Incidence of sodium-glucose cotransporter-2 inhibitor-associated perioperative ketoacidosis in surgical patients: a prospective cohort study.

PURPOSE: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients. METHODS: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis. RESULTS: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%). CONCLUSIONS: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases.

Removal characteristics of presepsin by operating conditions and hemofilter.

Presepsin, which is used as a biomarker for sepsis, is thought to be removed by dialysis, but the actual removal properties of dialysis are unknown. We investigated the presepsin removal properties of continuous hemodiafiltration using the high concentration of presepsin from human plasma drained by plasma exchange. Each solution in plasma exchange was connected to a continuous hemodiafiltration blood circuit and circulated at 4 conditions. The results show that presepsin was confirmed to be removed more efficiently in hemofiltration than in hemodialysis. In addition, when using a polymethylmethacrylate hemofilter for continuous hemodiafiltration, the lowest presepsin concentration is on the filtrate side, suggesting that the main removal mechanism is adsorption. Since presepsin has a molecular weight of 13,000, its removal efficiency is high by hemofiltration as per principle. In addition, since the main adsorption principle of polymethylmethacrylate hemofilter is hydrophobic bond, presepsin is considered to be adsorbed. Since presepsin is metabolized in the kidney, it is elevated in renal failure. In this paper, we confirmed that presepsin is eliminated by continuous hemodiafiltration not only in the kidney. Depending on the timing of presepsin measurement, there is a risk of missing the diagnosis of sepsis. Kidney function and continuous hemodiafiltration should be checked when measuring presepsin.

Selective optogenetic activation of NaV1.7-expressing afferents in NaV1.7-ChR2 mice induces nocifensive behavior without affecting responses to mechanical and thermal stimuli.

In small and large spinal dorsal root ganglion neurons, subtypes of voltage-gated sodium channels, such as NaV1.7, NaV1.8, and NaV1.9 are expressed with characteristically localized and may play different roles in pain transmission and intractable pain development. Selective stimulation of each specific subtype in vivo may elucidate its role of each subtype in pain. So far, this has been difficult with current technology. However, Optogenetics, a recently developed technique, has enabled selective activation or inhibition of specific neural circulation in vivo. Moreover, optogenetics had even been used to selectively excite NaV1.8-expressing dorsal root ganglion neurons to induce nocifensive behavior. In recent years, genetic modification technologies such as CRISPR/Cas9 have advanced, and various knock-in mice can be easily generated using such technology. We aimed to investigate the effects of selective optogenetic activation of NaV1.7-expressing afferents on mouse behavior. We used CRISPR/Cas9-mediated homologous recombination to generate bicistronic NaV1.7-iCre knock-in mice, which express iCre recombinase under the endogenous NaV1.7 gene promoter without disrupting NaV1.7. The Cre-driver mice were crossed with channelrhodopsin-2 (ChR2) Cre-reporter Ai32 mice to obtain NaV1.7iCre/+;Ai32/+, NaV1.7iCre/iCre;Ai32/+, NaV1.7iCre/+;Ai32/Ai32, and NaV1.7iCre/iCre;Ai32/Ai32 mice. Compared with wild-type mice behavior, no differences were observed in the behaviors associated with mechanical and thermal stimuli exhibited by mice of the aforementioned genotypes, indicating that the endogenous NaV1.7 gene was not affected by the targeted insertion of iCre. Blue light irradiation to the hind paw induced paw withdrawal by mice of all genotypes in a light power-dependent manner. The threshold and incidence of paw withdrawal and aversive behavior in a blue-lit room were dependent on ChR2 expression level; the strongest response was observed in NaV1.7iCre/iCre;Ai32/Ai32 mice. Thus, we developed a non-invasive pain model in which peripheral nociceptors were optically activated in free-moving transgenic NaV1.7-ChR2 mice.

Extracellular signal-regulated kinase phosphorylation enhancement and NaV1.7 sodium channel upregulation in rat dorsal root ganglia neurons contribute to resiniferatoxin-induced neuropathic pain: The efficacy and mechanism of pulsed radiofrequency therapy.

