Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on the Severity and the Mortality of Acute Myocardial Infarction in Japan　- Analysis From the JROAD-DPC Database.

Background: Coronavirus disease 2019 (COVID-19) has impacted on cardiovascular disease. However, it remains unclear whether the COVID-19 pandemic has impacted on disease severity and patients' prognosis of acute myocardial infarction (AMI) in Japan. Methods and Results: We retrospectively accumulated data from the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC) study (April 2019 to March 2021). Patients were divided into a before COVID-19 pandemic group or a during COVID-19 pandemic group. The proportion of patients who presented with cardiogenic shock (Killip class IV) was compared between groups, in association with 30-day mortality as the primary outcome. Killip class IV AMI significantly increased in the during COVID-19 pandemic group (15.7% vs. 14.5% in the before pandemic group, P<0.0001). The 30-day mortality was higher in the during COVID-19 pandemic group (9.6% vs. 9.2% in the before COVID-19 pandemic group, P=0.049). However, there was no significant difference in the adjusted 30-day mortality in each Killip class between the before and during COVID-19 pandemic groups. Conclusions: During the early stage of the COVID-19 pandemic in Japan, 30-day mortality of AMI increased, mainly because of the increase of Killip class IV AMI patients. However, irrespective of the COVID-19 pandemic, the adjusted 30-day mortality of each Killip classification group was unchanged.

Emphysematous pyelonephritis with ST elevation accompanied by reciprocal changes mimicking acute coronary syndrome.

Patients with infectious diseases including sepsis can develop ST segment changes on an electrocardiogram (ECG) in the absence of coronary artery disease. However, ST elevation with "reciprocal ST segment depression (RSTD)", which is recognized as a specific finding for ST-elevated myocardial infarction, is rare in such patients. Although a small number of cases have reported ST-segment elevation in gastritis, cholecystitis, and sepsis, regardless of coronary artery disease, none presented with reciprocal changes. Here, we describe a rare case of a patient with emphysematous pyelonephritis complicating septic shock who developed ST elevation accompanied by reciprocal changes with no coronary occlusion. Emergency physicians should consider the possibility of acute coronary syndrome mimicking, and choose non-invasive diagnostic procedures when investigating the causes of ECG abnormalities associated with critically ill patients.

Contribution of afferent renal nerve signals to acute and chronic blood pressure regulation in stroke-prone spontaneously hypertensive rats.

The activation of sympathetic nervous system plays a critical role in the development of hypertension. The input from afferent renal nerves may affect central sympathetic outflow; however, its contribution to the development of hypertension remains unclear. We investigated the role of afferent renal nerves in acute and chronic blood pressure regulation using normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Acute chemical stimulation of afferent renal nerves elicited larger increases in blood pressure and renal sympathetic nerve activity in young 9-week-old SHRSP compared to WKY. Selective afferent renal denervation (ARDN) and conventional total renal denervation (TRDN) ablating both afferent and efferent nerves in young SHRSP revealed that only TRDN, but not ARDN, chronically attenuated blood pressure elevation. ARDN did not affect plasma renin activity or plasma angiotensin II levels, whereas TRDN decreased both. Neither TRDN nor ARDN affected central sympathetic outflow and systemic sympathetic activity determined by neuronal activity in the parvocellular region of hypothalamic paraventricular nucleus and rostral ventrolateral medulla and by plasma and urinary norepinephrine levels, respectively. Renal injury was not apparent in young SHRSP compared with WKY, suggesting that renal afferent input might not be activated in young SHRSP. In conclusion, the chronic input from afferent renal nerves does not contribute to the development of hypertension in SHRSP despite the increased blood pressure response to the acute stimulation of afferent renal nerves. Efferent renal nerves may be involved in the development of hypertension via activation of the renin-angiotensin system in SHRSP.

