Simple procedure for assessing diffuse subarachnoid hemorrhage successfully created using filament perforation method in mice.

The murine model of subarachnoid hemorrhage (SAH) is a valuable experimental tool for investigating molecular and cellular mechanisms, and the endovascular filament perforation technique can be used to simulate prominent pathophysiological features observed after human SAH; however, current validation methods for assessing an appropriate SAH model are limited. Here, we introduce a simple procedure for selecting a mouse model of diffuse SAH. SAH was induced in 24 mice using a standard filament perforation method. After confirming survival at 24 h, SAH was scored 0-1 based on T2*-weighted images on whole-brain magnetic resonance imaging (MRI) and visual surveillance of the cisterna magna (CM) through the dura mater. The CM-based SAH grading correlated well with a reference parameter defined by extracted brain (r2 = 0.53, p < 0.0001). The receiver operating characteristic curve revealed a sensitivity of 85% and a specificity of 91% for detecting diffuse SAH, with a similar area under the curve (0.89 ± 0.06 [standard error of the mean]) as the MRI-based grading (0.72 ± 0.10, p = 0.12). Our data suggest that confirming an SAH clot in the CM is a valuable way to select a clinically relevant diffuse SAH model that can be used in future experimental studies.

Ivabradine ameliorates cardiomyopathy progression in a Duchenne muscular dystrophy model rat.

Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy caused by dystrophin mutations. Inevitable progressive cardiomyopathy is a current leading cause of premature death although respiratory management has improved the prognosis of patients with DMD. Recent evidence shows that reducing the heart rate is expected as one of the promising strategies for heart failure treatment, but administering a sufficient dose of ß-blocker for patients with DMD with tachycardia is difficult because of their low blood pressure (BP). Thus, this study aimed to clarify the role of ivabradine, which suppresses cardiac sinus node pacemakers without decreasing BP, in ameliorating cardiomyopathy progression in a rat model with DMD. A trans-oral single ivabradine administration demonstrated a declined dose-dependent heart rate without any significant BP reduction. Trans-gastric repeated administrations of 5 mg/kg of ivabradine twice a day for 3 months showed ameliorated cardiomyopathy in DMD rats based on echocardiography and histopathological observations (left ventricular dysfunction, right ventricular dysfunction, and myocardial fibrosis) as compared with vehicle administration. Our finding indicates that ivabradine is expected as another treatment choice for patients with DMD having tachycardia.

Plasticity occurs in a specific phenotype of neurons in the nucleus tractus solitarius of dystrophin gene-mutated rats.

Duchenne muscular dystrophy (DMD) is a severe progressive neuromuscular disorder that causes cardiac and respiratory failure. Patients with DMD have tachycardia and autonomic nervous dysfunction at a young age, which can potentially worsen cardiorespiratory function. Therefore, we hypothesised that plasticity occurs in neurons of the cardiorespiratory brainstem nucleus (nucleus tractus solitarius [NTS]) due to DMD, thus affecting neuronal regulation because afferent information from cardiorespiratory organs changes with disease progression. Patch-clamp experiments were performed on second-order NTS neurons from Dmd-mutated (Dm) rats that showed no functional dystrophin protein expression, as confirmed by immunohistochemistry. NTS neurons are classified into two electrophysiological phenotypes: one showing a delayed onset of spiking from hyperpolarised membrane potentials, namely, delayed-onset spiking (DS)-type neurons, and the other showing a rapid onset, namely, rapid-onset spiking-type neurons. Neuroplasticity mainly occurs in DS-type neurons in Dm rats and is characterised by blunted neuronal excitability accompanied by reduced outward currents and a facilitatory effect on synaptic transmission, that is, an increased frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) without changes in the amplitude and an increased amplitude of tractus solitarius-evoked EPSCs without changes in the paired-pulse ratio. Although we cannot rule out the possibility that the neuroplastic changes observed in Dm rats were caused by dystrophin deficiency in the neurons themselves, the plasticity could be caused by cardiorespiratory deterioration and/or adaptation in DMD patients.

Mastication stimuli regulate the heartbeat rate through rhythmic regulation by the hypothalamic-autonomic system; molecular and telemetric studies in weaning-stage rats.

