Satomi Konno

Mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla.

Objectives Reactive oxygen species (ROS) in the central nervous system are thought to contribute to sympathoexcitation in cardiovascular diseases such as hypertension and heart failure. Nicotinamide adenine dinucleotide phosphate oxidase is a major source of ROS in the central nervous system, which acts as a key mediator (mediators) of angiotensin II (AngII). It is not clear, however, whether mitochondria-derived ROS in the central nervous system also participate in sympathoexcitation. Methods In an in-vivo study, we investigated whether the AngII-elicited pressor response in the rostral ventrolateral medulla, which controls sympathetic nerve activity, is attenuated by adenovirus-mediated gene transfer of a mitochondria-derived antioxidant (Mn-SOD). In an in-vitro study, using differentiated PC-12 cells with characteristics similar to those of sympathetic neurons, we examined whether AngII increases mitochondrial ROS production. Results Overexpression of Mn-SOD attenuated the AngII-induced pressor response and also suppressed AngII-induced ROS production, as evaluated by microdialysis in the rostral ventrolateral medulla. Using reduced MitoTracker red, we showed that AngII increased mitochondrial ROS production in differentiated PC-12 cells in vitro. Overexpression of Mn-SOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed AngII-induced ROS production. Depletion of extracellular Ca2+ with ethylene glycol bis-N,N,N′,N′-tetraacetate (EGTA) and administration of p-trifluoromethoxycarbonylcyanide phenylhydrazone, which prevents further Ca2+ uptake into the mitochondria, blocked AngII-elicited mitochondrial ROS production. Conclusion These results indicate that AngII increases the intracellular Ca2+ concentration and that the increase in mitochondrial Ca2+ uptake leads to mitochondrial ROS production.

Angiotensin II Type 1 Receptor–Activated Caspase-3 Through Ras/Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase in the Rostral Ventrolateral Medulla Is Involved in Sympathoexcitation in Stroke-Prone Spontaneously Hypertensive Rats

In the rostral ventrolateral medulla (RVLM), angiotensin II-derived superoxide anions, which increase sympathetic nerve activity, induce a pressor response by activating the p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK) pathway. The small G protein Ras mediates a caspase-3–dependent apoptotic pathway through p38 MAPK, ERK, and c-Jun N-terminal kinase. We hypothesized that angiotensin II type 1 receptors activate caspase-3 through the Ras/p38 MAPK/ERK/c-Jun N-terminal kinase pathway in the RVLM and that this pathway is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human hypertension. The activities of Ras, p38 MAPK, ERK, and caspase-3 in the RVLM were significantly higher in SHRSP (14 to 16 weeks old) than in age-matched Wistar-Kyoto rats (WKY). The mitochondrial apoptotic proteins Bax and Bad in the RVLM were significantly increased in SHRSP compared with WKY. c-Jun N-terminal kinase activity did not differ between SHRSP and WKY. In SHRSP, intracerebroventricular infusion of a Ras inhibitor significantly reduced sympathetic nerve activity and improved baroreflex sensitivity, partially because of inhibition of the Ras/p38 MAPK/ERK, Bax, Bad, and caspase-3 pathway in the RVLM. Intracerebroventricular infusion of a caspase-3 inhibitor also inhibited sympathetic nerve activity and improved baroreflex sensitivity in SHRSP. Intracerebroventricular infusion of an angiotensin II type 1 receptor blocker in SHRSP partially inhibited the Ras/p38 MAPK/ERK, Bax, Bad, and caspase-3 pathway in the RVLM. These findings suggest that in SHRSP, angiotensin II type 1 receptor-activated caspase-3 acting through the Ras/p38 MAPK/ERK pathway in the RVLM might be involved in sympathoexcitation, which in turn plays a crucial role in the pathogenesis of hypertension.