Impact of Antithrombin Activity Levels Following Recombinant Antithrombin Gamma Therapy in Patients with Sepsis-Induced Disseminated Intravascular Coagulation.

Recombinant antithrombin gamma (rAT) is reported as an effective drug for patients with disseminated intravascular coagulation (DIC) in Japan. As the appropriate dose and targeted AT activity remain unknown, this study aimed to determine these aspects for sepsis-induced DIC. Thirty-one patients with septic shock and DIC with AT levels <70% were treated with rAT between May 2018 and December 2020. The recovery rates from DIC were 32.2% and 63.3% on day 3 and 5 post administration, respectively. Recovery and survival rates were significantly higher in patients who achieved AT activity ≥70% or 80% on day 3 post administration. Receiver operating characteristic curve analysis revealed that the cutoff values of post-treatment AT activity on day 3 for 28-day survival and 5-day recovery from DIC were 79.5% and 81.5%, respectively. Patients who did not achieve AT activity ≥80% on day 3 presented a lower base level of AT activity and lower dose supplementation. Our results suggest that targeted AT activity should be at least 70%, and ideally 80%, and sufficient doses to maintain this activity are required to achieve better outcomes.

Prediction of intracranial lesions in patients with consciousness disturbance by ultrasonography in the intensive care unit.

OBJECTIVE: This study was performed to evaluate the correlation between parameters measured by bedside ultrasonography and detection of intracranial organic lesions in patients with impaired consciousness in an intensive care unit (ICU) setting. METHODS: We retrospectively reviewed the medical records of patients who were admitted to our ICU from April 2017 to July 2019. Patients who underwent computed tomography or magnetic resonance imaging examination and measurement of the flow velocity of the carotid and intracranial arteries and the optic nerve sheath diameter by ultrasonography were selected for analysis. RESULTS: In total, 64 patients were analyzed in this study. Of these, intracranial lesions were detected by computed tomography or magnetic resonance imaging in 17 (27%) patients. The left:right ratio of the end-diastolic velocity of the bilateral common carotid artery (CCA-ED ratio) and the pulsatility index of the middle cerebral artery (MCA-PI) were significantly higher in patients with than in those without intracranial lesions. The cut-off value of the CCA-ED ratio was 1.55 (sensitivity, 66.7%; specificity, 81.6%), and that of the MCA-PI was 1.21 (sensitivity, 57.1%; specificity, 76.7%). CONCLUSION: Bedside ultrasonography is useful for predicting intracranial lesions requiring therapeutic intervention in ICU patients with impaired consciousness.

Hyperoxemia is Associated With Poor Neurological Outcomes in Patients With Out-of-Hospital Cardiac Arrest Rescued by Extracorporeal Cardiopulmonary Resuscitation: Insight From the Nationwide Multicenter Observational JAAM-OHCA (Japan Association for Acute Medicine) Registry.

BACKGROUND: Previous studies have shown an association between hyperoxemia and mortality in patients with out-of-hospital cardiac arrest (OHCA) after cardiopulmonary resuscitation (CPR); however, evidence is lacking in the extracorporeal CPR (ECPR) setting. OBJECTIVE: The aim of this study was to test the hypothesis that hyperoxemia is associated with poor neurological outcomes in patients treated by ECPR. METHODS: The Japanese Association for Acute Medicine OHCA Registry is a multicenter, prospective, observational registry of patients from 2014 to 2017. Adult (18 years or older) patients who had undergone ECPR after OHCA were included. Eligible patients were divided into two groups based on the partial pressure of oxygen in arterial blood (PaO2) levels at 24 h after ECPR: the high-PaO2 group (n = 242) defined as PaO2 ≥ 157 mm Hg (median) and the low-PaO2 group (n = 211) defined as PaO2 60 to < 157 mm Hg. The primary outcome was the favorable neurological outcome, defined as a Cerebral Performance Categories Scale score of 1 to 2 at 30 days after OHCA. RESULTS: Of 34,754 patients with OHCA, 453 patients were included. The neurological outcome was significantly lower in the high-PaO2 group than in the low-PaO2 group (15.9 vs. 33.5%; p < 0.001). After adjusting for potential confounders, high PaO2 was negatively associated with favorable neurological outcomes (adjusted odds ratio [aOR] 0.48; 95% confidence interval [CI] 0.24-0.97; p = 0.040). In a multivariate analysis with multiple imputation, high PaO2 was also negatively associated with favorable neurological outcomes (aOR 0.63; 95% CI 0.49-0.81; p < 0.001). CONCLUSIONS: Hyperoxemia was associated with worse neurological outcomes in OHCA patients with ECPR.