Mastication stimuli have been demonstrated to affect memory function and autonomic nerve activity; however, this process has not been well studied during weaning compared to old age. Previously, we conducted molecular analyses of the thalamus and hippocampus to elucidate the mechanisms underlying this memory-enhancing effect in weaning-stage rats. In this study, we aimed to evaluate the effect of masticatory stimuli on the regulation of heartbeat rate (HR) through the hypothalamic-autonomic system. Three-week-old male rats were administered a powdered diet (P group) or chow-diet (C group) for 10 days. Thereafter, transcriptome analysis was performed. Vasopressin, cocaine-amphetamine-regulated transcript prepropeptide, corticotropin-releasing hormone, and thyrotropin-releasing hormone, which are involved in sympathetic activation of heart rate, were downregulated in the C group. Electrocardiograms were recorded continuously for 12 days under the same condition. Interestingly, rats in the C group had a significantly lower HR than those in the P group on day 11. We checked several parameters representing the autonomic regulation of HR. The C group had higher values for the high-frequency band integration of the HR power spectrum (parasympathetic marker) and root mean square successive difference of R-wave intervals (parasympathetic marker) relative to the P group. Such findings provide a molecular and physiological basis for understanding the regulation of cardiovascular function in response to masticatory stimuli in the autonomic nervous system.

Acute exercise in a hot environment increases heat shock protein 70 and peroxisome proliferator-activated receptor γ coactivator 1α mRNA in Thoroughbred horse skeletal muscle.

Heat acclimatization or acclimation training in horses is practiced to reduce physiological strain and improve exercise performance in the heat, which can involve metabolic improvement in skeletal muscle. However, there is limited information concerning the acute signaling responses of equine skeletal muscle after exercise in a hot environment. The purpose of this study was to investigate the hypothesis that exercise in hot conditions induces greater changes in heat shock proteins and mitochondrial-related signaling in equine skeletal muscle compared with exercise in cool conditions. Fifteen trained Thoroughbred horses [4.6 ± 0.4 (mean ± SE) years old; 503 ± 14 kg] were assigned to perform a treadmill exercise test in cool conditions [COOL; Wet Bulb Globe Temperature (WBGT), 12.5°C; n = 8] or hot conditions (HOT; WBGT, 29.5°C; n = 7) consisting of walking at 1.7 m/s for 1 min, trotting at 4 m/s for 5 min, and cantering at 7 m/s for 2 min and at 90% of VO2max for 2 min, followed by walking at 1.7 m/s for 20 min. Heart rate during exercise and plasma lactate concentration immediately after exercise were measured. Biopsy samples were obtained from the middle gluteal muscle before and at 4 h after exercise, and relative quantitative analysis of mRNA expression using real-time RT-PCR was performed. Data were analyzed with using mixed models. There were no significant differences between the two groups in peak heart rate (COOL, 213 ± 3 bpm; HOT, 214 ± 4 bpm; p = 0.782) and plasma lactate concentration (COOL, 13.1 ± 1.4 mmoL/L; HOT, 17.5 ± 1.7 mmoL/L; p = 0.060), while HSP-70 (COOL, 1.9-fold, p = 0.207; HOT, 2.4-fold, p = 0.045), PGC-1α (COOL, 3.8-fold, p = 0.424; HOT, 8.4-fold, p = 0.010), HIF-1α (COOL, 1.6-fold, p = 0.315; HOT, 2.2-fold, p = 0.018) and PDK4 (COOL, 7.6-fold, p = 0.412; HOT, 14.1-fold, p = 0.047) mRNA increased significantly only in HOT at 4 h after exercise. These data indicate that acute exercise in a hot environment facilitates protective response to heat stress (HSP-70), mitochondrial biogenesis (PGC-1α and HIF-1α) and fatty acid oxidation (PDK4).

Pretreatment with tadalafil attenuates cardiotoxicity induced by combretastatin A4 disodium phosphate in rats.

