Kiyohiro Ogawa

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.

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.

Exercise Training Causes Sympathoinhibition Through Antioxidant Effect in the Rostral Ventrolateral Medulla of Hypertensive Rats

Exercise training normalizes sympathetic outflow in hypertension and chronic heart failure. The aim of this study was to determine whether the exercise training inhibits sympathetic nerve activity (SNA) via reduction of oxidative stress through blocked angiotensin II type 1 receptor (AT1R) in rostral ventrolateral medulla (RVLM). We divided stroke-prone spontaneously hypertensive rats (SHRSP) into SHRSP with exercised training (SHRSP-EX) and control (SHRSP-C). SNA and oxidative stress in the RVLM were significantly lower in SHRSP-EX than in SHRSP-C. These results suggest that exercise training inhibits SNA via reduction of oxidative stress through blocked AT1R in the RVLM of hypertension.

Brain AT1 receptor activates the sympathetic nervous system through Toll-like receptor 4 in mice with heart failure

Abstract The activation of angiotensin II type 1 receptor (AT1R) in the brain plays a pivotal role in enhanced sympathetic drive in heart failure (HF). Activation of the AT1R in the brain produces oxidative stress and inflammation. Toll-like receptor 4 (TLR4) signaling in the brain induces the inflammatory cascade. We hypothesized that sympathoexcitation is mediated by the AT1R-activated TLR4 in the brainstem in HF. As a model of HF, the left coronary artery was ligated to induce a large myocardial infarction and subsequent chronic heart failure (CHF) in Institute of Cancer Research mice. On day 10 after the surgery, we started intracerebroventricular infusion of losartan (CHF-Los) or vehicle (CHF-Veh) via osmotic minipumps for 14 days. Expression level of the TLR4 in the brainstem was significantly higher in HF mice than in sham mice and significantly lower in CHF-Los mice than in CHF-Veh mice. Urinary norepinephrine excretion was significantly higher in HF mice than in sham mice and was significantly lower in CHF-Los than in CHF-Veh. Chronic intracerebroventricular infusion of angiotensin II increased the expression level of the second messenger of the TLR4. These results suggest that activation of the TLR4 via AT1R in the brainstem contributes to the sympathoexcitation probably due to the inflammation in the brain of the myocardial infarction–induced HF.

Partially silencing brain toll-like receptor 4 prevents in part left ventricular remodeling with sympathoinhibition in rats with myocardial infarction-induced heart failure.

Background Left ventricular (LV) remodeling and activation of sympathetic nervous system (SNS) are cardinal features of heart failure. We previously demonstrated that enhanced central sympathetic outflow is associated with brain toll-like receptor 4 (TLR4) probably mediated by brain angiotensin II type 1 receptor in mice with myocardial infarction (MI)-induced heart failure. The purpose of the present study was to examine whether silencing brain TLR4 could prevent LV remodeling with sympathoinhibition in MI-induced heart failure. Methodology/Principal Findings MI-induced heart failure model rats were created by ligation of left coronary artery. The expression level of TLR4 in brainstem was significantly higher in MI-induced heart failure treated with intracerebroventricular (ICV) injection of hGAPDH-SiRNA than in sham. TLR4 in brainstem was significantly lower in MI-induced heart failure treated with ICV injection of TLR4-SiRNA than in that treated with ICV injection of hGAPDH-SiRNA. Lung weight, urinary norepinephrine excretion, and LV end-diastolic pressure were significantly lower and LV dimension was significantly smaller in MI-induced heart failure treated with TLR4-SiRNA than in that treated with hGAPDH-SiRNA for 2 weeks. Conclusions Partially silencing brain TLR4 by ICV injection of TLR4-SiRNA for 2 weeks could in part prevent LV remodeling with sympathoinhibition in rats with MI-induced heart failure. Brain TLR4 has a potential to be a target of the treatment for MI-induced heart failure.

Combination therapy of olmesartan and azelnidipine inhibits sympathetic activity associated with reducing oxidative stress in the brain of hypertensive rats

It has been demonstrated that the antihypertensive drugs with the antioxidant action on the brainstem inhibit the sympathetic activity and consequently decrease blood pressure and heart rate (HR) in hypertensive rats. Combination drugs of the angiotensin receptor blocker and calcium channel blocker, such as olmesartan (OLM)/azelnidipine (AZ) and candesartan (CAN)/amlodipine (AM), are widely used for treating hypertension in Japan. In this study, it was investigated whether there are differences in the antioxidant effect in the brain and the sympathoinhibitory effect between OLM/AZ and CAN/AM combination therapies in stroke-prone spontaneously hypertensive rats (SHRSP). OLM/AZ (10/8 mg kg−1 day−1), CAN/AM (4/2.5 mg kg−1 day−1), or vehicle was orally administered for 30 days to SHRSP. OLM/AZ and CAN/AM markedly decreased systolic blood pressure to the same extent. OLM/AZ decreased HR to a greater extent than CAN/AM. Urinary norepinephrine excretion as a marker of sympathetic activity was unchanged in the CAN/AM group, but reduced in the OLM/AZ group. Oxidative stress in the whole brain assessed using the in vivo electron spin resonance method was similarly decreased in both OLM/AZ and CAN/AM groups. Importantly, thiobarbituric acid reactive substance levels in the brainstem were significantly lower in the OLM/AZ group, but not in the CAN/AM group, than in the vehicle group. These results suggest that combination therapy of either OLM/AZ or CAN/AM does not induce reflex-mediated sympathetic activation despite the marked blood pressure reduction, which is associated with an antioxidant effect in the brain regions affecting the sympathetic activity. Furthermore, the antioxidant effect in the brainstem and the sympathoinhibitory effect of OLM/AZ combination may be greater than those of CAN/AM combination treatment.

Successful recovery of tachycardia-induced cardiomyopathy with severely depressed left ventricular systolic function by catheter ablation with mechanical hemodynamic support: a case report.

We describe the case that persistent atrial fibrillation refractory to rhythm control by pharmacotherapy and electrical cardioversions caused tachycardia‐induced cardiomyopathy with low ejection fraction and hemodynamic instability. Mechanical hemodynamic support using an intra‐aortic balloon pump is one of the choices of hemodynamic support during catheter ablation by pulmonary vein isolation.