Association between short-term neurological outcomes and extreme hyperoxia in patients with out-of-hospital cardiac arrest who underwent extracorporeal cardiopulmonary resuscitation: a retrospective observational study from a multicenter registry.

BACKGROUND: To investigate the impact of hyperoxia that developed immediately after extracorporeal membrane oxygenation (ECMO)-assisted cardiopulmonary resuscitation (ECPR) on patients' short-term neurological outcomes after out-of-hospital cardiac arrest (OHCA). METHODS: This study retrospectively analyzed data from the Japanese OHCA registry from June 2014 to December 2017. We analyzed adult patients (≥ 18 years) who had undergone ECPR. Eligible patients were divided into the following three groups based on their initial partial pressure of oxygen in arterial blood (PaO2) levels after ECMO pump-on: normoxia group, PaO2 ≤ 200 mm Hg; moderate hyperoxia group, 200 mm Hg < PaO2 ≤ 400 mm Hg; and extreme hyperoxia group, PaO2 > 400 mm Hg. The primary and secondary outcomes were 30-day favorable neurological outcomes. Logistic regression statistical analysis model of 30-day favorable neurological outcomes was performed after adjusting for multiple propensity scores calculated using pre-ECPR covariates and for confounding factors post-ECPR. RESULTS: Of the 34,754 patients with OHCA enrolled in the registry, 847 were included. The median PaO2 level was 300 mm Hg (interquartile range: 148-427 mm Hg). Among the eligible patients, 277, 313, and 257 were categorized as normoxic, moderately hyperoxic, and extremely hyperoxic, respectively. Moderate hyperoxia was not significantly associated with 30-day neurologically favorable outcomes compared with normoxia as a reference (adjusted odds ratio, 0.86; 95% confidence interval: 0.55-1.35; p = 0.51). However, extreme hyperoxia was associated with less 30-day neurologically favorable outcomes when compared with normoxia (adjusted odds ratio, 0.48; 95% confidence interval: 0.29-0.82; p = 0.007). CONCLUSIONS: For patients with OHCA who received ECPR, extreme hyperoxia (PaO2 > 400 mm Hg) was associated with 30-day poor neurological outcomes. Avoidance of extreme hyperoxia may improve neurological outcomes in patients with OHCA treated with ECPR.

Delayed administration of epinephrine is associated with worse neurological outcomes in patients with out-of-hospital cardiac arrest and initial pulseless electrical activity: insight from the nationwide multicentre observational JAAM-OHCA (Japan Association for Acute Medicine) registry.