Combretastatin A4 disodium phosphate (CA4DP) is a prodrug of combretastatin A4 (CA4), a microtubule-disassembling agent that exhibits antitumor effects by inhibiting tumor cell proliferation and inducing morphological changes and apoptosis in vascular endothelial cells in tumors. However, cardiotoxicity induced by ischemia and hypertension is a severe adverse event. In this study, we focused on the fact that phosphodiesterase (PDE) 5 inhibitors dilate the heart and peripheral blood vessels and aimed to investigate whether co-administration of tadalafil, a PDE5 inhibitor, can attenuate cardiotoxicity without altering the antitumor effect of CA4DP. To investigate cardiotoxicity, CA4DP and/or tadalafil were administered to rats, and blood pressure, echocardiography, histopathology, and cGMP concentration in the myocardium were examined. Administration of CA4DP increased systolic blood pressure, decreased cardiac function, lowered cGMP levels in the myocardium, and led to necrosis of myocardial cells. Co-administration of tadalafil attenuated these CA4DP-induced changes. To investigate the antitumor effect, canine mammary carcinoma cell lines (CHMp-13a) and human umbilical vein endothelial cells were cultured with CA4 and/or tadalafil, and cell proliferation and endothelial vascular tube disruption were examined. CHMp-13a cells were transplanted into nude mice and treated with CA4DP and/or tadalafil. CA4-induced inhibition of cell proliferation and disruption of the endothelial vascular tube were not affected by co-treatment with tadalafil, and the antitumor effects of CA4DP in xenograft mice were not reduced by co-administration of tadalafil. These results revealed that myocardial damage induced by CA4DP was attenuated by co-administration of tadalafil while maintaining antitumor efficacy.

Preliminary study of heart rate variability in Criollo horses for the elucidation of their neurophysiological characteristics of autonomic nerve function.

The Criollo is an Argentine horse breed with a calm temperament. Although its temperament is considered to be related to its neurophysiological characteristics, the details of this are unknown. Therefore, we analyzed the heart rate variability in Criollos as a preliminary study to deepen the neurophysiological understanding of their autonomic function. Electrocardiograms were recorded from Criollos and Thoroughbreds, and the power spectrum of heart rate variability was analyzed. Compared with Thoroughbreds, Criollos showed (i) a significantly higher high-frequency component, which is an index of parasympathetic nerve activity, and (ii) tendency toward a lower ratio of low- to high-frequency power, which is an index of the autonomic balance. These results revealed that parasympathetic nerves might be more active in Criollos compared with Thoroughbreds.

Behavior and heart rate variability after intranasal administration of oxytocin in Holstein steers.

Oxytocin (OXT) is a neuropeptide that regulates memory, emotion, stress response, and behavior in the brain. In our previous study with cattle, we demonstrated the anti-stress effect of intracerebroventricularly administered OXT on the central nervous system. However, it is important to investigate the effects of this peptide after intranasal administration, as it offers convenience and non-invasiveness for practical use. Therefore, this study investigated the effects of intranasal OXT on the behavior and autonomic nervous system of Holstein steers. The experiment followed a within-subjects design, including a total of six steers. Each steer received intranasal administration of either 1 mL of saline (SAL), 100 µg OXT (OXT100), or 200 µg OXT (OXT200). However, due to some issues, the sample size for the OXT200 group was reduced to five. After these treatments, we conducted electrocardiography recordings to analyze heart rate variability (HRV) and also made behavioral observations for 90 min. OXT200 tended to increase the time spent ruminating while lying down (Steel's multiple comparison test; P=0.053). In contrast, OXT treatment did not affect HRV indices. In conclusion, the current OXT dosage did not significantly affects behavior or the autonomic nervous system. However, the observed tendency to increase rumination may suggest a central effect of OXT.

Co-administration of JQ1, a bromodomain-containing protein 4 inhibitor, enhances the antitumor effect of combretastatin A4, a microtubule inhibitor, while attenuating its cardiotoxicity.

