Dissecting the Roles of the Autonomic Nervous System and Physical Activity on Circadian Heart Rate Fluctuations in Mice

Heart rate (HR) and blood pressure as well as adverse cardiovascular events show clear circadian patterns, which are linked to interdependent daily variations in physical activity and cardiac autonomic nerve system (ANS) activity. We set out to assess the relative contributions of the ANS (alone) and physical activity to circadian HR fluctuations. To do so, we measured HR (beats per minute, bpm) in mice that were either immobilized using isoflurane anesthesia or free-moving. Nonlinear fits of HR data to sine functions revealed that anesthetized mice display brisk circadian HR fluctuations with amplitudes of 47.1±7.4bpm with the highest HRs in middle of the dark (active) period (ZT 18: 589±46bpm) and lowest HRs in the middle of the light (rest) period (ZT 6: 497±54bpm). The circadian HR fluctuations were reduced by ~70% following blockade of cardiac parasympathetic nervous activity (PNA) with atropine while declining by <15% following cardiac sympathetic nerve activity (SNA) blockade with propranolol. Small HR fluctuation amplitudes (11.6±5.9bpm) remained after complete cardiac ANS blockade. Remarkably, circadian HR fluctuation amplitudes in freely moving, telemetrized mice were only ~32% larger than in anesthetized mice. However, after gaining access to running wheels for 1week, circadian HR fluctuations increase to 102.9±12.1bpm and this is linked directly to increased O2 consumption during running. We conclude that, independent of physical activity, the ANS is a major determinant of circadian HR variations with PNA playing a dominant role compared to SNA. The effects of physical activity to the daily HR variations are remarkably small unless mice get access to running wheels.

Nerve-Sparing Radical Hysterectomy: Kobayashi's Method

After Prof. S. Okabayashi introduced Okabayashi Operation in 1921, several surgeons introduced numerous improvements in Japan. One of them is so-called the Tokyo Method which was improved and revised by Dr. Kyusaku Ogino (1950), Prof. Takashi Kobayashi, University of Tokyo (1961, 1970), and Prof. Shoichi Sakamoto, University of Tokyo (1981). The nerve-sparing radical hysterectomy without sacrificing radicality was introduced in 19611 and improved in 1970 by Prof. Kobayashi.2 The autonomic nerve pathway including hypogastric nerve (sympathetic nerve), pelvic splanchnic nerve (parasympathetic nerve), and pelvic nerve plexus as a junction of the two nerves and the branch of the plexus to the bladder (vesical nerve branch) are preserved except in advanced cases. He divided the process of nerve-sparing surgery into four steps for separating the autonomic nerve pathway from adjacent tissues along the pathway consisting of cardinal, sacrouterine, rectouterine/vaginal, and vesicouterine ligaments. The first step is separation of the cardinal ligament (deep uterine vessels) from the pelvic splanchnic nerve. The second step is separation of the medial side of severed cardinal ligament from the pelvic nerve plexus. The first and second steps are performed in the lateral side of the autonomic nerve system. The third step is separation of sacrouterine and rectouterine/vaginal ligaments from hypogastric nerve and pelvic nerve plexus. The third step is necessary for achieving high radicality, namely, for severing the sacrouterine and rectouterine/vaginal ligaments near the rectum without damage to the pelvic nerve plexus. The fourth step is separation of paravaginal tissues and posterior (deep) layer of the vesicouterine ligament from the vesical nerve branches of the plexus. The third and fourth steps are performed in the medial side of the autonomic nerve system.

Regulation of the Autonomic Nervous System on Intestine

Intestine is composed of various types of cells including absorptive epithelial cells, goblet cells, endocrine cells, Paneth cells, immunological cells, and so on, which play digestion, absorption, neuroendocrine, immunological function. Intestine is innervated with extrinsic autonomic nerves and intrinsic enteric nerves. The neurotransmitters and counterpart receptors are widely distributed in the different intestinal cells. Intestinal autonomic nerve system includes sympathetic and parasympathetic nervous systems, which regulate cellular proliferation and function in intestine under physiological and pathophysiological conditions. Presently, distribution and functional characteristics of autonomic nervous system in intestine were reviewed. How autonomic nervous system regulates intestinal cell proliferation was discussed. Function of autonomic nervous system on intestinal diseases was extensively reviewed. It might be helpful to properly manipulate autonomic nervous system during treating different intestinal diseases.

Eplerenone inhibites atrial autonomic nerve remodeling via the ERK1/2 MAPK pathway in a rabbit model of atrial fibrillation

Aims:Aldosterone is closely associated with atrial fibrillation, and mineralocorticoid receptor antagonists (MRAs) have been proved to be effective in preventing atrial structural remodeling. Atrial autonomic nerve system (ANS) plays an important role in atrial fibrillation (AF). However, the effects of MRAs on ANS remodeling in AF and the underlying mechanisms are still unknown.Main methods:Twenty-one rabbits were randomized into sham, pacing(P), and pacing + eplerenone(P + E) groups. HL-1 cells were subject to control treatment or rapid pacing with or without eplerenone or U0126 (an inhibitor of ERK1/2). Atrial sympathetic and parasympathetic remodeling was detected by immunohistohistochemical analysis, western blotting and reverse transcription-polymerase chain reaction. Circulating neurohormone levels and atrial electrophysiology were also assessed.Key findings:The ERK1/2 MAPK pathway was significantly activated in AF rabbit/HL-1 cell models, resulting in the upregulation of key downstream proteins; this effect was significantly restored by eplerenone(P<0.05). Eplerenone also prevented the changes in circulating neurohormone levels, reduced the mRNA levels of sympathetic- and parasympathetic-related growth factors, and inhibited the inducibility and duration of AF.Significance:Eplerenone inhibited atrial autonomic nerve remodeling and the occurrence of AF by modulating the ERK1/2 MAPK pathway.

A Concise Paradigm on Radical Hysterectomy: The Comprehensive Anatomy of Parametrium, Paracolpium and the Pelvic Autonomic Nerve System and Its Surgical Implication

The current understanding of radical hysterectomy is more centered on the uterus and little is discussed regarding the resection of the vaginal cuff and the paracolpium as an essential part of this procedure. The anatomic dissections of two fresh and 17 formalin-fixed female pelvis cadavers were utilized to understand and decipher the anatomy of the pelvic autonomic nerve system (PANS) and its connections to the surrounding anatomical structures, especially the paracolpium. The study mandates the recognition of the three-dimensional (3D) anatomic template of the parametrium and paracolpium and provides herewith an enhanced scope during a nerve-sparing radical hysterectomy procedure by precise description of the paracolpium and its close anatomical relationships to the components of the PANS. This enables the medical fraternity to distinguish between direct infiltration of the paracolpium, where the nerve sparing technique is no longer possible, and the affected lymph node in the paracolpium, where nerve sparing is still an option. This study gives rise to a tailored surgical option that allows for abandoning the resection of the paracolpium by FIGO stage IB1, where less than 2 cm vaginal vault resection is demanded.