AIMS: The delayed administration of epinephrine has been proven to worsen the neurological outcomes of patients with out-of-hospital cardiac arrest (OHCA) and shockable rhythm or asystole. We aimed to investigate whether the delayed administration of epinephrine might also worsen the neurological outcomes of patients with witnessed OHCA and initial pulseless electrical activity (PEA). METHODS AND RESULTS: The JAAM-OHCA Registry is a multicentre registry including OHCA patients between 2014 and 2017. Patients with emergency medical services (EMS)-treated OHCA and initial PEA rhythm were included. The primary exposure was the time from the EMS call to the administration of epinephrine. The secondary exposure was the time to epinephrine dichotomized as early (≤15 min) or delayed (>15 min). The primary outcome was the achievement of a favourable neurological outcome, defined as Cerebral Performance Categories Scale 1-2 at 30 days after OHCA. Out of 34 754 patients with OHCA, 3050 patients were included in the present study. After adjusting for potential confounders, the delayed administration of the epinephrine was associated with a lower likelihood of achieving a favourable neurological outcome [adjusted odds ratio (OR) 0.96; 95% confidence interval (CI) 0.93-0.99; P = 0.016]. The percentage of patients who achieved a favourable neurological outcome in the delayed epinephrine group was lower than that in the early epinephrine group (1.3% vs. 4.7%; adjusted OR 0.33; 95% CI 0.15-0.72; P = 0.005). A restricted cubic spline analysis demonstrated that delayed epinephrine administration could decrease the likelihood of achieving a favourable neurological outcome; this was significant within the first 10 min. CONCLUSIONS: The delayed administration of epinephrine was associated with worse neurological outcomes in patients with witnessed OHCA patients with initial PEA.

L-citrulline inhibits body weight gain and hepatic fat accumulation by improving lipid metabolism in a rat nonalcoholic fatty liver disease model.

BACKGROUND: Body weight gain is a social issue all over the world. When body weight increased, hepatic fat accumulation also increased and it causes fatty liver disease. Therefore, developing a new treatment method and elucidating its mechanism is necessary. L-citrulline (L-Cit) is a free amino acid found mainly in watermelon. No reports regarding its effects on the improvement of hepatic steatosis and fibrogenesis are currently available. The aim of this study was to clarify the effect and the mechanism of L-Cit on inhibition of body weight gain and hepatic fat accumulation in high-fat and high-cholesterol fed SHRSP5/Dmcr rats. METHODS: L-Cit or water (controls) was administered to six-week-old male SHRSP5/Dmcr rats by gavage for nine weeks. We recorded the level of body weight and food intake while performing the administration and sacrificed rats. After that, the blood and lipid metabolism-related organs and tissues were collected and analyzed. RESULTS: L-Cit treatment reduced body weight gain and hepatic TC and TG levels, and serum levels of AST and ALT. L-Cit enhanced AMPK, LKB1, PKA, and hormone-sensitive lipase (HSL) protein phosphorylation levels in the epididymal fat. L-Cit treatment improved steatosis as revealed by HE staining of liver tissues and enhanced AMPK and LKB1 phosphorylation levels. Moreover, activation of Sirt1 was higher, while the liver fatty acid synthase (FAS) level was lower. Azan staining of liver sections revealed a reduction in fibrogenesis following L-Cit treatment. Further, the liver levels of TGF-ß, Smad2/3, and α-SMA, fibrogenesis-related proteins and genes, were lower in the L-Cit-treated group. CONCLUSIONS: From the results of analysis of the epididymal fat and the liver, L-Cit inhibits body weight gain and hepatic fat accumulation by activating lipid metabolism and promoting fatty acid ß-oxidation in SHRSP5/Dmcr rats.

Efficacy of thromboelastography in the management of anticoagulation for veno-venous extracorporeal membrane oxygenation in a coronavirus disease 2019 patient: A case report.