Combretastatin A4 (CA4) inhibits microtubule polymerization, and clinical trials of the prodrug, CA4 disodium phosphate (CA4DP), as an anti-cancer agent have been conducted. However, CA4DP has not been marketed to date because the margin between the effective dose and the cardiotoxic dose is insufficient. Meanwhile, bromodomain-containing protein 4 (BRD4) has been reported to be required for recovery from mitotic arrests induced by anti-microtubule drugs. BRD4 has also been reported to be involved in the progression of heart failure. Therefore, we hypothesized that the combined use of CA4DP with BRD4 inhibitors can enhance the antitumor effect and attenuate CA4DP-induced cardiotoxicity. In this study, the antitumor effect and cardiotoxicity caused by the co-administration of CA4DP with JQ1, a BRD4 inhibitor, were evaluated. CA4 or JQ1 alone reduced the viability of cultured canine mammary tumor cells (CHMp-13a). Viability was further reduced by co-administration, through the suppression of c-Myc. BRD4 positivity in CHMp-13a cytoplasm showed a significant increase when treated with CA4 alone, while the increase was not significant following co-administration. In CHMp-13a xenograft-transplanted mice, co-administration of CA4DP and JQ1 suppressed tumor growth significantly. In CA4DP-induced cardiac injury model rats, echocardiography showed a CA4DP-induced decrease in cardiac function and histopathology showed cardiomyocyte necrosis. Meanwhile, these cardiac changes tended to be milder following the co-administration of CA4DP and JQ1. These results suggest that CA4DP-JQ1 co-administration enhances the antitumor effect of CA4DP while attenuating its cardiotoxicity and therefore potentially open the doors to the development of a novel cancer chemotherapy with reduced cardiotoxicity risks.

Favorable Effects of Virgin Coconut Oil on Neuronal Damage and Mortality after a Stroke Incidence in the Stroke-Prone Spontaneously Hypertensive Rat.

Stroke is consistently one of the top ten causes of morbidity and mortality globally, whose outcomes are quite variable, necessitating case-specific management. Prophylactic diets before the onset of stroke have been implicated to work. In this research, the effects of virgin coconut oil (VCO) on stroke were evaluated using a stroke-prone spontaneously hypertensive rat (SHRSP) model. Eight-week-old SHRSPs were subjected to the repeated oral administration (5 mL/kg/day) of either 1% Tween 80 (group A) or VCO (group B). An early stroke onset was observed due to hypertension that was aggravation by the administration of 1% NaCl in water ad libitum. The following data were collected: the days until stroke occurred, the survival rate until the animal died, and blood pressure (BP) every two weeks using the tail-cuff method. After necropsy, the organs were harvested, and the brain was processed for a routine histopathological analysis. VCO delayed the incidence of it and prolonged their survival. Compared to group A, group B showed a significantly lowered BP by 20 mmHg at four weeks after the start of VCO treatment. Lastly, the brain histopathology showed that the structurally damaged areas were smaller in group B than they were in group A. The VCO could have protective effects on the brain before and even after stroke incidence.

Effects of Supplementation with a Quebracho Tannin Product as an Alternative to Antibiotics on Growth Performance, Diarrhea, and Overall Health in Early-Weaned Piglets.

This study assessed the feasibility of using a vegetable extract, MGM-P (quebracho tannin product), as an alternative to antibiotics for weaned piglets; it investigated MGM-P effects on growth performance, diarrhea, and overall health in early-weaned piglets. In total, 24 piglets were allocated to three treatment groups fed basal diets supplemented with 0, 0.2%, or 0.3% MGM-P for 20 days. The addition of 0.3% MGM-P to the diet of early-weaned piglets improved diarrhea incidence, hematological parameters, and intestinal mucosa structure. Furthermore, the addition of 0.2% or 0.3% MGM-P to the diet of early-weaned piglets did not affect their overall health. Importantly, MGM-P had no effects on average daily gain (ADG), average daily feed intake (ADFI), or feed conversion ratio (FCR). Gut morphology analysis showed that treatment with 0.3% MGM-P enhanced the jejunal villus height (p < 0.05) while reducing the ileal crypt depth (p < 0.05) and colon mucosal thickness (p < 0.05). Collectively, the findings suggested that the use of MGM-P as an alternative to dietary antibiotics could improve diarrhea incidence in early-weaned piglets without negative effects on growth performance or overall health.

Loss of Group II Metabotropic Glutamate Receptor Signaling Exacerbates Hypertension in Spontaneously Hypertensive Rats.

