Cyclosporin-induced endothelial dysfunction and hypertension: are nitric oxide system abnormality and oxidative stress involved?

Calò, Lorenzo A.; Semplicini, Andrea; Davis, Paul A.; Bonvicini, P.; Cantaro, S.; Rigotti, Paolo; D’Angelo, Angela; Livi, Ugolino; Antonello, Augusto

doi:10.1007/s001470050374

Cited by 29 publications

(20 citation statements)

References 24 publications

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“…3,7,8,10,47 The present study provides direct evidence that Ang II and ROS formations are actually augmented in CysA-induced hypertensive rats. We have also demonstrated that antihypertensive effects of AT 1 receptor blockade and Tempol are associated with reductions in ROS levels in these animals, indicating the contribution of Ang II-dependent ROS production to the development of CysA-induced hypertension.…”

Section: Perspectivessupporting

confidence: 61%

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Role of Angiotensin II and Reactive Oxygen Species in Cyclosporine A–Dependent Hypertension

et al. 2003

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Abstract-Treatment with cyclosporine A (CysA), a potent immunosuppressive agent, is associated with systemic and renal vasoconstriction, leading to hypertension. The present study was conducted to elucidate the contribution of angiotensin II (Ang II) to CysA-induced hypertension and reactive oxygen species (ROS) generation. CysA (30 mg/kg per day SC), given for 3 weeks in rats, increased systolic blood pressure (SBP) from 119Ϯ2 to 145Ϯ3 mm Hg (nϭ7). Plasma and kidney Ang II levels were significantly higher in CysA-treated rats (136Ϯ10 fmol/mL and 516Ϯ70 fmol/g) than in vehicle-treated (1 mL olive oil) rats (76Ϯ10 fmol/mL and 222Ϯ21 fmol/g, nϭ7). CysA treatment increased AT 1 receptor protein expression in the aorta (by 251Ϯ35%), whereas it was reduced in the kidney (by Ϫ32Ϯ4%). Superoxide anion production in aortic segments and kidney thiobarbituric acid-reactive substance (TBARS) contents were higher in CysA-treated rats (26Ϯ2 counts/min per milligram and 37Ϯ3 nmol/g) than in vehicle-treated rats (17Ϯ1 counts/min per milligram and 24Ϯ3 nmol/g). Concurrent administration of an AT 1 receptor antagonist, valsartan (30 mg/kg per day, in drinking water), to CysA-treated rats (nϭ7) significantly decreased SBP (113Ϯ4 mm Hg) and prevented increases in vascular superoxide (16Ϯ2 counts/min per milligram) and kidney TBARS contents (21Ϯ3 nmol/g). Similarly, treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6,-tetramethylpiperidine-N-oxyl (Tempol; 3 mmol/L in drinking water, nϭ7), prevented CysA-induced increases in SBP (115Ϯ3 mm Hg), vascular superoxide (16Ϯ1 counts/min per milligram), and kidney TBARS contents (19Ϯ2 nmol/g). These data suggest that ROS generation induced by augmented Ang II levels contributes to the development of CysA-induced hypertension. Key Words: angiotensin antagonist Ⅲ antioxidants Ⅲ receptors, angiotensin II Ⅲ renin C yclosporine A (CysA) is a potent immunosuppressive agent and is widely used after organ transplantation and in the treatment of several autoimmune diseases. 1 However, its clinical use is frequently complicated by systemic and renal vasoconstriction, leading to arterial hypertension. 2 Although numerous factors have been implicated, 2 several lines of evidence suggest an involvement of the renin-angiotensin system in the development of CysA-induced hypertension. 3-10 Increased plasma renin activity and renin content in kidney tissues were observed in rats treated with long-term CysA 4 . It was also shown that CysA treatment augmented angiotensin II (Ang II)-induced vasoconstriction in isolated arterioles 5 or calcium response in vascular smooth muscle cells. 6 Lasssila et al 7,8 demonstrated that treatment with an ACE inhibitor or an AT 1 receptor antagonist abrogates CysA-induced hypertension and vascular dysfunction in spontaneously hypertensive rats (SHR) fed a high salt diet. Further clinical studies showed that treatment with an ACE inhibitor or an AT 1 receptor antagonist reduced blood pressure in hypertensive CysA-treated patients after renal transplantation. 9,10...