Pulsed radiofrequency (PRF) therapy is one of the most common treatment options for neuropathic pain, albeit the underlying mechanism has not been hitherto elucidated. In this study, we investigated the efficacy and mechanism of PRF therapy on resiniferatoxin (RTX)-induced mechanical allodynia, which has been used as a model of postherpetic neuralgia (PHN). Adult male rats were intraperitoneally injected with a vehicle or RTX. Furthermore, PRF current was applied on a unilateral sciatic nerve in all RTX-treated rats. On both ipsilateral and contralateral sides, the paw mechanical withdrawal thresholds were examined and L4-6 dorsal root ganglia (DRG) were harvested. In the DRG of rats with RTX-induced mechanical allodynia, NaV1.7, a voltage-gated Na+ channel, was upregulated following the enhancement of extracellular signal-regulated kinase phosphorylation. Early PRF therapy, which was applied 1 week after RTX exposure, suppressed this NaV1.7 upregulation and showed an anti-allodynic effect; however, late PRF therapy, which was applied after 5 weeks of RTX exposure, failed to inhibit allodynia. Interestingly, late PRF therapy became effective after daily tramadol administration for 7 days, starting from 2 weeks after RTX exposure. Both early PRF therapy and late PRF therapy combined with early tramadol treatment suppressed NaV1.7 upregulation in the DRG of rats with RTX-induced mechanical allodynia. Therefore, NaV1.7 upregulation in DRG is related to the development of RTX-induced neuropathic pain; moreover, PRF therapy may be effective in the clinical management of patients with PHN via NaV1.7 upregulation inhibition.

Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain.

Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 µg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.

Effectiveness of Soluble Recombinant Human Thrombomodulin in Patients with Severe Acute Pancreatitis Complicated by Disseminated Intravascular Coagulation.

OBJECTIVE: We aimed to evaluate retrospectively the effect of soluble recombinant human thrombomodulin (rTM) on prognosis in patients with severe acute pancreatitis complicated by disseminated intravascular coagulation (DIC). METHODS: Based on Japanese diagnostic criteria of acute pancreatitis and DIC, patients who entered our intensive care unit (ICU) were selected. Comparisons were made between patients treated with rTM (rTM group) and without rTM (control group). RESULTS: A total of 38 patients were selected, and rTM was administered to 13 patients. Mortality on the 60th day after entering the ICU was significantly lower in the rTM group (15%) as compared with the control group (56%) (p=0.036). Although the platelet count was significantly lower in the rTM group at the start of treatment, the reversal rate from DIC was significantly higher than in the control group (rTM 62%, control 24%, p=0.035). According to logistic regression analysis of therapeutics, only rTM contributed to survival on the 60th day (odds ratio, 12.5; 95% confidence interval, 1.80-160; p=0.009). CONCLUSION: In patients with severe acute pancreatitis complicated by DIC, it was suggested that rTM might improve the prognosis of survival, even if the platelet count was markedly reduced.

Comparison of the effect of continuous intravenous infusion and two bolus injections of remifentanil on haemodynamic responses during anaesthesia induction: a prospective randomised single-centre study.