High blood pressure is a major risk factor of cerebro-cardiovascular outcomes. Blood pressure is partly regulated by the autonomic nervous system and its reflex functions; therefore, we hypothesized that pharmacological intervention in the brainstem that can regulate blood pressure could be a novel therapeutic strategy to control hypertension. We infused a group II metabotropic glutamate receptor (mGluR) antagonist (LY341495, 0.40 µg/day), using a mini-osmotic pump, into the dorsal medulla oblongata in young spontaneously hypertensive rats (SHRs), as this area is adjacent to the nucleus tractus solitarius (NTS), of which the neurons are involved in baroreflex pathways with glutamatergic transmission. Blood pressure was recorded for conscious rats with the tail cuff method. A 6-week antagonist treatment from 6 to 12 weeks of age slightly but significantly increased systolic blood pressure by >30 mmHg, compared to that in SHRs without treatment. Moreover, the effect continued even 3 weeks after the treatment ended, and concurred with an increase in blood catecholamine concentration. However, heart rate variability analysis revealed that LY341495 treatment had little effect on autonomic activity. Meanwhile, mRNA expression level of mGluR subtype 2, but not subtype 3 in the brainstem was significantly enhanced by the antagonist treatment in SHRs, possibly compensating the lack of mGluR signaling. In conclusion, mGluR2 signaling in the dorsal brainstem is crucial for preventing the worsening of hypertension over a relatively long period in SHRs, through a mechanism of catecholamine secretion. This may be a specific drug target for hypertension therapy.

Chronic stimulation of group II metabotropic glutamate receptors in the medulla oblongata attenuates hypertension development in spontaneously hypertensive rats.

Baroreflex dysfunction is partly implicated in hypertension and one responsible region is the dorsal medulla oblongata including the nucleus tractus solitarius (NTS). NTS neurons receive and project glutamatergic inputs to subsequently regulate blood pressure, while G-protein-coupled metabotropic glutamate receptors (mGluRs) play a modulatory role for glutamatergic transmission in baroreflex pathways. Stimulating group II mGluR subtype 2 and 3 (mGluR2/3) in the brainstem can decrease blood pressure and sympathetic nervous activity. Here, we hypothesized that the chronic stimulation of mGluR2/3 in the dorsal medulla oblongata can alleviate hypertensive development via the modulation of autonomic nervous activity in young, spontaneously hypertensive rats (SHRs). Compared with that in the sham control group, chronic LY379268 application (mGluR2/3 agonist; 0.40 µg/day) to the dorsal medulla oblongata for 6 weeks reduced the progression of hypertension in 6-week-old SHRs as indicated by the 40 mmHg reduction in systolic blood pressure and promoted their parasympathetic nervous activity as evidenced by the heart rate variability. No differences in blood catecholamine levels or any echocardiographic indices were found between the two groups. The improvement of reflex bradycardia, a baroreflex function, appeared after chronic LY379268 application. The mRNA expression level of mGluR2, but not mGluR3, in the dorsal medulla oblongata was substantially reduced in SHRs compared to that of the control strain. In conclusion, mGluR2/3 signaling might be responsible for hypertension development in SHRs, and modulating mGluR2/3 expression/stimulation in the dorsal brainstem could be a novel therapeutic strategy for hypertension via increasing the parasympathetic activity.

Cardiac lesions in Duchenne muscular dystrophy model rats with out-of-frame Dmd gene mutation mediated by CRISPR/Cas9 system.

Duchenne muscular dystrophy (DMD) is a progressive muscular disorder caused by X-chromosomal DMD gene mutations. Recently, a new CRISPR/Cas9-mediated DMD rat model (cDMDR) was established and is expected to show cardiac lesions similar to those in humans. We therefore investigated the pathological and pathophysiological features of the cardiac lesions and their progression in cDMDR. For our cDMDR, Dmd-mutated rats (W-Dmd em1Kykn ) were obtained. Dmd heterozygous-deficient females and wild-type (WT) males were mated, and male offspring including WT as controls were used. (1) Hearts were collected at 3, 5, and 10 months of age, and HE- and Masson's trichrome-stained specimens were observed. (2) Electrocardiogram (ECG) recordings were made and analyzed at 3, 5, and 8 months of age. (3) Echocardiography was performed at 9 months of age. In cDMDR rats, (1) degeneration/necrosis of cardiomyocytes and myocardial fibrosis prominent in the right ventricular wall and the outer layer of the left ventricular wall were observed. Fibrosis became more prominent with aging. (2) Lower P wave amplitudes and greater R wave amplitudes were detected. PR intervals tended to be shorter. QT intervals were longer at 3 months but tended to be shorter at 8 months. Sinus irregularity and premature ventricular contraction were observed at 8 months. (3) Echocardiography indicated myocardial sclerosis and a tendency of systolic dysfunction. Pathological and pathophysiological changes occurred in cDMDR rat hearts and progressed with aging, which is, to some extent, similar to what occurs in humans. Thus, cDMDR could be a valuable model for studying cardiology of human DMD.