RATIONALE: In coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome refractory to optimal conventional management, we should consider the indication for veno-venous extracorporeal membrane oxygenation (V-V ECMO). Growing evidence indicates that COVID-19 frequently causes coagulopathy, presenting as hypercoagulation and incidental thrombosis. For these reasons, a multifactorial approach with several anticoagulant markers should be considered in the management of anticoagulation using heparin in COVID-19 patients on V-V ECMO. PATIENT CONCERNS: A 48-year-old man was infected with COVID-19 with a worsening condition manifesting as acute respiratory distress syndrome. DIAGNOSES: He was refractory to conventional therapy, thus we decided to introduce V-V ECMO. We used heparin as an anticoagulant therapy for V-V ECMO and adjusted the doses of heparin by careful monitoring of the activated clotting time (ACT) and activated partial thromboplastin time (APTT) to avoid both hemorrhagic and thrombotic complications. We controlled the doses of heparin in the therapeutic ranges of ACT and APTT, but clinical hemorrhaging and profound elevation of coagulant marker became apparent. INTERVENTIONS: Using thromboelastography (TEG; Haemonetics) in addition to ACT and APTT, we were able to clearly detect not only sufficient coagulability of COVID19 on V-V ECMO (citrated rapid thromboelastography-R 0.5 min, angle 75.5°, MA 64.0 mm, citrated functional fibrinogen-MA 20.7 mm) but also an excessive effect of heparin (citrated kaolin -R 42.7 min, citrated kaolin with heparinase 11.7 min). OUTCOMES: Given the TEG findings indicating an excessive heparin effect, the early withdrawal of ECMO was considered. After an evaluation of the patient's respiratory capacity, withdrawal from V-V ECMO was achieved and then anticoagulation was stopped. The hemorrhagic complications and elevated thrombotic marker levels dramatically decreased. LESSONS: TEG monitoring might be a useful option for managing anticoagulation in COVID-19 patients on V-V ECMO frequently showing a hypercoagulative state and requiring massive doses of heparin, to reduce both hemorrhagic and thrombotic complications.

Use of venovenous extracorporeal membrane oxygenation for perioperative management of acute respiratory distress syndrome caused by fat embolism syndrome: A case report and literature review.

INTRODUCTION: Fat embolism syndrome (FES) is a known complication of long bone fracture and can affect multiple organs. The organ most commonly affected with FES is the lung. Severe cases of FES from long bone fracture can cause acute respiratory distress syndrome (ARDS). Although the treatment of ARDS remains challenging, it is reported that a lung protection strategy and prone positioning are effective. In addition, early fixation is reported to be beneficial in respiratory failure due to FES, though it may exacerbate respiratory failure during the perioperative period. We report the use of venovenous extracorporeal membrane oxygenation (VV-ECMO) for the successful perioperative management of a patient diagnosed with ARDS due to FES. PATIENT CONCERNS: A 24-year-old man injured in a traffic accident was brought to our emergency department due to shock and consciousness disorder. DIAGNOSIS: After examining the patient, we noted bilateral pneumothorax, liver and spleen injuries, and multiple long bone fractures. Four days after admission, he was diagnosed with FES due to a prolonged consciousness disorder, progressive hypoxia with diffuse lung damage, and cutaneous and mucosal petechiae. INTERVENTION: As respiratory failure progressed, VV-ECMO was initiated on the 6th day. To improve the respiratory failure caused by ARDS, prone position therapy was necessary. Thus, we performed osteosynthesis on the 9th day under ECMO. Prone position therapy was started after surgery. OUTCOMES: Subsequently, his respiratory condition and chest radiographs improved steadily. VV-ECMO was discontinued on the 17th day and the ventilator was removed on the 28th day. His consciousness levels improved without residual central nervous system complications. CONCLUSION: Our study reveals the successful improvement of FES-induced ARDS by osteosynthesis and prone positioning under VV-ECMO. This strategy prioritizes supportive treatment over pharmacologic interventions.

Feasibility and efficacy of an ultra-short side branch-dedicated balloon in coronary bifurcation stenting.

