Role of Nitric Oxide in Cyclosporine A–Induced Hypertension

Oriji, G.K.; Keiser, Harry R.

doi:10.1161/01.hyp.32.5.849

Cited by 70 publications

(46 citation statements)

References 32 publications

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“…The potential role of calcineurin in eNOS regulation also may help to explain the underlying mechanism involved in the development of arterial hypertension in organ transplant recipients who are administered cyclosporin A (30). This negative side effect seems to be caused by reduced NO release from the endothelium (31,32). The molecular mechanism by which cyclosporin A affects NO release is not known but likely involves the drug acting as a selective inhibitor of the Ca 2ϩ -CaM-dependent serine/threonine-specific protein phosphatase calcineurin (27).…”

Section: Resultsmentioning

confidence: 99%

Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin Stimulation

Harris

Venema

et al. 2001

Journal of Biological Chemistry

339

275

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Section: Resultsmentioning

confidence: 99%

Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin Stimulation

Harris

Venema

et al. 2001

Journal of Biological Chemistry

339

275

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“…Reduced NO production is implicated in the mechanisms not only for vasoconstriction and tubular fibrosis (Andoh et al, 1997;Assis et al, 1997) but also for extrarenal complications of CsA (Oriji and Keiser, 1998;Fiore et al, 2000). Assis et al (1997) and Zhang et al (1999) also reported that Larginine improves renal function in transplanted patients with CsA.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Production Modulates Cyclosporin A-Induced Distal Renal Tubular Acidosis in the Rat

Tsuruoka¹,

Schwartz²,

Wakaumi³

et al. 2003

J Pharmacol Exp Ther

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Cyclosporine A (CsA) causes distal renal tubular acidosis (dRTA) in humans and rodents. Because mice deficient in nitricoxide (NO) synthase develop acidosis, we examined how NO production modulated H ϩ excretion during acid loading and CsA treatment in a rat model. Rats received CsA, L-arginine (L-Arg), or N -nitro-L-arginine methyl ester (L-NAME), or combinations of CsA and L-NAME or L-Arg, followed by NH 4 Cl (acute acid load). In vehicle-treated rats, NH 4 Cl loading reduced serum and urine (HCO 3 Ϫ ) and urine pH, which was associated with increases in serum [K ϩ ] and [Cl Ϫ ] and urine NH 3 excretion. Similar to CsA (7.5 mg/kg), L-NAME impaired H ϩ excretion of NH 4 Cl-loaded animals. The combination CsA and L-NAME reduced H ϩ excretion to a larger extent than either drug alone. In contrast, administration of L-Arg ameliorated the effect of CsA on H ϩ excretion. Urine pH after NH 4 Cl was 5.80 Ϯ 0.09, 6.11 Ϯ 0.13*, 6.37 Ϯ 0.16*, and 5.77 Ϯ 0.09 in the vehicle, CsA, CsA ϩ L-NAME and CsA ϩ L-Arg groups, respectively (*P Ͻ 0.05). The effect of CsA and alteration of NO synthesis were mediated at least in part by changes in bicarbonate absorption in perfused cortical collecting ducts. CsA or L-NAME reduced net HCO 3 Ϫ absorption, and, when combined, completely inhibited it. CsA ϩ L-Arg restored HCO 3 Ϫ absorption to near control levels. Administration of CsA along with L-NAME reduced NO production to below levels observed with either drug alone. These results suggest that CsA causes dRTA by inhibiting H ϩ pumps in the distal nephron. Inhibition of NO synthesis may be one of the mechanisms underlying the CsA effect.

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“…7,8,24 The reduction in aortic cNOS activity might be better explained by an effect on its complex enzymatic profile rather than by a reduction of L-arginine content or consumption, since previous studies have demonstrated that L-arginine supplementation was unable to prevent CsA-induced HT. 19,25 Thus, an effect on the enzymatic cofactors of cNOS may not be excluded, as already documented in other pathophysiological conditions.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Previous studies from our group, as well as from others, have shown a disequilibrium in the nitric oxide (NO)/cyclic guanosine-3=,5=-monophosphate (cGMP) system, which may contribute to the vascular hyperreactivity. 7,8 The NO system is essential to the relaxation of vascular smooth muscles cells (VSMC) and plays a pathophysiological role in reactive oxygen or nitrogen species (ROS) generation. 9 In addition, oxidative stress could also have a key role in CsA-associated cardiovascular toxicity.…”

Section: P Osttransplantation Hypertension (Ht)mentioning

confidence: 99%

Oxidative Stress in Cyclosporine-Induced Hypertension: Evidence of Beneficial Effects or Tolerance Development With Nitrate Therapy

Reis

Rocha‐Pereira

Lemos

et al. 2007

Transplantation Proceedings

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The aim of this study was to evaluate the effect of cyclosporine (CsA) on oxidative stress as well as the use of a nitric oxide (NO) donor, the organic nitrate isosorbide-5-mononitrate (Is-5-Mn), to prevent or reverse CsA-induced toxicity, namely on the vascular NO-cGMP pathway or on oxidative equilibrium. The following rat groups (n ϭ 8) were tested: (1) a control group; (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the preventive group (Is-5-Mn ϩ CsA) treated for 2 weeks with Is-5-Mn only, and thereafter with both drugs for 7 weeks; (5) the curative group (CsA ϩ Is-5-Mn) beginning 7 weeks after CsA, and following thereafter with both drugs for 5 weeks. The following parameters were evaluated: aortic cNOS activity and cGMP content; plasma levels of lipid peroxidation (malondialdehyde [MDA] levels); antioxidant capacity (glutathione peroxidase [GPx] and superoxide dismutase [SOD] activities, total antioxidant status, and vitamins A, C, and E); and peroxynitrite formation (3-nitrotyrosine [3-NT] content). Is-5-Mn ϩ CsA therapy showed, when compared with the CsA group, total prevention of CsAinduced NO and cGMP attenuation, and no relevant influence on antioxidant indices, as well as on MDA and 3-NT levels. However, when compared with this CsA group, the curative group (CsA ϩ Is-5-Mn) showed NO-cGMP values only partially reversed, and an enhancement in lipid peroxidation (5.6 Ϯ 1.4 vs 12.78 Ϯ 3.63 mol/L; P Ͻ .05) and in peroxynitrite formation (16.7% incidence of positives vs 83.3% incidence of positives). Our data suggested that nitrate therapy may provide a valid choice to prevent CsA-induced NO-cGMP decrease, without a negative influence on the oxidative equilibrium. However, when the local environment is adverse, as occurs after CsA therapy, Is-5-Mn seemed to enhance the CsA-induced oxidative stress, promoting even worse deleterious effects, probably through the generation of the cytotoxic ROS peroxynitrite.

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Role of Nitric Oxide in Cyclosporine A–Induced Hypertension

Cited by 70 publications

References 32 publications

Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin Stimulation

Reciprocal Phosphorylation and Regulation of Endothelial Nitric-oxide Synthase in Response to Bradykinin Stimulation

Nitric Oxide Production Modulates Cyclosporin A-Induced Distal Renal Tubular Acidosis in the Rat

Oxidative Stress in Cyclosporine-Induced Hypertension: Evidence of Beneficial Effects or Tolerance Development With Nitrate Therapy

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