Azelnidipine decreases sympathetic nerve activity via antioxidant effect in the rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats

The long-acting dihydropyridine calcium channel blocker, azelnidipine, is suggested to inhibit sympathetic nerve activity. We previously demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM) activates sympathetic nerve activity. The aim of the present study was to determine whether oral administration of azelnidipine inhibits sympathetic nerve activity and if so to determine whether the effect is mediated by antioxidant effect in the RVLM. Azelnidipine, hydralazine, or vehicle was orally administered for 28 days to stroke-prone spontaneously hypertensive rats. Reductions in systolic blood pressure were similar in azelnidipine and hydralazine groups. Heart rate was significantly higher in the hydralazine group than in the control, but not altered in the azelnidipine group. Urinary norepinephrine excretion as an indicator of sympathetic nerve activity was significantly lower in the azelnidipine group, whereas it was significantly higher in the hydralazine group than in the control. Levels of thiobarbituric acid-reactive substances and nicotinamide adenine dinucleotide phosphate oxidase activity were significantly lower in the azelnidipine group than in control. Superoxide dismutase activity was significantly increased in the azelnidipine group more than in the control. These results suggest that azelnidipine decreases an indicator of sympathetic nerve activity by antioxidant effect mediated through inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity and activation of superoxide dismutase in the RVLM of stroke-prone spontaneously hypertensive rats.

Angiotensin II receptor blockers improve endothelial dysfunction associated with sympathetic hyperactivity in metabolic syndrome.

Objectives: Renin–angiotensin system inhibitors are preferred for the treatment of hypertension with metabolic syndrome (MetS). Underlying endothelial dysfunction and sympathetic nervous system (SNS) activation are critically involved in the pathogenesis of hypertension in MetS. We investigated whether treatment with angiotensin II type 1 receptor blockers (ARBs) improves endothelial and autonomic function in patients with MetS. Methods and results: We conducted a prospective, randomized, open-label, blinded endpoint trial. Sixty patients with MetS were randomized into three treatment groups: telmisartan, candesartan, or diet therapy (control; n = 20 each), and treated for 6 months. To evaluate the endothelial function of forearm resistance arteries, blood flow and vascular resistance were measured using a strain-gauge plethysmograph during intra-arterial infusion of acetylcholine (ACh) or sodium nitroprusside (SNP). At 6 months, both telmisartan and candesartan comparably decreased blood pressure. Furthermore, ARB treatment ameliorated impaired forearm vasodilation in response to ACh. Telmisartan had a greater effect than candesartan on ACh-induced forearm vasodilation. In contrast, forearm vasodilation in response to SNP was comparable between the telmisartan and candesartan-treated groups. ARB treatment increased high-molecular-weight (HMW) adiponectin levels and baroreflex sensitivity, but telmisartan had a stronger effect than candesartan. In addition, only telmisartan treatment significantly decreased plasma norepinephrine concentrations, blood pressure variability, and heart rate variability based on spectral analysis. Conclusion: These findings indicate that ARBs improve impaired endothelial and baroreflex function, and increase HMW adiponectin levels in patients with MetS. Telmisartan exhibited more beneficial effects than candesartan, and only telmisartan reduced sympathetic hyperactivity, despite similar depressor effects.

SYMPATHOINHIBITORY EFFECTS OF TELMISARTAN THROUGH THE REDUCTION OF OXIDATIVE STRESS IN THE ROSTRAL VENTROLATERAL MEDULLA OF OBESITY-INDUCED HYPERTENSIVE RATS