BACKGROUND: Remifentanil is an effective drug for protecting against adverse haemodynamic responses to tracheal intubation. We compared the haemodynamic responses during anaesthesia induction between continuous intravenous (IV) infusion and two bolus injections of remifentanil. METHODS: This prospective, randomised, open-label, single-centre study included patients with American Society of Anesthesiologists physical status I-II, scheduled to undergo elective surgery under general anaesthesia. Patients were randomised into two groups based on remifentanil administration type: the continuous IV infusion group (Group C) receiving a 0.3-µg/kg/min remifentanil infusion for 5 min followed by a 0.1-µg/kg/min remifentanil infusion, and the IV bolus group (Group B) receiving a combination of two bolus injections of remifentanil (first bolus of 0.4 µg/kg and second bolus of 0.6 µg/kg after 3 min) and 0.1 µg/kg/min remifentanil. General anaesthesia was induced with 1 mg/kg propofol and 0.6 mg/kg rocuronium 3 min after remifentanil infusion (Group C) or immediately after the first bolus of remifentanil (Group B). Tracheal intubation was performed 4 min after the injection of propofol and rocuronium. Heart rate and non-invasive blood pressure were recorded at 1-min intervals from baseline (i.e., before induction) to 5 min after tracheal intubation. RESULTS: A total of 107 patients were enrolled (Group C, 55; Group B, 52). Normotensive patients with no history of antihypertensive medication use were assigned to the normotensive subgroup (41 each in both groups), while those with hypertension but without a history of antihypertensive medication use were assigned to the untreated hypertensive subgroup (Group C vs. B, n = 7 vs. 4). Finally, patients with a history of antihypertensive medication use were assigned to the treated hypertensive subgroup (7 each in both Groups C and B). No differences in heart rate and blood pressure were observed between Groups C and B within each subgroup. CONCLUSIONS: Haemodynamic responses during anaesthesia induction were similar between continuous infusion and two bolus injections of remifentanil within both normotensive and hypertensive patients with or without medication. TRIAL REGISTRATION: The trial was retrospectively registered with Japanese Clinical Trial Registry "UMIN-CTR" on 20 October 2016 and was given a trial ID number UMIN000024495 .

[Anchor Fast endotracheal tube securing device for a pediatric patient during therapeutic hypothermia].

A 5-year-old girl was admitted to our hospital after resuscitation from cardiac arrest due to near-drowning accident in a river. On admission, Glasgow Coma Scale score was 7; arterial blood pressure was 113/73 mm Hg; heart rate was 157 beats x min(-1), and percutaneous oxygen saturation was 99% on 10 l x min(-1) of oxygen. The patient was intubated with a 5.0 mm internal diameter endotracheal tube, and therapeutic hypothermia was started for neural protection. Hypothermia in the target temperature of 34 degrees C was maintained for 24 hours using Arctic Sun System. Although the patient had been sedated with fentanyl 0.6-1.2 microg x kg(-1) x hr(-1), midazolam 0.2-0.4 mg x kg(-1) x hr(-1) and dexmedetomidine 0.6-1.0 mirog x kg(-1) x hr(-1), agitation increased during the rewarming period following hypothermia. To avoid accidental extubation, we used Anchor Fast as a device for securing oral endotracheal tube. Anchor Fast kept the tube position properly even though the patient was turned or moved. Seventy-two hours later, she was rewarmed and extubated as scheduled. Ten days after admission, she was discharged without any neurological deficits.

Involvement of the orexin system in adrenal sympathetic regulation.

Orexin (hypocretin) is a neuropeptide secreted from hypothalamic neurons that is known to be activated during motivated behaviors and active waking. Presently, our knowledge of orexin is mainly limited to the central nervous system, and the involvement of the orexin system in peripheral tissues has received little attention. In the present study, we analyzed the existence of the orexin system in the adrenal medulla, which is part of the sympathetic nervous system. Orexin and its receptors are expressed in the bovine adrenal medulla. Orexins stimulated intracellular calcium changes and epinephrine release from cultured bovine adrenal medullary cells. Applied orexin decreased expression of prepro-orexin, orexin receptor-1 and orexin receptor-2, suggesting negative feedback regulation in the adrenal gland. Our results indicate involvement of the orexin system in the sympathetic regulation of the adrenal medulla.

High-dose remifentanil increases blood pressure and heart rate mediated by sympatho-activation in conscious rats.

PURPOSE: The ultra-short-acting µ-opioid receptor agonist, remifentanil, is commonly used in clinical anesthesia; however, there are limited data about the hemodynamic effects of remifentanil itself without anesthetics. We investigated the effects of an ultra-short-acting µ-opioid receptor agonist, remifentanil, on cardiovascular and sympathetic function in conscious rats. METHODS: The mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded during continuous intravenous (i.v.) infusion of remifentanil at a moderate-dose (0.25 and 0.5 µg/kg/min) and a high-dose (1.0 and 2.0 µg/kg/min) in conscious intact and sino-aortic denervated (SAD) rats. Baroreflex sensitivity was examined during remifentanil administration. Rats were administered saline or naloxone to assess the involvement of the µ-opioid receptor in the remifentanil-induced responses. RESULTS: High-dose remifentanil induced biphasic changes in MAP and HR. Mediated by sympatho-activation, these parameters increased after briefly decreasing once. Subpressor-dose remifentanil enhanced baroreflex sensitivity. Changes in MAP, HR, and RSNA induced by remifentanil were inhibited by naloxone. CONCLUSIONS: High-dose remifentanil decreases MAP and HR transiently and increases these parameters mediated by the activation of sympathetic nerve activity in conscious rats.

