Arterial baroreflex impairment and functional plasticity of cardiac autonomic neurons in rat models of liver cirrhosis

      Cardiovascular autonomic dysfunction, as manifested by impairment of arterial baroreflex, is prevalent irrespective of etiology and contributes to the elevated morbidity and mortality in cirrhotic patients. However, the cellular mechanisms underlying cirrhosis-impaired arterial baroreflex currently remain unknown. In the present study, we examined whether cirrhosis-impaired arterial baroreflex is attributable to functional plasticity of cardiac autonomic neurons. In this regard, biliary and nonbiliary cirrhotic rats were produced by common bile duct ligation (CBDL) and intraperitoneal injections of thioacetamide (TAA), respectively. Histological and molecular biological examinations confirmed the development of fibrosis in the livers of both cirrhotic rat models. As assessed by measuring the heart rate changes during phenylephrine-induced baroreceptor activation, the baroreflex sensitivity was blunted in CBDL and TAA rats. Using the gramicidin-perforated patch-clamp technique, the action potential (AP) generated by current injection was recorded in the stellate ganglion (STG) and intracardiac ganglion (ICG) neurons from sham control and cirrhotic rats. As results, the AP frequency was significantly increased and decreased in the STG neurons and the ICG neurons of cirrhotic rats, respectively compared with sham control. Consistent with these findings, the rheobase and AP duration were altered in the opposite direction in both types of neurons. Molecular biological examination and voltage-clamp recording revealed that A- and M-type potassium channels were down-regulated in the STG neurons, while M-type potassium and N-type calcium channels were up-regulated in ICG neurons of cirrhotic rats. Therefore, liver cirrhosis-impaired baroreflex may arise from functional plasticity of the cardiac sympathetic and parasympathetic neurons in the reflex arc. This research was supported by Basic Science research Program through the National Research Foundation (NRF) funded by the Ministry of Education, Science and Technology (2013R1A1A2013424).
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