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Section: Perspectivessupporting

confidence: 61%

“…Recent clinical studies indicate that ROS levels are elevated in CysA-treated hypertensive patients. 10,47 Therefore, the antioxidative actions of AT 1 receptor blockade could explain some of beneficial effects of AT 1 receptor antagonists in recently reported clinical studies. 3,9,10 …”

Section: Perspectivesmentioning

confidence: 99%

Role of Angiotensin II and Reactive Oxygen Species in Cyclosporine A–Dependent Hypertension

et al. 2003

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“…Similar to our study, they also found cyclosporine induced up-regulation of the NO system in transplanted patients. 9 Antioxidant defense system is important for counter-balancing increased oxidative stress; however, using antioxidants for the long term and in high levels can cause their consumption and make them insufficient to overcome the increased burden. In our study, plasma glutathione levels before transplant were higher in patients than in controls.…”

Section: Discussionmentioning

confidence: 99%

“…4,8 Patients in these studies also demonstrate upregulation of the nitric oxide (NO) system, as suggested by increased endothelial nitric oxide synthase (NOS) gene expression and nitrite/nitrate levels. 9,10 In another study, the effects of cyclosporine and tacrolimus on advanced oxidation protein products and total antioxidant status were compared for 6 months and no significant differences were found. 11 Kanbay and associates also found no differences on serum uric acid levels in stable kidney transplant recipients using both calcineurin inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Changes in Oxidative Stress in Renal Graft Patients Receiving Calcineurin Inhibitors: Cyclosporine Versus Tacrolimus

Akbasli¹,

Keven²,

Erbay³

et al. 2012

Exp Clin Transplant

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“…In hypertensive kidney transplant patients under chronic CsA treatment, in fact, quantification of mononuclear cell endothelial NO synthase mRNA and NO metabolites plasma levels showed, compared to normotensive controls, an upregulation of NO system notwithstanding the presence of hypertension, in addition to increased hydroperoxides and peroxynitrite plasma levels, which were also present in patients compared to control subjects [26]. This suggests that CsA-induced vasoconstriction and hypertension cannot be a consequence of decreased levels of ecNOS as both ecNOS mRNA as well as NOS enzymatic activity were increased, as indicated by increased levels of plasma NO metabolites [26], making rationale the case of the induction of a NO mediated counterregulatory mechanism protective from CsA-induced vasoconstriction. This counterregulatory mechanism was also shown in normal human volunteers in whom acute infusion of CsA produced vasoconstriction and a simultaneous increase in endothelial NO release, and in cultured endothelial cells where the incubation with CsA increased ecNOS gene expression [27].…”

Section: Angiotensin II and Oxidative Stressmentioning

confidence: 99%

Pathophysiology of Post Transplant Hypertension in Kidney Transplant: Focus on Calcineurin Inhibitors Induced Oxidative Stress and Renal Sodium Retention and Implications with RhoA/Rho Kinase Pathway

Calò¹,

Ravarotto²,

Simioni³

et al. 2017

Kidney Blood Press Res

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Post-transplant hypertension is a common occurrence during treatment with calcineurin inhibitors (CNIs) in kidney transplant population. The pathogenesis of vasoconstriction induced by CNIs involves vascular tone alterations and kidney sodium transport regulation. Among the factors involved a key role is played by the activation of intrarenal renin-angiotensin system with enhanced release of Angiotensin II (Ang II) and increase of oxidative stress. A common pathway between oxidative stress and hypertension induced by CNIs may be identified in the involvement of the activation of RhoA/Rho kinase pathway, key for the induction of hypertension and cardiovascular-renal remodeling, of the oxidative stress mediated increased nitric oxide (NO) metabolism and increased renal sodium retention via increased activity of thiazide-sensitive sodium chloride cotransporter (NCC) in the distal tubule. We examined literature data including those coming from our group regarding the role of oxidative stress and sodium retention in CNIs induced hypertension and their involvement in cardiovascular-renal remodeling. Based on the available data, we have provided support to the activation of RhoA/Rho kinase pathway as an important effector in the pathophysiology of CNIs induced post-transplant hypertension via activation of oxidative stress and sodium retention. Clarification of how the biochemical and molecular mechanisms that regulate the processes involved in CNIs induced post transplant hypertension work and interact, would provide further insights not only into the comprehension of the pathophysiology of CNIs induced post transplant hypertension but could also have a positive impact on the clinical ground through the identification of significant targets. Their specific pharmacologic targeting might have multiple beneficial effects on the whole cardiovascular-renal function. The demonstration that in kidney transplanted patients with CNIs induced post-transplanted hypertension, the treatment of hypertension with different antihypertensive drugs inducing a comparable blood pressure reduction but different effects for example on oxidative stress and oxidative stress related proteins and/or Rho kinase and sodium retention, could be helpful for the choice of the antihypertensive treatment in these patients which takes advantage from effects of these drugs beyond blood pressure reduction.

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Cyclosporin-induced endothelial dysfunction and hypertension: are nitric oxide system abnormality and oxidative stress involved?

Cited by 29 publications

References 24 publications

Role of Angiotensin II and Reactive Oxygen Species in Cyclosporine A–Dependent Hypertension

Role of Angiotensin II and Reactive Oxygen Species in Cyclosporine A–Dependent Hypertension

Changes in Oxidative Stress in Renal Graft Patients Receiving Calcineurin Inhibitors: Cyclosporine Versus Tacrolimus

Pathophysiology of Post Transplant Hypertension in Kidney Transplant: Focus on Calcineurin Inhibitors Induced Oxidative Stress and Renal Sodium Retention and Implications with RhoA/Rho Kinase Pathway

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