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

DIABETOLOGY

DPP-4 inhibition with linag in cerebral oxidative stress in transient cerebral ischemia-subjected diabetic mice. Furthermore, linagliptin rotective uation of strategy fo

Blocking Periostin Prevented Development of Inflammation in Rhabdomyolysis-Induced Acute Kidney Injury Mice Model

Background: Rhabdomyolysis is the collapse of damaged skeletal muscle and the leakage of muscle-cell contents, such as electrolytes, myoglobin, and other sarcoplasmic proteins, into the circulation. The glomeruli filtered these products, leading to acute kidney injury (AKI) through several mechanisms, such as intratubular obstruction secondary to protein precipitation. The prognosis is highly mutable and depends on the underlying complications and etiologies. New therapeutic plans to reduce AKI are now needed. Up to now, several cellular pathways, with the nuclear factor kappa beta (NF-kB), as well as the proinflammatory effects on epithelial and tubular epithelial cells, have been recognized as the major pathway for the initiation of the matrix-producing cells in AKI. Recently, it has been mentioned that periostin (POSTN), an extracellular matrix protein, is involved in the development of inflammation through the modulation of the NF-kB pathway. However, how POSTN develops the inflammation protection in AKI by rhabdomyolysis is uncertain. This study aimed to investigate the role of POSTN in a rhabdomyolysis mice model of AKI induced by an intramuscular injection of 50% glycerol. Methods: In vivo, we performed an intramuscular injection of 50% glycerol (5 mg/kg body weight) to make rhabdomyolysis-induced AKI. We examined the expression level of POSTN through the progression of AKI after glycerol intramuscular injection for C57BL/6J wildtype (WT) mice. We sacrificed mice at 72 h after glycerol injection. We made periostin-null mice to examine the role of POSTN in acute renal failure. The role of periostin was further examined through in vitro methods. The development of renal inflammation is linked with the NF-kB pathway. To examine the POSTN function, we administrated hemin (100 μM) on NIH-3T3 fibroblast cells, and the following signaling pathways were examined. Results: The expression of periostin was highly increased, peaking at about 72 h after glycerol injection. The expression of inflammation-associated mRNAs such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-a) and IL-6, and tubular injury score in H-E staining were more reduced in POSTN-null mice than WT mice at 72 h after glycerol injection. Conclusion: POSTN was highly expressed in the kidney through rhabdomyolysis and was a positive regulator of AKI. Targeting POSTN might propose a new therapeutic strategy against the development of acute renal failure

Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: The critical role of ASK1 and VEGF

This study was undertaken to elucidate a novel mechanism underlying angiotensin II-induced cardiac injury, focusing on the role of oxidative stress and myocardial capillary density. Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats), a useful model for hypertensive cardiac remodeling or heart failure, were orally given irbesartan (an AT1 receptor blocker), tempol (a superoxide dismutase mimetic) or hydralazine (a vasodilator). Irbesartan significantly ameliorated left ventricular ischemia and prevented the development of cardiac hypertrophy and fibrosis in DS rats. The benefits were associated with the attenuation of oxidative stress, normalization of myocardial capillary density and inhibition of capillary endothelial apoptosis. Moreover, DS rats with significant cardiac hypertrophy and fibrosis displayed decreased myocardial vascular endothelial growth factor (VEGF) expression and increased cardiac apoptosis signal-regulating kinase 1 (ASK1) activation. Treatment with irbesartan significantly reversed these phenotypes. Tempol treatment of DS rats mimicked all the above-mentioned effects of irbesartan, indicating the critical role of oxidative stress in cardiac injury. We also investigated the role of VEGF and ASK1 in oxidative stress-induced endothelial apoptosis by using cultured endothelial cells from wild-type and ASK1-deficient mice. Oxidative stress-induced ASK1 activation led to endothelial apoptosis, and VEGF treatment prevented oxidative stress-induced endothelial apoptosis by inhibiting ASK1 activation. We obtained the first evidence that oxidative stress-induced cardiac VEGF repression and ASK1 activation caused the enhancement of endothelial apoptosis and contributed to a decrease in myocardial capillary density. These effects resulted in angiotensin II-induced progression of cardiac injury