The relationship between the initial pH and neurological outcome in patients with out-of-hospital cardiac arrest is affected by the status of recovery of spontaneous circulation on hospital arrival.

The early prediction of neurological outcomes is useful for out-of-hospital cardiac arrest (OHCA). The initial pH was associated with neurological outcomes, but the values varied among the studies. Patients admitted to our division with OHCA of cardiac origin between January 2015 and December 2022 were retrospectively examined (N = 199). A good neurological outcome was defined as a Glasgow-Pittsburgh cerebral performance category (CPC) of 1-2 at discharge. Patients were divided according to the achievement of recovery of spontaneous circulation (ROSC) on hospital arrival, and the efficacy of pH in predicting good neurological outcomes was compared. In patients with ROSC on hospital arrival (N = 100), the initial pH values for good and poor neurological outcomes were 7.26 ± 0.14 and 7.09 ± 0.18, respectively (p < 0.001). In patients without ROSC on hospital arrival (N = 99), the initial pH values for good and poor neurological outcomes were 7.06 ± 0.23 and 6.92 ± 0.15, respectively (p = 0.007). The pH associated with good neurological outcome was much lower in patients without ROSC than in those with ROSC on hospital arrival (P = 0.003). A higher initial pH is associated with good neurological outcomes in patients with OHCA. However, the pH for a good or poor neurological outcome depends on the ROSC status on hospital arrival.

Middle Cerebral Artery Pulsatility Index Correlates with Prognosis and Diastolic Dysfunctions in Acute Ischemic Stroke.

OBJECTIVE: To determine transcranial Doppler ultrasonography (TCD) parameters related to unfavorable outcomes, and to clarify the correlations between those parameters and heart functions in acute ischemic stroke without major vessel stenoses and occlusions. MATERIALS AND METHODS: Patients were selected from a comprehensive stroke center between October 2012 and June 2019. Inclusion criteria were: 1) acute ischemic stroke without major vessel stenoses and occlusions; and 2) ability to measure blood flow in the middle cerebral artery by TCD. Unfavorable outcomes were defined as a modified Rankin Scale score of 2-6 at 3 months after onset. First, we investigated TCD parameters related to unfavorable outcomes. Second, correlations between those parameters and heart functions as assessed by transthoracic echocardiography were evaluated. RESULTS: We screened 1,527 consecutive ischemic stroke patients, including 130 patients (109 [83%] male; median age, 60 years). Middle cerebral artery pulsatility index (M1 PI) (Odds ratio (OR) 0.057, 95%confidence interval (CI) 0.007-0.494, p = 0.009) was independently associated with unfavorable outcomes. Concerning the relation between M1 PI and heart functions, peak early filling velocity/velocity of mitral annulus early diastolic motion (E/e') (OR 1.195, 95%CI 1.011-1.413, p = 0.037) was a factor independently associated with high M1 PI. CONCLUSIONS: High M1 PI predicts unfavorable outcome regardless of ischemic stroke subtype without major vessel stenoses and occlusions. High M1 PI correlates with high E/e', suggesting diastolic dysfunction.

Organ-specific activation of the gastric branch of the efferent vagus nerve by ghrelin in urethane-anesthetized rats.

Ghrelin plays multiple physiological roles such as growth hormone secretion and exerting orexigenic actions; however, its physiological roles in the electrical activity of autonomic nerves remain unclear. Here, we investigated the effects of human ghrelin on several autonomic nerve activities in urethane-anesthetized rats using an electrophysiological method. Intravenous injection of ghrelin at 3 µg/kg significantly and transiently potentiated the efferent activity of the gastric vagus nerve; however, it did not affect the efferent activity of the hepatic vagus nerve. The activated response to ghrelin in the gastric efferent vagus nerve was not affected by the gastric afferent vagotomy, suggesting that this effect was not induced via the gastric afferent vagus nerve. Ghrelin did not affect the efferent activity of the brown adipose tissue, adrenal gland sympathetic nerve, and the renal sympathetic nerve. In addition, rectal temperature and the plasma concentrations of norepinephrine, corticosterone, and renin were also not changed by ghrelin. These findings demonstrate that ghrelin stimulates the gastric efferent vagus nerve in an organ-specific manner without affecting the gastric afferent vagus nerve and that ghrelin does not acutely affect the efferent basal activity of the sympathetic nerve in rats.

