title: Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure.
abstract: The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor-expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 μg/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-β receptor I in CHF rats. Pressure-volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF.
authors: From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
authors: Han-Jun
authors: HJ
authors: Wang
authors: From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
authors: Wei
authors: W
authors: Wang
authors: From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
authors: Kurtis G
authors: KG
authors: Cornish
authors: From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.
authors: George J
authors: GJ
authors: Rozanski
authors: From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha. izucker@unmc.edu.
authors: Irving H
authors: IH
authors: Zucker
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000344:Afferent Pathways / Q000378:metabolism / Q000601:surgery; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006332:Cardiomegaly / Q000503:physiopathology / Q000517:prevention & control; D002319:Cardiovascular System / Q000294:innervation / Q000503:physiopathology*; D002908:Chronic Disease; D004224:Diterpenes / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000294:innervation / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000503:physiopathology* / Q000601:surgery; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D004224:Diterpenes; D011943:Receptors, Adrenergic, beta; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C024353:resiniferatoxin; D007545:Isoproterenol
keywords: autonomic nervous system; heart failure