Tissue Angiotensin II During Progression or Ventricular Hypertrophy to Heart Failure in Hypertensive Rats; Differential Effects on PKCε and PKCβ

Inagaki, Kenji; Iwanaga, Yoshitaka; Sarai, Nobuaki; Onozawa, Yoko; Takenaka, Hiroyuki; Mochly‐Rosen, Daria; Kihara, Yasuki

doi:10.1006/jmcc.2002.2089

Cited by 52 publications

(53 citation statements)

References 26 publications

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“…Our study is the first to our knowledge to provide direct evidence of BBB disruption caused by δPKC activation in an in vivo animal model. Although βIPKC is activated in the DS rat model (30), it is unlikely to be critical in this function because the βIPKC inhibitor did not affect the incidence of encephalopathy (data not shown).…”

Section: Figurementioning

confidence: 96%

“…Hypertensive DS rats develop symptoms of encephalopathy and stroke between 11 and 15 weeks of age while maintaining normal cardiac functions (30). During this period, about 60% of the animals die of encephalopathy.…”

Section: Introductionmentioning

confidence: 99%

“…During this period, about 60% of the animals die of encephalopathy. Around 16-17 weeks of age, the surviving rats (about 40% of the animals) begin to develop heart failure, and the animals die at about 21 weeks of age (30). Because we focused on encephalopathy, we only studied animals between the ages of 11 and 15 weeks.…”

Section: Introductionmentioning

confidence: 99%

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Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats

Qi¹,

Inagaki²,

Sobel³

et al. 2007

J. Clin. Invest.

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Hypertensive encephalopathy is a potentially fatal condition associated with cerebral edema and the breakdown of the blood-brain barrier (BBB). The molecular pathways leading to this condition, however, are unknown. We determined the role of δPKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using δV1-1 -a selective peptide inhibitor of δPKC. As a model of hypertensive encephalopathy, Dahl salt-sensitive rats were fed an 8% high-salt diet from 6 weeks of age and then were infused s.c. with saline, control TAT peptide, or δV1-1 using osmotic minipumps. The mortality rate and the behavioral symptoms of hypertensive encephalopathy decreased significantly in the δV1-1-treated group relative to the control-treated group, and BBB permeability was reduced by more than 60%. Treatment with δV1-1 was also associated with decreased δPKC accumulation in capillary endothelial cells and in the endfeet of capillary astrocytes, which suggests decreased microvasculature disruption. Treatment with δV1-1 prevented hypertension-induced tight junction disruption associated with BBB breakdown, which suggests that δPKC may specifically act to dysregulate tight junction components. Together, these results suggest that δPKC plays a role in the development of hypertension-induced encephalopathy and may be a therapeutic target for the prevention of BBB disruption.

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Section: Figurementioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats

Qi¹,

Inagaki²,

Sobel³

et al. 2007

J. Clin. Invest.

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“…Changes in plasma and tissue components of the reninangiotensin system (RAS) after salt loading are currently under debate because recent studies in Dahl salt-sensitive rats, an established model of salt-sensitive hypertension, have suggested that salt-sensitive hypertension is accompanied by an increase of cardiac ANG II (18,47) or renal angiotensinogen (23), whereas standard textbook theory predicts a decrease. In fact, it has been a general consensus that both plasma and tissue RAS activity are suppressed by short-term salt loading (7,24,45).…”

mentioning

confidence: 99%

“…In addition, it has been documented that a high-salt diet causes hypertension in rodents, such as Dahl salt-sensitive rats and DOCA-salt-sensitive rats (18,47), but not in normotensive wild-type (WT) mice. Establishing a salt-sensitive mouse model of hypertension would allow us to study the role of chymase in salt-dependent hypertension because WT mice carry human type ␣-chymase (mouse mast cell chymase-4 and -5).…”

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confidence: 99%

Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension

Devarajan

Yahiro

Uehara

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Devarajan S, Yahiro E, Uehara Y, Habe S, Nishiyama A, Miura S, Saku K, Urata H. Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension. Am J Physiol Heart Circ Physiol 309: H1987-H1996, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00721.2014.-The aim of the present study was to determine whether long-term high salt intake in the drinking water induces hypertension in wild-type (WT) mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. Eight-week-old male WT mice were supplied with drinking water containing 2% salt for 12 wk (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at four different doses (25, 50, 75, or 100 mg/kg), captopril (75 mg/kg), losartan (100 mg/kg), hydrochlorothiazide (3 mg/kg), eplerenone (200 mg/kg), or amlodipine (6 mg/kg). Control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, whereas a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan-and eplerenone-treated groups but not in the captopril-, hydrochlorothiazide-, and amlodipine-treated groups. A high salt load significantly increased chymasedependent ANG II-forming activity in the alimentary tract. In addition, the relative contribution of chymase to ANG II formation, but not actual average activity, showed a significant increase in skin and skeletal muscle, whereas angiotensin-converting enzyme-dependent ANG II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary renin-angiotensin system components were significantly increased in the high-salt group but were significantly suppressed in the chymase inhibitor-treated group. In conclusion, 2% salt water drinking for 12 wk caused moderate hypertension and activated the renin-angiotensin system in WT mice. A chymase inhibitor suppressed both the elevation of blood pressure and heart rate, indicating a definite involvement of chymase in salt-sensitive hypertension. mouse; high salt; hypertension; renin-angiotensin system; chymase inhibitor NEW & NOTEWORTHYOur study, for the first time, has provided 1) a new establishment of the salt-sensitive hypertensive mice model, 2) confirmation of direct involvement of chymase-mediated mechanisms proved using a specific chymase inhibitor, and 3) the inhibition of all renin-angiotensin-aldosterone components by a chymase inhibitor.THE ASSOCIATION between high salt (HS) intake and elevated blood pressure has been well established by cross-sectional and longitudinal epidemiological studies. Observational studies and clinical trials performed in the general population have indicated that a higher or lower salt intake is associated with an increase or a decrease of blood pressure, respectively (20, 32). However, the response of blood pressure to changes in salt intake...

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Biophysics of Membrane Currents in Heart Failure

Liu

Brahmanandam

Dudley

2013

Biophysics of the Failing Heart

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Tissue Angiotensin II During Progression or Ventricular Hypertrophy to Heart Failure in Hypertensive Rats; Differential Effects on PKCε and PKCβ

Cited by 52 publications

References 26 publications

Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats

Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats

Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension

Biophysics of Membrane Currents in Heart Failure

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