Role of L-carnosine in the control of blood glucose, blood pressure, thermogenesis, and lipolysis by autonomic nerves in rats: involvement of the circadian clock and histamine.

L-carnosine (ß-alanyl-L-histidine; CAR) is synthesized in mammalian skeletal muscle. Although the physiological roles of CAR have not yet been clarified, there is evidence that the release of CAR from skeletal muscle during physical exercise affects autonomic neurotransmission and physiological functions. In particular, CAR affects the activity of sympathetic and parasympathetic nerves innervating the adrenal glands, liver, kidney, pancreas, stomach, and white and brown adipose tissues, thereby causing changes in blood pressure, blood glucose, appetite, lipolysis, and thermogenesis. CAR-mediated changes in neurotransmission and physiological functions were eliminated by histamine H1 or H3 receptor antagonists (diphenhydramine or thioperamide) and bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN), a master circadian clock. Moreover, a carnosine-degrading enzyme (carnosinase 2) was shown to be localized to histamine neurons in the hypothalamic tuberomammillary nucleus (TMN). Thus, CAR released from skeletal muscle during exercise may be transported into TMN-histamine neurons and hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of CAR on neurotransmission and physiological function. Thus, CAR appears to influence hypoglycemic, hypotensive, and lipolytic activity through regulation of autonomic nerves and with the involvement of the SCN and histamine. These findings are reviewed and discussed in the context of other recent reports, including those on carnosine synthetases, carnosinases, and carnosine transport.

Dietary free glutamate prevents diarrhoea during intra-gastric tube feeding in a rat model.

Recent studies indicate that l-glutamate (l-Glu), abundant in many foods, is a stimulator of gastric vagal afferent nerves. The aim of the present study was to examine the possibility that l-Glu supplementation of a protein-rich liquid diet may prevent the incidence of diarrhoea during repetitive intra-gastric tube feeding. The gastric vagal afferent nerve recording of rats indicated that intra-gastric administration of a protein-rich liquid diet supplemented with 0·5 % monosodium glutamate enhanced the basal afferent activities seen with the protein-rich diet alone. The examination of the faeces showed that the addition of monosodium glutamate to the liquid diet significantly prevented the incidence of diarrhoea induced by repetitive gastric feeding. In conclusion, supplementation of an enteral liquid diet with free l-Glu may ameliorate diarrhoea during intra-gastric tube feeding by sending visceral glutamate information from the stomach to the brain.

Cancer and malnutrition were independently associated with a poor prognosis in patients with heart failure.

BACKGROUND: Recent advances in treatment have improved the survival of cancer patients. Such survivors may go on to develop heart failure (HF) later in life. HF and cancer are wasting diseases, and malnutrition is associated with a poor prognosis in patients with HF or cancer. METHODS AND RESULTS: Patients admitted to our hospital with HF from April 2012 to March 2020 were retrospectively reviewed. They were divided into 2 groups: cancer patients (N = 185) and patients without cancer (N = 930). Patients discharged alive and followed by our outpatient clinic were also examined (N = 857, median follow-up period: 794 days). RESULTS: In cancer patients, the geriatric nutritional risk index and prognostic nutritional index were lower and the controlling nutritional status score was higher than in HF patients without cancer; nutrition was disturbed in HF patients with cancer. The in-hospital mortality rates of the two groups were not markedly different; however, cancer patients showed higher long-term mortality in comparison to HF patients without cancer. A multivariate analysis revealed that cancer and malnutrition were independently associated with all-cause death. CONCLUSIONS: The long-term mortality of HF patients with cancer was higher than that of HF patients without cancer. Malnutrition was associated with long-term mortality, independently of the presence of cancer. Multidisciplinary treatment is needed when treating HF patients with cancer.

Signals from intra-abdominal fat modulate insulin and leptin sensitivity through different mechanisms: neuronal involvement in food-intake regulation.