Lidocaine treatment during synapse reformation periods permanently inhibits NGF-induced excitation in an identified reconstructed synapse of Lymnaea stagnalis.

PURPOSE: Nerve growth factor (NGF) has been reported to affect synaptic transmission and cause neuropathic pain. In contrast, lidocaine has been used to reduce neuropathic pain; however, the effect of NGF and lidocaine on spontaneous transmitter release and synapse excitation has not been fully defined. Therefore, the effect of NGF and lidocaine on nerve regeneration, synapse reformation, and subsequent spontaneous transmitter release was investigated. We used Lymnaea stagnalis soma-soma-identified synaptic reconstruction to demonstrate that a transient increase in both frequency and amplitude of spontaneous events of miniature endplate potentials (MEPPs) occurs following NGF treatment and a short burst of action potentials in the presynaptic cell; in addition, the effect of lidocaine on NGF-induced synapse reformation was investigated. METHODS: Using a cell culture and electrophysiological and FM-143 imaging techniques for exocytosis on unequivocally identified presynaptic visceral dorsal 4 (VD4) and postsynaptic somata left pedal (LPeE) neurons from the mollusc Lymnaea stagnalis, the effects of NGF and lidocaine on nerve regeneration, synapse reformation, and its electrophysiological spontaneous synaptic transmission between cultured neurons were described. RESULTS: NGF increased axonal growth, frequency, and amplitudes of MEPPs. Lidocaine exposure during synapse reformation periods was drastically and permanently reduced axonal growth and the incidence of synapse excitation by NGF. CONCLUSION: NGF increased amplitudes and frequencies of MEPPs and induced synaptic excitation by increasing axonal growth and exocytosis. Lidocaine exposure during synapse reformation periods permanently suppressed NGF-induced excitation by suppressing axonal growth and exocytosis of presynaptic neurons in the identified reconstructed synapse of L. stagnalis.

Clinical dose of lidocaine destroys the cell membrane and induces both necrosis and apoptosis in an identified Lymnaea neuron.

PURPOSE: Although lidocaine-induced cell toxicity has been reported, its mechanism is unclear. Cell size, morphological change, and membrane resistance are related to homeostasis and damage to the cell membrane; however, the effects of lidocaine on these factors are unclear. Using an identified LPeD1 neuron from Lymnaea stagnalis, we sought to determine how lidocaine affects these factors and how lidocaine is related to damage of the cell membrane. METHODS: Cell size and morphological form were measured by a micrograph and imaging analysis system. Membrane potential and survival rate were obtained by intracellular recording. Membrane resistance and capacitance were measured by whole-cell patch clamp. Phosphatidyl serine and nucleic acid were double stained and simultaneously measured by annexin V and propidium iodide. RESULTS: Lidocaine at a clinical dose (5-20 mM) induced morphological change (bulla and bleb) in the neuron and increased cell size in a concentration-dependent manner. Membrane potential was depolarized in a concentration-dependent manner. At perfusion of more than 5 mM lidocaine, the depolarized membrane potential was irreversible. Lidocaine decreased membrane resistance and increased membrane capacitance in a concentration-dependent manner. Both phosphatidyl serine and nucleic acid were stained under lidocaine exposure in a concentration-dependent manner. CONCLUSIONS: A clinical dose of lidocaine greater than 5 mM destroys the cell membrane and induces both necrosis and apoptosis in an identified Lymnaea neuron.

Effects of orexin-A on propofol anesthesia in rats.