Objectives: Sympathetic nervous system (SNS) activity is critically involved in the development and progression of obesity-induced hypertension. Angiotensin II type 1 receptor (AT1R)-induced oxidative stress in the rostral ventrolateral medulla (RVLM), a vasomotor center in the brainstem, activates the SNS in hypertensive rats. The aim of the present study was to determine whether oral administration of an AT1R blocker (ARB) inhibits SNS activity via antioxidative effects in the RVLM of rats with dietary-induced obesity. Methods and results: Obesity-prone rats fed a high-fat diet were divided into groups treated with either telmisartan obesity-prone (TLM-OP), or losartan obesity-prone (LOS-OP), or vehicle obesity-prone (VEH-OP). SBP, SNS activity, and oxidative stress in the RVLM were significantly higher in obesity-prone rats than in obesity-resistant rats. Body weight, visceral fat, blood glucose, serum insulin, and plasma adiponectin concentrations were significantly lower in TLM-OP and LOS-OP than in VEH-OP, and plasma adiponectin concentrations were significantly higher in TLM-OP than in LOS-OP. Although SBP was reduced to similar levels both in TLM-OP and LOS-OP, both oxidative stress in the RVLM and SNS activity were significantly lower in TLM-OP than in LOS-OP or VEH-OP. Conclusion: Orally administered telmisartan inhibited SNS activity through antioxidative effects via AT1R blockade in the RVLM of obesity-prone rats. AT1R and oxidative stress in the RVLM might be novel treatment targets for obesity-induced hypertension through sympathoinhibition, and telmisartan might be preferable for obesity-induced hypertension.

Calorie Restriction inhibits Sympathetic Nerve Activity via Anti-Oxidant Effect in the Rostral Ventrolateral Medulla of Obesity-Induced Hypertensive Rats

Abstract In the patients and animals with metabolic syndrome (MetS), sympathetic nerve activity (SNA) is increased. We have demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM), a vasomotor center in the brainstem, increases SNA. The aim of the present study was to determine whether calorie restriction inhibits SNA via anti-oxidant effect in the RVLM of obesity-induced obesity rats. Male Sprague-Dawley rats were fed on a high-fat diet and segregated into obesity-prone (OP) showing a MetS profile and obesity-resistant (OR) after 13 weeks. Obesity-prone was divided into OP treated with calorie restriction (CR-OP) for 8 weeks and control (CTR-OP). Systolic blood pressure (SBP), heart rate (HR), SNA, and thiobarbituric acid-reactive substances (TBARS) levels as a marker of oxidative stress in the RVLM were significantly higher and the depressor effects due to the microinjection of tempol, a superoxide dismutase mimetic into the RVLM, were significantly greater in OP than in OR. Body weight was significantly lower in CR-OP than in CTR-OP. SBP, HR, SNA, TBARS, and the depressor effects due to the microinjection of tempol into the RVLM were significantly lower in CR-OP than in CTR-OP. These results suggest that calorie restriction inhibits SNA via anti-oxidant effect in the RVLM of obesity-induced obesity rats.

Cilnidipine Inhibits the Sympathetic Nerve Activity and Improves Baroreflex Sensitivity in Patients with Hypertension

N-type calcium channel blocker, cilnidipine, is reported not to increase the heart rate in spite of the strong depressor effect. However, it has not been determined whether cilnidipine has the sympatho-inhibitory effects or not. Moreover, the effect of cilnidipine on the baroreflex control has not been determined. The aim of this study was to determine the effect of cilnidipine on sympathetic and parasympathetic nerve activity, and baroreflex sensitivity. We studied five hypertensive patients treated with 10 mg cilnidipine (10-mg group) and five hypertensive patients treated with 20 mg cilnidipine (20-mg group). Before the treatment and 6 months after the treatment, we measured the blood pressure, spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV), and blood pressure variability (BPV). After 6 months, systolic blood pressure (SBP) and the low-frequency component of systolic BPV expressed in normalized units (LFnuSBP), as the parameter of sympathetic nerve activity, was significantly decreased in both groups, and the suppressive effects were stronger in the 20-mg group than in the 10-mg group. The high-frequency component of HRV expressed in normalized units, as the parameter of parasympathetic nerve activity, and BRS were significantly increased in 20-mg group, but not significant in 10-mg group. These results suggest that 6 months treatment with cilnidipine for hypertension has the sympatho-inhibtory effect, and that high-dose cilnidipine improves the parasympathetic nerve activity and baroreflex control in patients with hypertension.

Sympathoinhibition induced by centrally administered atorvastatin is associated with alteration of NAD(P)H and Mn superoxide dismutase activity in rostral ventrolateral medulla of stroke-prone spontaneously hypertensive rats.