Intra-abdominal fat accumulation is involved in development of the metabolic syndrome, which is associated with insulin and leptin resistance. We show here that ectopic expression of very low levels of uncoupling protein 1 (UCP1) in epididymal fat (Epi) reverses both insulin and leptin resistance. UCP1 expression in Epi improved glucose tolerance and decreased food intake in both diet-induced and genetically obese mouse models. In contrast, UCP1 expression in Epi of leptin-receptor mutant mice did not alter food intake, though it significantly decreased blood glucose and insulin levels. Thus, hypophagia induction requires a leptin signal, while the improved insulin sensitivity appears to be leptin independent. In wild-type mice, local-nerve dissection in the epididymis or pharmacological afferent blockade blunted the decrease in food intake, suggesting that afferent-nerve signals from intra-abdominal fat tissue regulate food intake by modulating hypothalamic leptin sensitivity. These novel signals are potential therapeutic targets for the metabolic syndrome.

Skin application of urea-containing cream affected cutaneous arterial sympathetic nerve activity, blood flow, and water evaporation.

BACKGROUND/PURPOSE: We observed that olfactory stimulation with scent of grapefruit oil elevated the activities of sympathetic nerves, and increased the plasma glycerol concentration and blood pressure. In contrast, olfactory stimulation with scent of lavender oil had opposite effects in rats. These suggest that changes in autonomic activities cause physiological functions via histaminergic H1 and H3 receptor. Moreover, it has been reported that somatic sensory stimulation affected autonomic neurotransmission. To examine effects of skin application of urea-containing cream on cutaneous arterial sympathetic nerve activity (CASNA), blood flow, and transepidermal water loss (TEWL). METHOD: The activity of CASNA was determined by electrophysiological method, and cutaneous blood flow was determined using laser flowmeter in urethane-anesthetized rats, TEWL was measured using VapoMeter in the back skin of HWY hairless rats. RESULTS: CASNA was markedly and significantly inhibited by skin application of 10% urea-containing cream, whereas cutaneous blood flow was significantly elevated via histaminergic H3-receptor. In conscious hairless rats, TEWL was significantly decreased 24 h after application of 10% urea-containing cream to the back skin. CONCLUSION: These findings suggest that skin application of 10% urea-containing cream increases the cutaneous blood flow and water retaining ability, and that histaminergic H3-receptors may mediate these effects.

Effect of anserine ingestion on hyperglycemia and the autonomic nerves in rats and humans.

Anserine and L-carnosine are similar dipeptides synthesized by muscles of vertebrates. The functional role of anserine is unknown, although previous studies showed hypoglycemic effects of carnosine through autonomic nerves. Thus, we evaluated the effects of anserine on blood glucose levels and the neural activities. Intraperitoneal administration of specific doses of anserine to hyperglycemic rats reduced hyperglycemia and plasma glucagon concentrations, whereas thioperamide eliminated the effects of anserine. Intraduodenal injection of 0.1 mg anserine to anesthetized rats after laparotomy suppressed sympathetic nerve activity and enhanced activity of the vagal gastric efferent. In addition, oral administration of anserine reduced blood glucose levels during oral glucose tolerance testing in humans. These results suggest the possibility that anserine might be a control factor for the blood glucose, and that histaminergic nerves may be involved in the hypoglycemic effects of anserine.

Effect of anserine ingestion on the hyperglycemia and autonomic nerves in rats and humans.

Anserine and L-carnosine are similar dipeptides synthesized by muscles of vertebrates. The functional role of anserine is unknown, although previous studies showed hypoglycemic effects of carnosine through autonomic nerves. Thus, we evaluated the effects of anserine on blood glucose levels and neural activities. Intraperitoneal administration of specific doses of anserine to hyperglycemic rats reduced hyperglycemia and plasma glucagon concentrations, whereas thioperamide eliminated the effects of anserine. Intraduodenal injection of 0.1 mg anserine to anesthetized rats after laparotomy suppressed sympathetic nerve activity and enhanced activity of the vagal gastric efferent. In addition, oral administration of anserine reduced blood glucose levels during oral glucose tolerance testing in humans. These results suggest the possibility that anserine might be a control factor for blood glucose, and that histaminergic nerves may be involved in the hypoglycemic effects of anserine.

Role played by afferent signals from olfactory, gustatory and gastrointestinal sensors in regulation of autonomic nerve activity.