PURPOSE: An active sleep homeostatic process is present during propofol anesthesia. Activation of the orexin system induces wakefulness, and inhibition of the orexin system causes narcolepsy. We hypothesized that orexin would affect propofol anesthesia. METHODS: The effects of an intracerebroventricular (i.c.v.) injection of orexin-A (OXA) or an orexin-1 (OX-1) receptor antagonist, SB-334867, on the times to the loss and return of the righting reflex induced by propofol were examined in Wistar rats. The effects of propofol or OXA on norepinephrine (NE) and dopamine (DA) release from the prefrontal cortex (PFC) were examined using in vivo microdialysis. RESULTS: An i.c.v. injection of OXA (1 nmol) decreased the time to emergence from propofol anesthesia mediated by the OX-1 receptor without changing anesthetic induction (n = 8). An i.c.v. injection of SB-334867 (5 and 50 nmol) increased the time to emergence from propofol anesthesia without changing anesthetic induction (n = 8). Intravenous infusion of propofol decreased NE (48 ± 8%; n = 8) and DA (61.2 ± 11%; n = 8) release from PFC mediated by the GABA(A) receptor. An i.c.v. injection of OXA reversed the decreases in NE and DA release induced by propofol mediated by the OX-1 receptor (n = 8). CONCLUSION: These results indicate that the orexin system may accelerate the emergence from propofol anesthesia associated with increases in the central noradrenergic and dopaminergic activity.

Capsaicin indirectly suppresses voltage-gated Na+ currents through TRPV1 in rat dorsal root ganglion neurons.

BACKGROUND: Capsaicin is used to treat a variety of types of chronic pain, including arthritis and trigeminal neuralgia. Although the cellular effects of capsaicin have been widely studied, little is known about the effects of capsaicin on intracellular sodium ([Na(+)]i) concentrations and voltage-gated Na(+) currents (INa(+)) in nociceptive afferent neurons. Therefore, in this study we sought to characterize the effect of capsaicin on tetrodotoxin-sensitive (TTX-s) and resistant (TTX-r) INa(+). METHODS: The effects of capsaicin on INa(+) in rat dorsal root ganglion neurons were studied for both TTX-s and TTX-r components using whole-cell patch-clamp techniques and intracellular sodium imaging. RESULTS: In both TTX-s and TTX-r INa(+) of capsaicin-sensitive neurons, capsaicin (0.1 to 10 µM) reduced inward currents in a dose-dependent manner. Capsaicin induced a hyperpolarization shift in the steady-state inactivation curves. SB366791 (10 µM), a potent and selective transient receptor potential vanilloid member1 (TRPV1) antagonist, significantly attenuated the reduction in INa(+). Capsaicin induced an increase in the [Na(+)]i, and SB366791 (10 µM) significantly reduced the [Na(+)]i increase. An increase in [Na(+)]i with gramicidin also dependently suppressed INa(+) and induced a hyperpolarization shift in the steady-state inactivation curves by increasing the [Na(+)]i. CONCLUSION: The findings suggest that capsaicin decreases both TTX-s and TTX-r INa(+) as a result of an increase in [Na(+)]i through TRPV1.

Cardiovascular responses to intravenous injection of a novel isoindolin-1-one derivate in conscious rats.

An isoindolin-1-one derivate, JM-1232(-), was recently developed as a sedative and hypnotic agent with a strong affinity for the central benzodiazepine binding site of gamma-aminobutyric acid(A) (GABA(A)) receptors. The purpose of this study was to examine the effects of JM-1232(-) on the cardiovascular and sympathetic functions of conscious rats. We investigated the effect of JM-1232(-) on the mean arterial pressure (MAP), heart rate (HR), baroreflex activity, and plasma catecholamine levels in conscious rats. The intravenous (i.v.) administration of JM-1232(-) (0.1, 0.3, and 1.0 mg/kg/min) for 20 min decreased MAP and increased HR in intact rats. In sinoaortic denervated (SAD) rats, JM-1232(-) decreased MAP and HR. A decrease in MAP induced by JM-1232(-) was prevented by pre-treatment with hexamethonium and enhanced by SAD. An increase in HR induced by JM-1232(-) was prevented by pre-treatment with atropine, propranolol, or hexamethonium. A decrease in MAP and an increase in HR induced by JM-1232(-) were antagonized by co-administration of flumazenil. A high dose of JM-1232(-) decreased the plasma norepinephrine concentration, and a subdepressor dose of JM-1232(-) did not affect the baroreceptor reflex. These results show that the i.v. administration of JM-1232(-) decreased MAP mediated by benzodiazepine-GABA(A) receptors.