Oxidative stress in the rostral ventrolateral medulla (RVLM) increases sympathetic nervous system activity (SNA). Oral treatment with atorvastatin decreases SNA through antioxidant effects in the RVLM of stroke-prone spontaneously hypertensive rats (SHRSP). We aimed to examine whether centrally administered atorvastain reduces SNA in SHRSP and, if so, to determine whether it is associated with the reduction of oxidative stress induced by alteration of activities of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase and superoxide dismutase (SOD) in the RVLM of SHRSP. SHRSP received atorvastatin (S-ATOR) or vehicle (S-VEH) by continuous intracerebroventricular infusion for 14 days. Mean blood pressure, heart rate, and SNA were significantly lower in S-ATOR than in S-VEH. Oxidative stress, Rac1 activity, NAD(P)H oxidase activity, Rac1, gp91phox and p22phox expression in the membrane fraction, and p47phox and p40phox expression in the cytosolic fraction in the RVLM were significantly lower in S-ATOR than in S-VEH. Rac1 expression in the cytosolic fraction and Mn-SOD activity, however, were significantly higher in S-ATOR than in S-VEH. Our findings suggest that centrally administered atorvastatin decreases SNA and is associated with decreasing NAD(P)H oxidase activity and upregulation of Mn-SOD activity in the RVLM of SHRSP, leading to suppressing oxidative stress.

Atorvastatin Improves the Impaired Baroreflex Sensitivity via Anti-Oxidant Effect in the Rostral Ventrolateral Medulla of SHRSP

We have demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM), a vasomotor center in brainstem, increases sympathetic nerve activity (SNA) and that oral administration of atorvastatin inhibited SNA via anti-oxidant effect in the RVLM of stroke-prone spontaneously hypertensive rats (SHRSPs). The impairment of baroreflex sensitivity (BRS) is known as the predictive factor of mortality in the hypertension and BRS is impaired in SHRSP. The aim of the present study was to determine whether oral administration of atorvastatin improved the impaired BRS via anti-oxidant effect in the RVLM in SHRSP. Atorvastatin (20 mg/kg/day) or vehicle was orally administered for 28 days in SHRSPs. Systolic blood pressure (SBP), heart rate, and 24-h urinary norepinephrine excretion as an indicator of SNA were comparable between atorvastatin- and control-SHRSP. Thiobarbituric acid-reactive substance (TBARS) levels as a marker of oxidative stress was significantly lower in atorvastatin-SHRSP than in control-SHRSP. Baroreflex sensitivity measured by the spontaneous sequence method was significantly higher in atorvastatin-SHRSP than in control-SHRSP. These results suggest that atorvastatin improves the impaired BRS in SHRSP via its anti-oxidant effect in the RVLM of SHRSP.

New Scoring System Available at Home Health Care for Prediction of 14 DaysSurvival in Lung Cancer Complicated with Lymphangitic Carcinomatosis

Objective: Patients with lung cancer often greeted their terminal phase in the treatment at home, and many cases complicated with lymphangitic carcinomatosis took a sudden turn. The aim of the present study was to determine a scoring system available at home health care for prediction of short-term survival of lung cancer complicated with lymphangitic carcinomatosis. Methods: In 14 lung cancer patients with lymphangitic carcinomatosis in our medical care at home, we determined significant close correlated and independent factors for assuming death during 14 days by logisticregression analysis, and made out new scoring system. Moreover, we determined cut-off value on receiveroperating characteristics analysis. Results: In our scoring system calculated as the summation points awarded for the presence of 5 parameters (i.e., systolic blood pressure 100 beats/minute, 3 point; blood oxygen saturation 2 L/minute, 2 point; respiratory frequency>20 times/minute, 3 point), cut-off value was 8 (sensitivity 90%, specificity 68%). Conclusions: We made a new a scoring system available at home health care for prediction of 14 days survival of lung cancer complicated with lymphangitic carcinomatosis assumed systolic blood pressure, pulse rate, respiratory frequency, blood oxygen saturation, and oxygen dose.