Tetsuji Katayama

Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

Objective— There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal–regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood–brain barrier breakdown and white matter lesions. Approach and Results— A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCAS-induced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1−/−) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-&agr; expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1−/− mice. BCAS decreased claudin-5 expression and disrupted blood–brain barrier in the corpus callosum of wild-type but not ASK1−/− mice. Cerebral nitrotyrosine was increased in wild-type and ASK1−/− BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-&agr; stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1−/− mice. Conclusions— Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through blood–brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion–induced cognitive impairment.

Long-Term Renal Denervation Normalizes Disrupted Blood Pressure Circadian Rhythm and Ameliorates Cardiovascular Injury in a Rat Model of Metabolic Syndrome

Background Although renal denervation significantly reduces blood pressure in patients with resistant hypertension, the role of the renal nerve in hypertension with metabolic syndrome is unknown. We investigated the impact of long‐term renal denervation on SHR/NDmcr‐cp(+/+) (SHRcp) rats, a useful rat model of metabolic syndrome, to determine the role of the renal nerve in hypertension with metabolic syndrome. Methods and Results SHRcp rats were divided into (1) a renal denervation (RD) group and (2) a sham operation group (control) to examine the effects of long‐term RD on blood pressure circadian rhythm, renal sodium retention‐related molecules, the renin‐angiotensin‐aldosterone system, metabolic disorders, and organ injury. RD in SHRcp rats not only significantly reduced blood pressure but also normalized blood pressure circadian rhythm from the nondipper to the dipper type, and this improvement was associated with an increase in urinary sodium excretion and the suppression of renal Na+‐Cl− cotransporter upregulation. RD significantly reduced plasma renin activity. RD significantly prevented cardiovascular remodeling and impairment of vascular endothelial function and attenuated cardiovascular oxidative stress. However, RD failed to ameliorate obesity, metabolic disorders, and renal injury and failed to reduce systemic sympathetic activity in SHRcp rats. Conclusions By including the upregulation of the Na+‐Cl− cotransporter, the renal sympathetic nerve is involved in the disruption of blood pressure circadian rhythm as well as hypertension in metabolic syndrome. Thus, RD seems to be a useful therapeutic strategy for hypertension with metabolic syndrome.

Novel Mechanism for Disrupted Circadian Blood Pressure Rhythm in a Rat Model of Metabolic Syndrome—The Critical Role of Angiotensin II

Background This study was performed to determine the characteristics and mechanism of hypertension in SHR/NDmcr‐cp(+/+) rats (SHRcp), a new model of metabolic syndrome, with a focus on the autonomic nervous system, aldosterone, and angiotensin II. Methods and Results We measured arterial blood pressure (BP) in SHRcp by radiotelemetry combined with spectral analysis using a fast Fourier transformation algorithm and examined the effect of azilsartan, an AT1 receptor blocker. Compared with control Wistar‐Kyoto rats (WKY) and SHR, SHRcp exhibited a nondipper‐type hypertension and displayed increased urinary norepinephrine excretion and increased urinary and plasma aldosterone levels. Compared with WKY and SHR, SHRcp were characterized by an increase in the low‐frequency power (LF) of systolic BP and a decrease in spontaneous baroreflex gain (sBRG), indicating autonomic dysfunction. Thus, SHRcp are regarded as a useful model of human hypertension with metabolic syndrome. Oral administration of azilsartan once daily persistently lowered BP during the light period (inactive phase) and the dark period (active phase) in SHRcp more than in WKY and SHR. Thus, angiotensin II seems to be involved in the mechanism of disrupted diurnal BP rhythm in SHRcp. Azilsartan significantly reduced urinary norepinephrine and aldosterone excretion and significantly increased urinary sodium excretion in SHRcp. Furthermore, azilsartan significantly reduced LF of systolic BP and significantly increased sBRG in SHRcp. Conclusions These results strongly suggest that impairment of autonomic function and increased aldosterone in SHRcp mediate the effect of angiotensin II on circadian blood pressure rhythms.

