrophy and ultimately right heart failure. However, the underlying pathophysiologic mechanisms are poorly understood. We previously showed that 3,4-l-dihydroxylphenyalanine (DOPA) sensitizes vasomotor response to sympathetic tone via coupling between the adrenergic receptor alpha1 (ADRA1) and a G protein-coupled receptor 143 (GPR143), a DOPA receptor. We investigated whether DOPA similarly enhances ADRA1-mediated contraction in pulmonary arteries isolated from rats, and whether GPR143 is involved in the PH pathogenesis. Pretreating the isolated pulmonary arteries with DOPA 1 μM enhanced vasoconstriction in response to phenylephrine, an ADRA1 agonist, but not to U-46619, a thromboxane A2 agonist or endothelin-1. We generated Gpr143 gene-deficient (Gpr143-/y) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response in Gpr143-/y rat pulmonary arteries. We utilized a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in the Gpr143-/y rats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed in Gpr143-/y pulmonary artery smooth muscle cells than in WT cells. Our result suggests that GPR143 is involved in the PH pathogenesis in the rat models of PH.