Heart rate variability in dairy cows with postpartum fever during night phase.

Autonomic nervous function evaluated by heart rate variability (HRV) and blood characteristics were compared between Holstein Friesian cows that developed postpartum fever (PF; n = 5) and clinically healthy (CH; n = 6) puerperal cows in this case-control study. A cow was defined as having PF when its rectal temperature rose to ≥39.5°C between 1 and 3 days postpartum. We recorded electrocardiograms during this period using a Holter-type electrocardiograph and applied power spectral analysis of HRV. Comparisons between the groups were analyzed by t test or Mann-Whitney U test, and the relationship between rectal temperature and each parameter was analyzed using multiple regression analysis. Heart rate was higher in PF cows than in CH cows (Mean ± SE, 103.3 ± 2.7 vs. 91.5 ± 1.7 bpm). This result suggested that PF cows had a relatively dominant sympathetic nervous function. Total (44,472 ± 2,301 vs. 55,373 ± 1,997 ms) and low frequency power (24.5 ± 3.8 vs. 39.9 ± 5.3 ms) were lower in PF cows than in CH cows. These findings were possibly caused by a reduction in autonomic nervous function. The total white blood cell count (54.3 ± 5.1 vs. 84.5 ± 6.4 ×102/µL) and the serum magnesium (2.1 ± 0.1 vs. 2.4 ± 0.1 mg/dL) and iron (81.5 ± 8.0 vs. 134.4 ± 9.1 µg/dL) concentrations were lower and the serum amyloid A concentration (277 ± 33 vs. 149 ± 21 µg/mL) was higher in PF cows than in CH cows. These results imply that more inflammation was present in PF cows than in CH cows. Multiple regression analysis showed that both of low frequency power and concentration of serum iron were associated with rectal temperature. We found differences in changes in hematologic results, biochemical findings, and HRV patterns between PF cows and CH cows.

Radiocesium transfer rates among pigs fed haylage contaminated with low levels of cesium at two differentiation stages.

The objective of this study was to determine the radiocesium transfer rates of pigs fed haylage contaminated with low levels of cesium at different growth stages. We measured the body weight of juvenile and adult pigs during the treatment period to confirm their health status. We also performed pig blood hematologic and biochemical analyses at both growth stages. To our knowledge, this is the first study to report pig radiocesium transfer coefficient rates after 1 month of chronic oral treatment, which is the period assumed to be required for body equilibrium under a diet of radiocesium-contaminated food. The results showed higher radiocesium retention rates in the kidneys, liver, spleen, genitals, psoas major, bladder, thyroid, and urine than in the blood and bone (tibia and femur) of pigs at both growth stages. The radiocesium retention levels were generally higher in juvenile pigs than in adult pigs, with the highest transfer coefficient ratio in the kidneys (16.2%).

Distillation remnants of shochu, a traditional Japanese liquor, improve pork meat quality by reducing stress.

Distillation remnants of Shochu, a traditional Japanese liquorare fed to livestock, but their effects on livestock health have not been investigated. Here, we investigated the effects of these remnants on pig stress and pork quality (N = 6/group). The remnants reduced plasma cortisol (17.94 ± 0.92 [control] and 10.59 ± 1.28 [sample]) and increased salivary IgA (6.06 ± 2.21 [control] and 21.60 ± 5.37 [sample]). Blind sensory assessments showed that, in remnant-fed pork, sirloin tenderness (3.18 ± 0.19 [control] and 4.27 ± 0.38 [sample]) and the juiciness, umami, and fat tastiness of fillets were improved. Oleic acid percentages were higher (35.23 ± 0.65 [control] and 37.87 ± 0.60 [sample]) in remnant-fed pork, contributing to a favorable sensory evaluation. Two-group comparisons were analyzed by student's t test. p < 0.05. This study promotes the reutilization of remnants to reduce livestock stress and improve meat quality.

