title: Substance P receptor antagonism: a potential novel treatment option for viral-myocarditis.
abstract: Viral-myocarditis is an important cause of heart failure for which no specific treatment is available. We previously showed the neuropeptide substance P (SP) is associated with the pathogenesis of murine myocarditis caused by encephalomyocarditis virus (EMCV). The current studies determined if pharmacological inhibition of SP-signaling via its high affinity receptor, NK1R and downstream G-protein, Ras homolog gene family, member-A (RhoA), will be beneficial in viral-myocarditis. Aprepitant (1.2 mg/kg), a SP-receptor antagonist, or fasudil (10 mg/kg), a RhoA inhibitor, or saline control was administered daily to mice orally for 3 days, prior to, or 5 days following, intraperitoneal infection with and without 50 PFU of EMCV, following which disease assessment studies, including echocardiogram and cardiac Doppler were performed in day 14 after infection. Pretreatment and posttreatment with aprepitant significantly reduced mortality, heart and cardiomyocyte size, and cardiac viral RNA levels (P < 0.05 all, ANOVA). Only aprepitant pretreatment improved heart functions; it significantly decreased end systolic diameter, improved fractional shortening, and increased peak aortic flow velocity (P < 0.05 all, ANOVA). Pre- or posttreatment with fasudil did not significantly impact disease manifestations. These findings indicate that SP contributes to cardiac-remodeling and dysfunction following ECMV infection via its high affinity receptor, but not through the Rho-A pathway. These studies suggest that SP-receptor antagonism may be a novel therapeutic-option for patients with viral-myocarditis.
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Prema
authors.initials: P
authors.lastname: Robinson
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Nikita
authors.initials: N
authors.lastname: Engineer
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Mitra
authors.initials: M
authors.lastname: Khumbatta
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Bahrom
authors.initials: B
authors.lastname: Firozgary
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Reynolds
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Thuy
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Tushar
authors.initials: T
authors.lastname: Bulsara
authors.affiliation: Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Gohar
authors.initials: G
authors.lastname: Firozgary
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000188:drug therapy* / Q000503:physiopathology* / Q000821:virology; D005240:Feasibility Studies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000188:drug therapy* / Q000503:physiopathology* / Q000821:virology; D064729:Neurokinin-1 Receptor Antagonists / Q000627:therapeutic use*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1
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