Renal Denervation Prevents Stroke and Brain Injury via Attenuation of Oxidative Stress in Hypertensive Rats

Background Although renal denervation (RD) is shown to reduce blood pressure significantly in patients with resistant hypertension, the benefit of RD in prevention of stroke is unknown. We hypothesized that RD can prevent the incidence of stroke and brain injury in hypertensive rats beyond blood pressure lowering. Methods and Results High‐salt‐loaded, stroke‐prone, spontaneously hypertensive rats (SHRSP) were divided into 4 groups: (1) control; (2) sham operation; (3) bilateral RD; and (4) hydralazine administration to examine the effect of RD on stroke and brain injury of SHRSP. RD significantly reduced the onset of neurological deficit and death in SHRSP, and this protection against stroke by RD was associated with the increase in cerebral blood flow (CBF), the suppression of blood–brain barrier disruption, the limitation of white matter (WM) lesions, and the attenuation of macrophage infiltration and activated microglia. Furthermore, RD significantly attenuated brain oxidative stress, and NADPH oxidase subunits, P67 and Rac1 in SHRSP. On the other hand, hydralazine, with similar blood pressure lowering to RD, did not significantly suppress the onset of stroke and brain injury in SHRSP. Furthermore, RD prevented cardiac remodeling and vascular endothelial impairment in SHRSP. Conclusions Our present work provided the first experimental evidence that RD can prevent hypertensive stroke and brain injury, beyond blood pressure lowering, thereby highlighting RD as a promising therapeutic strategy for stroke as well as hypertension.

Pretreatment with rosuvastatin protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress and inflammation.

This study aimed to examine the potential protective effect of rosuvastatin against cerebral ischemia/reperfusion injury and its mechanisms. Forty-eight male SD rats underwent 90 min of transient middle cerebral artery occlusion (tMCAO), followed by reperfusion. Rats were orally given (1) rosuvastatin 1mg/kg, (2) rosuvastatin 10mg/kg or (3) water (vehicle) once a day from 7 days before to 1 day after induction of tMCAO. Neurological score, infarct volume, and oxidative stress-related molecules (assessed by immunohistochemistry, dihydroethidium staining, or western blotting) were estimated at 24h after reperfusion. Rosuvastatin prevented the impairment of neurological function and decreased the infarct volume, compared with the vehicle group. The increases in activated microglia, macrophage, and superoxide levels usually caused by ischemia/reperfusion were significantly ameliorated by rosuvastatin. Rosuvastatin also inhibited the upregulation of gp91(phox) and p22phox, phosphorylation of nuclear factor-kappa B, and induction of cyclooxygenase 2 and inducible nitric oxide synthase, compared with vehicle. The results suggest that pretreatment with rosuvastatin may be a promising therapeutic strategy for cerebral ischemia/reperfusion injury, through attenuation of oxidative stress and inflammation.

Telmisartan Exerts Sustained Blood Pressure Control and Reduces Blood Pressure Variability in Metabolic Syndrome by Inhibiting Sympathetic Activity

BACKGROUND Accumulating evidence on blood pressure (BP) reduction with various angiotensin II receptor blockers (ARBs) show that the magnitudes and durations of BP control differ across ARBs. However, the mechanism of ARBs is unknown. This work was undertaken to compare telmisartan and valsartan in duration of BP control, BP variability, and effects on the autonomic nervous system. METHODS Using radiotelemetry combined with spectral analysis with a fast Fourier transformation algorithm, we compared the effects of various doses of telmisartan and valsartan on BP and its variability during dark (active phase) and light (inactive phase) periods over 5 weeks in SHR/NDmcr-cp(+/+)(SHRcp) rats, a model of metabolic syndrome. We also compared the effects of these ARBs on autonomic nervous system, central oxidative stress, and inflammation in SHRcp rats. RESULTS Telmisartan exerted a longer-lasting BP-lowering effect and greater attenuation of BP variability in SHRcp than valsartan. Telmisartan decreased low frequency power of systolic BP and increased spontaneous baroreflex gain in SHRcp during both the dark and light periods more than valsartan. Telmisartan reduced 24-hour urinary norepinephrine excretion more than valsartan. Furthermore, telmisartan attenuated oxidative stress and the numbers of gp91(phox)-positive cells and activated microglia and astrocytes in the rostral ventrolateral medulla of SHRcp rats more than valsartan. CONCLUSIONS The superiority of telmisartan over valsartan in sustained BP control and reduction of BP variability was attributed to more suppression of sympathetic activity and more improvement of baroreceptor reflex. The greater suppression of sympathetic activity by telmisartan appeared to be partially mediated by a stronger amelioration of central oxidative stress.

Calcium Channel Blockers, More than Diuretics, Enhance Vascular Protective Effects of Angiotensin Receptor Blockers in Salt-Loaded Hypertensive Rats

The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.