Effects of environmental enrichment on autonomic nervous activity in NSY mice.

Environmental enrichment (EE) can reduce anxiety and stress in experimental animals, while little is known about the influence on autonomic nervous activity especially in disease animal models. Diabetes mellitus (DM) is associated with cardiovascular autonomic dysfunction, which can be characterized by a higher resting heart rate and a lower heart rate variability (HRV). We hypothesized that EE can enhance parasympathetic nervous activity while reducing disease progression in type 2 diabetic mice. A telemetry transmitter was implanted in NSY mice to continuously record electrocardiograms (ECG). Animals were kept in a cage with or without a nest box as EE. The autonomic nervous activity was evaluated using power spectral analysis of HRV. Four weeks of EE could increase high frequency (HF) power, but no change was observed in the absence of EE. Although animals showed impaired glucose tolerance at 48 weeks of age regardless of EE, a worsen case was observed in control. These results indicate that EE can be necessary for long-term housing of experimental animals and may reduce the risk of impaired glucose tolerance in NSY mice by enhancing parasympathetic nervous activity. In future, it is demanded whether increasing parasympathetic nervous activity, whatever the method is, can prevent diabetes from worsening.

Early attenuation of autonomic nervous function in senescence accelerated mouse-prone 8 (SAMP8).

The senescence-accelerated mouse (SAM) strain has been established as an inbred strain with an accelerated aging phenotype. SAM prone-8 (SAMP8), one of the SAM strain, exhibits learning disability, immune deficiency, and circadian rhythm loss at a relatively young age. However, it has not been clarified whether aging affects the autonomic nervous activity in SAMP8. The aim of this study was to clarify the utility of SAMP8 in age-related studies of autonomic nervous function. Electrocardiogram (ECG), body temperature, and locomotor activity were recorded to evaluate bio-behavioral activities. Autonomic nervous activity was evaluated via power spectral analysis of heart rate variability from ECG recordings. SAMP8 significantly decreased both biological and autonomic nervous functions, and the animals exhibited circadian rhythm loss of locomotive activity at as early as 40 weeks of age compared with a control strain at the same age. We concluded that the SAMP8 strain can be used as an animal model for age-related studies of autonomic nervous function.

Histopathological and functional changes in a single-dose model of combretastatin A4 disodium phosphate-induced myocardial damage in rats.

Cardiotoxicity is a concern in the development of microtubule-disassembling agents (MDAs) as vascular-disrupting agents of tumors. This study investigated cardiotoxicity in rats induced by a single-dose of combretastatin A4 disodium phosphate (CA4DP), an MDA and discussed the use of this rat model in nonclinical studies of MDAs. First, CA4DP (120 mg/kg) was administered to rats intravenously, and cardiac histopathology and blood biomarkers were examined after 0.5, 24, and 72 h. Next, CA4DP (120 mg/kg) was administered to rats intravenously, and the electrocardiography and echocardiography results were analyzed. The results showed that at 0.5 h after dosing, plasma creatine kinase (CK), CK-muscle/brain (CK-MB), and fatty acid binding protein 3 levels increased. At 24 h, lactate dehydrogenase (LDH)-1, CK, and CK-MB levels increased, and multifocal vacuolar degeneration of myocardial cells was observed in the apical inner layer. At 72 h, LDH-1 levels were increased, and multifocal myocardial necrosis was observed in the interventricular septum and inner layer of the apex of left ventricular wall. Furthermore, at 0.5 h, heart rate (HR), ejection fraction (EF), and cardiac output (CO) decreased. At 24 h, CO decreased. Finally, at 72 h, HR, EF, and CO decreased, and depression of the T-wave amplitude was observed. In conclusion, myocardial injury, bradycardia, and depressed cardiac function were induced in rats by a single-dose of CA4DP. The lesion distribution and electrocardiographic features suggested that myocardial injury was induced by ischemia. These findings are similar to MDA-induced cardiotoxicity in humans, and this rat model will prove useful in studies of the cardiotoxicity in humans.