Effects of landiolol on the cardiovascular response during tracheal extubation.

The objective of this study was to investigate the effect of landiolol on the cardiovascular responses to emergence from anesthesia and tracheal extubation. Fifty-nine patients without cardiovascular disorders who were scheduled for tympanoplasty were randomly allocated to receive a loading dose of landiolol at 0.125 mg x kg(-1) x min(-1) for 1 min, followed by an infusion at 0.01 mg x kg(-1) x min(-1) (group L1), 0.02 mg x kg(-1) x min(-1) (group L2), 0.03 mg x kg(-1) x min(-1) (group L3), or 0.04 mg x kg(-1) x min(-1) (group L4). At the end of surgery, sevoflurane and nitrous oxide were discontinued, and landiolol was started. The mean arterial pressure (MAP), heart rate (HR), and rate pressure product (RPP) in the four groups were compared before anesthesia induction, just after extubation, 5 min after extubation, 10 min after extubation, and at discharge from the operating room. Just after extubation compared with the baseline, the MAP increased significantly in all groups; the HR increased in groups L1 and L2; and the RPP increased in all groups, except for group L4. Continuous administration of landiolol, at 0.03 or 0.04 mg x kg(-1) x min(-1), may prevent the increases in HR and RPP, respectively, that occur at the emergence from anesthesia and tracheal extubation.

The effects of centrally administered dexmedetomidine on cardiovascular and sympathetic function in conscious rats.

BACKGROUND: The alpha2-receptor is expressed in the brain, including the hypothalamus, where it is implicated in autonomic nervous system control. The effects of systemic administration of dexmedetomidine (DEX) on cardiovascular responses are well known; however, little is known about the effects of central administration of DEX on cardiovascular responses in conscious animals. In this study, we explored the effects and the mechanism of intracerebroventricularly (icv) administered DEX on cardiovascular responses and sympathetic nerve activity in conscious, unrestrained rats. METHODS: We administered DEX (0.5, 1, and 2 microg/kg) icv and measured the mean arterial blood pressure (MAP), heart rate (HR), and plasma catecholamine in conscious rats (n = 58). Rats were also administered atropine (n = 8), propranolol (n = 8), or hexamethonium (n = 8) to assess the influence of vagal or sympathetic efferent activity in the DEX-induced responses. Some of the rats underwent carotid sinus and aortic nerve denervation to exclude the effect of the baroreceptor reflex. RESULTS: Intracerebroventricular administration of DEX dose-dependently decreased MAP, HR, and plasma norepinephrine. Large dose of DEX decreased plasma epinephrine. The amplitude of MAP reduction induced by DEX was reduced by hexamethonium or propranolol. The amplitude of HR reduction was reduced by atropine or propranolol. The amplitude of MAP and HR reduction induced by DEX were smaller in hexamethonium-pretreatment rats than in intact ones. The amplitude of MAP and HR reduction induced by DEX were larger in sinus and aortic nerve denervation rats than in intact ones. CONCLUSIONS: These results indicate that icv administration of DEX decreases MAP by sympathetic inhibition and decreases HR by sympathetic inhibition and vagal stimulation.

Activation of a G protein-coupled inwardly rectifying K+ current and suppression of Ih contribute to dexmedetomidine-induced inhibition of rat hypothalamic paraventricular nucleus neurons.