Afferent signals from the olfactory system, gustatory system and gastrointestinal (GI) tract control visceral functions such as oral and gut secretions and several digestive, endocrine, thermogenic, cardiovascular and renal responses via autonomic reflexes. It is well known that odors and tastes, such as umami, can stimulate oral and GI secretions to improve food intake and digestion in a process termed the cephalic phase response. The perception of GI nutrients, such as carbohydrates and amino acids, can control food digestion, absorption and utilization via the vago-vagal reflex during a meal. Recent advances in understanding the molecular physiology of taste indicate that taste receptors able to sense such nutrients are widely distributed in the GI tract, including the oral cavity. These receptors act as nutrient sensors to trigger food digestion, the release of GI peptides and the formation of food preferences. In this paper, we review recent evidence on the regulation of GI functions by the autonomic nervous system via peripheral odor and nutrient sensors.

Effects of gastric vagotomy on visceral cell proliferation induced by ventromedial hypothalamic lesions: role of vagal hyperactivity.

In rats, ventromedial hypothalamic (VMH) lesions induce cell proliferation in the visceral organs (stomach, small intestine, liver, and pancreas) due to hyperactivity of the vagus nerve. To investigate the effects of selective gastric vagotomy on VMH lesion-induced cell proliferation and secretion of gastric acid, we assessed the mitotic index (the number of proliferating cell nuclear antigen (PCNA)-immunopositive cells per 1,000 cells in the gastric mucosal cell layer) and measured the volume of secreted basal gastric acid. Furthermore, to explore whether or not ethanol-induced acute gastric mucosal lesions (AGML) lead to ulcer formation in VMH-lesioned rats, we assessed the ulcer index of both sham-operated and VMH-lesioned rats after administration of ethanol. VMH lesions resulted in an increased mitotic index and thickness of the gastric mucosal cell layer and gave rise to the hypersecretion of gastric acid. Selective gastric vagotomy restored these parameters to normal without affecting cell proliferation in other visceral organs. Ethanol-induced AGML caused ulcers in sham VMH-lesioned rats, whereas VMH-lesioned rats were less likely to exhibit such ulcers. These results suggest that VMH lesion-induced vagally mediated cell proliferation in the visceral organs is associated with hyperfunction in these organs, and VMH lesion-induced resistance to ethanol may be due to thickening of the gastric mucosal cell layer resulting from cell proliferation in the gastric mucosa-this in turn is due to hyperactivity of the vagus nerve.

Effect of auditory stimulation on parasympathetic nerve activity in urethane-anesthetized rats.

Previously, it has been demonstrated that auditory stimulation with music (Traeumerei [TM] by Schumann) decreased renal sympathetic nerve activity (RSNA) and blood pressure (BP) with a central mechanism, while it is unknown whether TM affects parasympathetic nerve activity. Here, the effects of auditory stimulation with TM on gastric vagal nerve activity (GVNA) in urethane-anesthetized rats were investigated. Auditory stimulation with TM, but not with white noise (WN) caused a significant elevation of GVNA. In addition, exposure to TM increased the number of c-Fos-immunoreactive cells in the auditory cortex (AuC). These findings suggest that exposure to music can increase GVNA through the auditory pathway.

Day-night difference in thermoregulatory responses to olfactory stimulation.

Previously, we observed that olfactory stimulation with scent of grapefruit oil (SGFO) or scent of lavender oil (SLVO) affected, elevated or lowered brown adipose tissue temperature (BAT-T) in conscious mice, respectively. In the present study, to test the day-night difference in the actions of olfactory stimulations, we examined the responses of BAT-T and body temperature (BT) measured as the abdominal temperature to SGFO or SLVO during day-time at 14:00 and night-time at 2:00 in conscious rats. In the light period, BAT-T and BT were suppressed after SLVO and elevated after SGFO whereas in the dark period, these parameters remained unchanged with olfactory stimulations. Bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) eliminated the effects of olfactory stimulations with SGFO and SVLO on BAT-T and BT. Moreover, sympathetic nerve activity innervating brown adipose tissue (BAT-SNA) changes after SGFO or SLVO were abolished in SCN-lesioned rats. Thus, we concluded that there is day-night difference in the effects of SGFO or SLVO on BAT-T and BT, and that the SCN might be involved in these effects.