BACKGROUND: Side branch (SB) dilation with an ultra-short balloon after main vessel (MV) stenting may minimise stent failure in coronary bifurcation lesions. AIMS: We sought to investigate the feasibility and efficacy of the Glider balloon (GB), a side branch (SB)-dedicated balloon 4 mm in length, in coronary bifurcation stenting. METHODS: In bench testing, stent configuration was examined with micro-focus computed tomography after crossover stenting followed by GB dilation or kissing balloon inflation (KBI). In the clinical study we performed GB dilatation after MV stenting for 207 lesions in 194 patients. Failure of the GB dilation and additional procedures due to inducible stent failure were investigated as well as adverse cardiac events at 1-year follow-up. RESULTS: In bench testing GB dilation maintained cross-sectional stent area without significant deformation and presented effective jailed strut removal in a high-angled bifurcation model. In the clinical study the cohort included left main, true bifurcation lesion, and two-stent treatment in 42.0%, 45.9%, and 14.0%, respectively. The proximal optimisation technique (POT) or POT-like inflation was performed in 82.1%. GB crossing failure, SB stenting due to dissection, and stent deformation requiring correction by KBI or MV dilation occurred in 8.7%, 1.4%, and 5.8%, respectively. Finally, simple GB dilation without KBI was completed in 91.8% for SB dilation. At one-year follow-up, target lesion revascularisation, cardiac death, myocardial infarction, and stent thrombosis were found in 7.2%, 2.1%, 2.1%, and 1.0%, respectively. CONCLUSIONS: Simple GB dilation after adequate expansion of the proximal MV stent provided acceptable acute and long-term results as an alternative to KBI.

Olmesartan combined with renal denervation reduces blood pressure in association with sympatho-inhibitory and aldosterone-reducing effects in hypertensive mice with chronic kidney disease.

BACKGROUND: Augmented sympathetic nerve activity (SNA) and renin-angiotensin-aldosterone system (RAAS) activity are involved in the pathogenesis of hypertension (HT) accompanied by chronic kidney disease (CKD). Oxidative stress in the hypothalamus increases SNA in HT. Administration of an angiotensin ΙΙ receptor blocker (olmesartan; OLM) or renal denervation (RDN) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combination therapy with OLM and RDN reduces both SNA by decreasing oxidative stress in the hypothalamus and RAAS activity in hypertensive mice with CKD. METHODS AND RESULTS: In 5/6-nephrectomized ICR-mice (Nx-mice) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by increased SNA and albuminuria compared with control-mice. Nx-mice were orally administered OLM, vehicle, or underwent RDN during OLM administration, and divided into Nx-OLM, Nx-VEH, and Nx-OLM/RDN groups, respectively. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH at 8-weeks after treatment, SBP was significantly decreased and both SNA and oxidative stress levels in the hypothalamus were significantly suppressed, without worsened creatinine clearance. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH, albuminuria was also suppressed, and the heart per body weight was decreased. In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration was significantly decreased compared with Nx-VEH. CONCLUSION: These findings suggest that combination therapy with OLM/RDN has antihypertensive effects in association with suppressing SNA by reducing oxidative stress in the hypothalamus and the plasma aldosterone concentration in hypertensive mice with CKD.

Renal denervation enhances GABA-ergic input into the PVN leading to blood pressure lowering in chronic kidney disease.

OBJECTIVE: Sympathoexcitation plays an important role in the pathogenesis of hypertension in patients with chronic kidney disease (CKD). The paraventricular nucleus of the hypothalamus (PVN) in the brain controls sympathetic outflow through γ-amino butyric acid (GABA)-ergic mechanisms. Renal denervation (RDN) exerts a long-term antihypertensive effect in hypertension with CKD; however, the effects of RDN on sympathetic nerve activity and GABA-ergic modulation in the PVN are not clear. We aimed to elucidate whether RDN modulates sympathetic outflow through GABA-ergic mechanisms in the PVN in hypertensive mice with CKD. METHODS AND RESULTS: In 5/6-nephrectomized male Institute of Cancer Research mice (Nx) at 4 weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by sympathoexcitation. The Nx-mice underwent RDN or sham operation, and the mice were divided into three groups (Control, Nx-Sham, and Nx-RDN). At 2 weeks after RDN, SBP was significantly decreased and urinary sodium excretion was increased in Nx-RDN compared with Nx-Sham. Urinary norepinephrine excretion (uNE) levels did not differ significantly between Nx-RDN and Nx-Sham. At 6 weeks after RDN, SBP continued to decrease and uNE levels also decreased in Nx-RDN compared with Nx-Sham. Bicuculline microinjection into the PVN increased mean arterial pressure and lumbar sympathetic nerve activity in all groups. The pressor responses and change in lumbar sympathetic nerve activity were significantly attenuated in Nx-Sham, but were enhanced in Nx-RDN at 6 weeks after RDN. CONCLUSIONS: The findings from the present study indicate that RDN has a prolonged antihypertensive effect and, at least in the late phase, decreases sympathetic nerve activity in association with enhanced GABA-ergic input into the PVN in mice with CKD.