BACKGROUND: Alpha2-adrenoceptor agonist has been reported to produce inhibition of arginine vasopressin release, diuresis, and sympatholytic effects. However, its mechanisms of central action remain incompletely understood. Hypothalamic paraventricular nucleus (PVN) neurons, which are in direct contact with noradrenergic synapses and are controlled by the hyperpolarization-activated currents, are called Ih (H current). The effect of dexmedetomidine, a highly selective and potent agonist, at alpha2 adrenoceptors on Ih is unknown. The purpose of this study was to examine the effects of dexmedetomidine on the PVN neuron, which is involved in the arginine vasopressin release and autonomic regulation. METHODS: The authors investigated the effects of dexmedetomidine on the membrane properties in PVN magnocellular neurons and an Ih in PVN parvocellular neurons with a whole cell patch clamp technique using a rat brain slice preparation. RESULTS: Dexmedetomidine dose-dependently hyperpolarized PVN magnocellular neurons. In the voltage clamp mode, dexmedetomidine induced an outward current, with a reversal potential of -94 mV, and this was shown to depend on the external concentration of K. Pretreatment with Ba or peptide toxin tertiapin blocked hyperpolarization induced by dexmedetomidine. The effect of dexmedetomidine was blocked by an alpha2-adrenoceptor antagonist, yohimbine. Ih was suppressed dose dependently by dexmedetomidine in PVN parvocellular neurons. Pretreatment with Cs occluded the Ih suppression by dexmedetomidine. Yohimbine blocked the Ih suppression by dexmedetomidine. The Ih sensitive to dexmedetomidine was weakly modulated by intracellular cyclic adenosine monophosphate. CONCLUSIONS: Dexmedetomidine inhibited PVN magnocellular neurons by activation of the G protein-coupled inwardly rectifying K current and inhibited PVN parvocellular neurons by suppression of Ih.

[Central action of orexins on sympathetic outflow and cardiovascular function with a focus on the paraventricular nucleus of the hypothalamus].

Orexins were initially reported as regulators of food intake. More recent reports suggest that they might play roles in the multiple functions of neuronal systems, causing medical conditions such as narcolepsy, a sleep disorder. Orexins and their receptors (OX1R and OX2R) are distributed in the neural tissue and brain regions involved in the autonomic and neuroendocrine control. Within the hypothalamus, orexin fibers and orexin receptors, especially OX2R, are found extensively in the paraventricular nucleus (PVN) of the hypothalamus. The PVN is an integrative center of the autonomic nervous system and the neuroendocrine system. Thus, orexins may play a role in the regulation of cardiovascular and autonomic nervous systems. This article provides a summary of our studies, in which we used direct recording of renal sympathetic nerve and PVN neuronal activities in conscious freely-moving rats and the in vitro whole cell patch-clamp technique to examine the direct effect of orexins on PVN neurons using a hypothalamic slice. Functional studies demonstrated that intracerebroventricularly (i.c.v.) administered orexins evoke increases in blood pressure, heart rate, and sympathetic nerve activity and depolarize both the magno- and parvo-cellular neurons through the activation of non-selective cation channels. The present studies suggest that PVN plays a role as one of the efferent pathways of orexin-induced activation of the sympathetic outflow.

[Optimal dose of fentanyl for postoperative epidural analgesia after cesarean section].

BACKGROUND: The aim of this study was to investigate which dose of fentanyl in ropivacaine for epidural anesthesia will provide effective analgesia with minimal side effects after cesarean section (CS). METHODS: Fifty eight patients scheduled for CS were randomly allocated to two groups according to fentanyl dose in epidural analgesia: group F1 (11 microg x hr(-1); n=30) or group F 2 (21 microg x hr(-1); n= 28). Ropivacaine 0.2% 100 ml with fentanyl 400 or 800 microg was administered into the epidural space in the groups F1 and F 2, respectively. Pain scores (visual analogue scale: VAS) with cough or movement, Bromage score, incidence of diclofenac or pentazocine administration, satisfaction score (VAS) and side effects (nausea, vomiting and pruritus) were recorded after CS. RESULTS: Pain scores with cough or movement were significantly lower in the group F 2 than the group F 1 at twelve and twenty-four hours after CS. Bromage score at twelve hours was lower in the group F 2 than the group F 1. The incidences of side effects were similar between the two groups. Satisfaction score was significantly higher in the group F 2 than the group F 1. CONCLUSIONS: We conclude that continuous epidural administration of fentanyl 21 microg x hr(-1) with ropivacaine provides the optimum balance between pain relief and side effects compared with fentanyl 11 microg x hr(-1) with ropivacaine after CS.