Biphasic effects of orexin-A on autonomic nerve activity and lipolysis.

Previously, we showed that orexin-A, a 33-aa peptide, influences renal sympathetic nerve activity. Because the autonomic nervous system plays an important role in the regulation of lipid metabolism, we investigated the in vivo effects of orexin-A on the sympathetic nerve activity innervating white adipose tissue (WAT-SNA) and lipolysis. We found that intracerebroventricular (icv) administration of orexin-A at doses of 1 microg/rat and 10 ng/rat elevated and suppressed WAT-SNA, respectively. The effect of the high dose of orexin-A (1 microg/rat) was eliminated by pretreatment with diphenhydramine hydrochloride, a histamine H(1) receptor antagonist. In contrast, the effect of the low dose of orexin-A (10 ng/rat) was suppressed by thioperamide maleate salt, a histamine H(3) receptor antagonist. Moreover, icv administration of 1 microg/rat and 10 ng/rat of orexin-A increased and decreased the levels of plasma free fatty acids (FFAs), respectively. The effect of 1 microg/rat of orexin-A on plasma FFA was eliminated by propranolol hydrochloride, a beta-adrenergic receptor blocker, and also by diphenhydramine. The effect of orexin-A at dose of 10 ng/rat disappeared by pretreatment with atropine sulfate, a muscarinic receptor blocker, and thioperamide maleate salt. Our results suggest that high doses of orexin-A may regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nervous system, which is driven by histamine neurons through the H(1) receptor, and that the beta(3)-receptor may be involved in this enhanced lipolytic response. Low doses of orexin-A, on the other hand, may lower lipolysis by suppressing sympathetic nerve activity via the H(3)-receptor, and the muscarinic receptor may be related to this response.

Effects of olfactory stimulations with scents of grapefruit and lavender oils on renal sympathetic nerve and blood pressure in Clock mutant mice.

Previously, we observed that in mice, olfactory stimulation with scent of grapefruit oil elevates renal sympathetic nerve activity and blood pressure. In contrast, olfactory stimulation with scent of lavender oil has opposite effects in mice. Moreover, electrolytic lesions of the mouse hypothalamic suprachiasmatic nucleus eliminated changes in renal sympathetic nerve activity and blood pressure induced by either scent of grapefruit oil or scent of lavender oil. Here, we show that grapefruit oil-induced elevations in renal sympathetic nerve activity and blood pressure were not observed in Clock mutant mice, which harbor mutations in Clock and lack normal circadian rhythms, whereas lavender oil-suppressions were preserved in Clock mutant mice. In addition, responses of c-Fos inductions in the suprachiasmatic nucleus and paraventricular nucleus of the hypothalamus to scent of grapefruit oil observed in wild-type mice were not observed in Clock mutant mice. These findings suggest that the Clock gene might be implicated in elevating responses of autonomic and cardiovascular functions to olfactory stimulation with scent of grapefruit oil.

In vivo effects of leptin on autonomic nerve activity and lipolysis in rats.

Leptin, a 16-kDa protein, is produced by white adipose tissue (WAT), and is thought to serve as a feedback signal indicating the size of fat stores. Considerable amount of data have shown that leptin can mediate lipid metabolism. However, its possible direct effects on the metabolism of lipids in vivo and the mechanisms involved have not been fully characterized. In this study, we investigated the in vivo effects of leptin on the autonomic nerve activity and lipolysis. We found that intravenous administration of leptin (10 microg/rat) excited the sympathetic nerves innervating WAT, and this effect was abolished by the pretreatment with diphenhydramine, a histamine H(1) receptor antagonist. Moreover, intraperitoneal administration of leptin (130 microg/kg) elevated the levels of plasma glycerol and free fatty acid (FFA). The effect of leptin on plasma FFA was eliminated by pretreatment with diphenhydramine and propranolol, a beta-adrenergic receptor blocker, and disappeared in suprachiasmatic nucleus (SCN)-lesioned rats. Our results suggest that leptin might regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nerves, driven by histamine neurons through the H(1) receptor, and a beta-adrenergic receptor, probably the beta(3)-receptor, is involved in the lipolytic response to leptin. The actions of leptin in this study are supposed to be controlled by the SCN.