Combining irbesartan and trichlormethiazide enhances blood pressure reduction via inhibition of sympathetic activity without adverse effects on metabolism in hypertensive rats with metabolic syndrome.

Sympathoexcitation and oxidative stress in the brain have pivotal roles in hypertension with metabolic syndrome (MetS). Here, we examined whether oral administration of irbesartan (IRB) and trichlormethiazide (TCM) decreases blood pressure (BP) via inhibiting sympathetic activity through anti-oxidant effects in the brain of spontaneously hypertensive rats (SHR-cp). IRB/TCM treatment decreased BP more profoundly than IRB monotherapy. Urinary norepinephrine excretion and oxidative stress in the brain were decreased in both IRB and IRB/TCM groups without any adverse effect on the metabolic profile. These findings suggest that IRB/TCM profoundly decreases BP in SHR-cp by inhibiting sympathetic activity via anti-oxidant effects in the brain.

[Effect of sympathetic nervous system on circadian rhythm of blood pressure].

There is evidence that the abnormal circadian rhythm of blood pressure (BP), such as absent of nocturnal BP fall and exaggerated morning BP surge, assessed by ambulatory BP monitoring is associated with cardiovascular events independent of BP levels in hypertensive patients. The activation of the sympathetic nervous system (SNS) is one of the most important pathophysiological mechanisms underlying abnormalities in circadian BP by affecting cardiac output, salt and volume balance in the kidney, and peripheral vascular resistance. In treating hypertension, especially accompanied by the abnormal circadian rhythm of BP, the effect of antihypertensive drug on SNS activity, as well as the timing of drug administration or the duration of the drug efficacy, should be considered.

Different role of oxidative stress in paraventricular nucleus and rostral ventrolateral medulla in cardiovascular regulation in awake spontaneously hypertensive rats.

OBJECTIVE: The rostral ventrolateral medulla (RVLM) of the brainstem and the paraventricular nucleus of the hypothalamus (PVN) are involved in the neural mechanisms of hypertension. Oxidative stress in the RVLM contributes to the enhanced central sympathetic outflow that leads to hypertension in experimental models of hypertension, such as spontaneously hypertensive rats (SHRs). We investigated the relative contribution of oxidative stress in the PVN and RVLM of SHR in blood pressure (BP) regulation. METHODS AND RESULTS: We transfected adenovirus vectors encoding the manganese superoxide dismutase gene (AdMnSOD) or ß-galactosidase gene (AdLacZ) bilaterally into the RVLM or PVN. Mean arterial pressure (MAP) and heart rate (HR) were monitored using a radiotelemetry system. Oxidative stress levels in the PVN of SHR evaluated by thiobarbituric acid-reactive substances were enhanced compared with those of Wistar-Kyoto rats and reduced by MnSOD transfection compared with nontransfected SHR. MAP and HR of AdMnSOD-RVLM-transfected SHR were decreased compared with AdLacZ-RVLM-transfected SHR. In contrast, MAP of AdMnSOD-PVN-transfected SHR was not decreased compared with AdLacZ-PVN-transfected SHR, but HR was decreased compared with AdLacZ-PVN-transfected SHR. MnSOD transfection into both the RVLM and PVN of SHR decreased MAP and elicited a profound decrease in HR. CONCLUSION: These findings indicate that inhibition of oxidative stress in the PVN decreases HR, but not BP in SHR, and elicits a further decrease in HR, but not BP, by interacting with the RVLM. Taken together, the oxidative stress in the PVN and RVLM plays a different role for cardiovascular regulation in SHR.

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats.

Mineralocorticoid receptor (MR) is recognized as a target for therapeutic intervention in hypertension and heart failure. MRs in the central nervous system are thought to have an important role in blood pressure regulation. Thus, we examined whether activation of the MR pathway in the rostral ventrolateral medulla (RVLM) of the brainstem contributes to the neural mechanism of hypertension in stroke-prone spontaneously hypertensive rats (SHRSPs). We microinjected eplerenone, aldosterone or Na(+)-rich artificial cerebrospinal fluid (aCSF) into the RVLM of anesthetized Wistar-Kyoto (WKY) rats and SHRSPs. Arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. The expressions of the MR protein and the serum- and glucocorticoid-regulated kinase protein (Sgk1), which is a marker of MR activity, in the RVLM were measured by western blot analysis. Bilateral microinjection of eplerenone into the RVLM decreased AP and RSNA in WKY rats and SHRSPs, and the decreases in those variables were significantly greater in SHRSPs than WKY rats. Microinjection of aldosterone or Na(+)-rich aCSF into the RVLM increased AP and RSNA dose-dependently. The increases in those variables were significantly greater in SHRSPs than in WKY rats. The pressor responses of aldosterone or Na(+)-rich aCSF were attenuated by the prior injection of eplerenone in SHRSPs. Sgk1 expression levels in the RVLM were significantly greater in SHRSPs than in WKY rats. These findings suggest that activation of MRs in the RVLM enhances sympathetic activity, thereby contributing to the neural mechanism of hypertension in the SHRSP.

Oxidative stress in the rostral ventrolateral medulla modulates excitatory and inhibitory inputs in spontaneously hypertensive rats.

OBJECTIVES: The rostral ventrolateral medulla (RVLM) of the brainstem and the paraventricular nucleus (PVN) of the hypothalamus play crucial roles in central cardiovascular regulation. In hypertensive rats, an imbalance of excitatory and inhibitory inputs to the RVLM enhances central sympathetic outflow. Increased reactive oxygen species (ROS) in the RVLM also contribute to sympathoexcitation, leading to hypertension. The aim of the present study was to elucidate whether ROS in the RVLM modulate synaptic transmission via excitatory and inhibitory amino acids and influence the excitatory inputs to the RVLM from the PVN in spontaneously hypertensive rats (SHRs). METHODS AND RESULTS: We transfected adenovirus vectors encoding the manganese superoxide dismutase (AdMnSOD) gene to scavenge ROS in the RVLM both in Wistar-Kyoto rats and SHRs. The decreases in blood pressure and renal sympathetic nerve activity (RSNA) evoked by injecting kynurenic acid, a glutamate receptor blocker, into the RVLM were attenuated, and the increases in blood pressure and RSNA evoked by injecting bicuculline, a γ-amino butyric acid (GABA) receptor blocker, into the RVLM were enhanced in AdMnSOD-transfected SHRs compared with adenovirus vectors encoding the ß-galactosidase (AdLacZ) gene-transfected SHRs. Furthermore, the increases in blood pressure and RSNA evoked by injecting bicuculline into the PVN were attenuated in AdMnSOD-transfected SHRs compared with AdLacZ-transfected SHRs. CONCLUSION: These findings suggest that ROS in the RVLM enhance glutamatergic excitatory inputs and attenuate GABAergic inhibitory inputs to the RVLM, thereby increasing sympathoexcitatory input to the RVLM from the PVN in SHRs.