Autonomic and cardiovascular responses to scent stimulation are altered in cry KO mice.

Previously, we observed that in rats, olfactory stimulation with scent of grapefruit oil (SGFO) elevates the activities of sympathetic nerves. SGFO also suppresses gastric vagal (parasympathetic) nerve activity (GVNA), increases the plasma glycerol concentration, blood pressure (BP) and body temperature, and reduces appetite. In contrast, olfactory stimulation with scent of lavender oil (SLVO) has opposite effects in rats. Here, we show that in mice, olfactory stimulation with SGFO elevated activities of sympathetic nerves innervating the kidney, adrenal gland and brown adipose tissue as well as increasing BP and suppressing GVNA, whereas olfactory stimulation with SLVO decreased these sympathetic nerve activities and BP, and elevated GVNA. Electrolytic lesions of the mouse hypothalamic suprachiasmatic nucleus (SCN) eliminated changes in renal sympathetic nerve activity (RSNA), BP and GVNA induced by either SGFO or SLVO. Furthermore, SGFO-induced elevations in RSNA and BP and the SLVO-induced GVNA increase were not observed in Cryptochrome (Cry)-deficient mice, which harbor mutations in both cry1 and cry2 and lack normal circadian rhythms. These findings suggest that SGFO and SLVO affect autonomic neurotransmission and BP via the SCN in mice. Moreover, the molecular clock mechanism in the SCN, which involves the cry1 and cry2 genes, is partially involved in mediating these autonomic and cardiovascular actions of SGFO and SLVO.

Auditory stimulation affects renal sympathetic nerve activity and blood pressure in rats.

Here, we examined the effects of auditory stimulation at 50 dB with white noise (WN) or music (Traeumerei [TM] by Schumann or Etude by Chopin) on renal sympathetic nerve activity (RSNA) and BP in urethane-anesthetized rats. Auditory stimulation with TM, but not with WN or the Etude, significantly decreased RSNA and BP. Complete bilateral destruction of the cochleae and bilateral lesions of the auditory cortex (AuC) eliminated the effects of TM stimulation on RSNA and BP, but bilateral lesions of primary somatosensory cortex (S1C) had no effect. Bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) or intracerebral administration of thioperamide, a histaminergic H3 receptor antagonist, also abolished TM-induced decreases in RSNA and BP. These findings suggest that exposure to music can decrease RSNA and BP through the auditory pathway, histaminergic neurons, and the SCN.

Mechanism of changes induced in plasma glycerol by scent stimulation with grapefruit and lavender essential oils.

In a previous study, we found that stimulation with scent of grapefruit oil (SGFO) elevated plasma glycerol levels in rats. However, stimulation with scent of lavender oil (SLVO) triggered a negative effect. To identify the mechanism of these changes during lipolysis, we examined the role of autonomic blockers and bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) in the modification of plasma glycerol in rats exposed to SGFO and SLVO. We found that intraperitoneal injection of propranolol hydrochloride and atropine sulfate eliminated the changes in plasma glycerol levels induced by SGFO and SLVO, respectively. Bilateral lesions of the SCN completely abolished the effects of SGFO and SLVO on lipolysis. In addition, we investigated tyrosine phosphorylation of the transmembrane glycoprotein BIT (a brain immunoglobulin-like molecule with tyrosine-based activation motifs, a member of the signal-regulator protein family), which was found to be involved in the activation of renal sympathetic nerves and increase in body temperature on cold exposure. SGFO was found to enhance the immunoreactivity of BIT to the 4G10 anti-phosphotyrosine antibody in the SCN, whereas SLVO decreased the immunoreactivity. The changes in BIT phosphorylation resulting from the exposure to SGFO and SLVO were eliminated by the corresponding histamine receptor antagonists, which eliminated the changes in plasma glycerol concentration. The results suggest that SGFO and SLVO affect the autonomic neurotransmission and lipolysis. The SCN and histamine neurons are involved in the lipolytic responses to SGFO and SLVO, and tyrosine phosphorylation of BIT is implicated in the relevant signaling pathways.