Mechanisms of the endothelial toxicity of cyclosporin A. Role of nitric oxide, cGMP, and Ca2+.

Gallego, M J; Villalón, A. L. García; Farré, A.J.; García, José Luis Rueda; Garrón, M P; Casado, Santos; Hernando, L; Caramelo, Carlos

doi:10.1161/01.res.74.3.477

Cited by 86 publications

(40 citation statements)

References 17 publications

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“…Our finding that CsA impairs the vasodilator response of rat aortic rings agrees with the findings of many studies. 8,18,21,22 Some investigators have reported findings similar to our own in narrowly defined aspects of the problem, but they have not integrated them into a comprehensive explanation of CsA-induced hypertension; for example, Gallego et al 23 showed that chronically administered CsA-induced endothelial dysfunction in rings of rat femoral artery and a decrease in ACh-induced endothelium-dependent relaxation, which was corrected by incubation of the rat arteries with L-Arg, 23 results that were similar to our findings. Where we differ is that while Gallego et al concentrated on Ca 2ϩ uptake, we showed that NO 2 /NO 3 , surrogates for NO production and cGMP, which mediates NO action, were decreased in both urine and aortic rings of animals treated with CsA and that chronic L-Arg administration reversed both in vivo and in vitro effects of CsA.…”

Section: Discussionmentioning

confidence: 76%

“…L-Arg completely normalized the excessive tension in response to ET that occurred in CsA-treated rats and it restored completely the vasodilatory response to ACh. Both Gallego et al, 23 who used rat femoral artery strips, and Kim et al, 15 who used rat thoracic aortic rings, found only partial restoration of ACh-induced vasodilation after preincubation of the aortic rings of CsA-treated rats with L-Arg. Both Gallego et al 23 and Kim et al 15 incubated the aortic rings with L-Arg and did not study the effects of L-Arg on MAP, whereas we administered L-Arg by intraperitoneal injection in the whole animal and studied changes in both MAP and tension.…”

Section: Discussionmentioning

confidence: 96%

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Role of Nitric Oxide in Cyclosporine A–Induced Hypertension

Oriji

Keiser

1998

Hypertension

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Abstract-Cyclosporine A (CsA) is an immunosuppressive agent that also causes hypertension. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and isolated rat aortic rings. Male rats weighing 250 to 300 g were given either CsA (25 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) in olive oil or vehicle by intraperitoneal injection for 7 days. CsA administration produced a 42% increase (PϽ0.001) in mean arterial pressure (MAP) that reached a plateau after 3 days. Conversely, the levels of both nitrate/nitrite, metabolites of nitric oxide (NO), and cGMP, which mediates NO action, decreased by 50% (PϽ0.001) and 35% (PϽ0.001), respectively, in the urine. Thoracic aortic rings from rats treated with CsA and precontracted with endothelin (10 Ϫ9 mol/L) showed a 35% increase (PϽ0.001) in tension, whereas endothelium-dependent relaxation induced by acetylcholine (ACh, 10 Ϫ9 mol/L) was inhibited 65% (PϽ0.001) compared with that in untreated rats. This response was similar to that of endothelium-denuded aortic rings from untreated rats in which ACh-induced relaxation was completely abolished (PϽ0.001), but relaxation induced by S-nitroso-Nacetylpenicillamine (SNAP, 10 Ϫ8 mol/L) was unaffected (PϽ0.001). ACh-induced formation of both nitrate/nitrite and cGMP by both denuded and CsA-treated aortic rings was inhibited 95% (PϽ0.001) and 65% (PϽ0.001), respectively, compared with intact aortic rings. The effects of CsA were reversed both in vivo and in vitro by pretreatment with L-arginine (10 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 IP), the precursor of NO. There were no changes in MAP and tension in rats treated with L-arginine alone. In summary, CsA inhibits endothelial NO activity, with resulting increases in MAP and tension, and this inhibition can be overcome by parenteral administration of L-arginine. (Hypertension. 1998;32:849-855.)Key Words: cyclosporine Ⅲ arginine Ⅲ endothelin Ⅲ acetylcholine Ⅲ nitrates Ⅲ rats Ⅲ aortic rings C yclosporine A (CsA) is a potent immunosuppressive agent that is associated with the development of arterial hypertension.1,2 Numerous articles have reported data that support many possible causes for the hypertension, but none have really clarified the mechanism.3 As a result, effective treatment of CsA-induced hypertension remains empiric.Therefore, this study aimed to answer the following questions: (1) What vasoactive system abnormalities, if any, accompany CsA-induced hypertension in the whole animal? (2) Are similar abnormalities found in isolated aortic rings from CsA-treated animals? (3) Does direct measurement of the vasoactive substance(s) produced by the rings provide evidence of the abnormality? (4) Can CsA toxicity be overcome by administration of an agent that should remedy the abnormality? By performing complementary studies in the whole animal, isolated aortic rings, and the fluid that bathed those rings, we found that CsA toxicity is associated with an inhibition of nitric oxide (NO) activity that can be overcome by pretreatment with L-arginine (L-Arg). Methods AnimalsMale Sprague-Dawley rats weighing 2...

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 96%

Role of Nitric Oxide in Cyclosporine A–Induced Hypertension

Oriji

Keiser

1998

Hypertension

View full text Add to dashboard Cite

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“…The endothelium-dependent relaxation to Ach and the endothelium-independent relaxation to SNP were tested on arteries precontracted with 10 -5 mol·L -1 phenylephrine as reported previously. 13 The doseresponse curves were determined in a cumulative manner. All the experiments were performed in the presence of indomethacin (10 -5 mol·L -1 ) to block any effect mediated by the activation of cyclooxygenase which could hide the NO-related effects.…”

Section: Méthode : Les Expériences Ont éTé Réalisées Sur Des Segmentsmentioning

confidence: 99%

Sevoflurane reduces endothelium-dependent vasorelaxation: role of Superoxide anion and endothelin

et al. 2002

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“…Interestingly, other studies emphasized the potential role of different mediators, prostaglandins, endothelins, nitric oxide, TGF-␤, etc. (13,21,24,29,34). However, despite these efforts, the information gathered at the present from the various experimental approaches cannot be assembled in an unifying view of the CsA-induced nephrotoxicity.…”

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confidence: 99%

Cyclosporine A Amplifies Ca2+ Signaling Pathway in LLC-PK1 Cells through the Inhibition of Plasma Membrane Ca2+ Pump

Calderaro

Boccellino

Cirillo³

et al. 2003

Journal of the American Society of Nephrology

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ABSTRACT. Cyclosporine A (CsA), a neutral, highly hydrophobic cyclic peptide with 11 amino acids, is currently the most widely used immunosuppressive drug for preventing graft rejection and autoimmune diseases. Despite its efficacy, the use of CsA is limited by severe side effects, mainly nephrotoxicity and arterial hypertension. Single cell microfluorimetry was used to evaluate the role of CsA on Ca2+ signaling pathway in intact cells of the porcine proximal tubule-like cell line LLC-PK1; the assay of the in vitro activity of the plasma membrane Ca2+ pump (PMCA) was carried out through the preparation and isolation of membranes. The addition of CsA to incubation medium at doses ranging from 0.1 to 2 μM did not change the basal level of intracellular calcium ([Ca2+]i), whereas it affected the [Ca2+]i response to thapsigargin (TG), a powerful inhibitor of microsomal Ca2+ pump. In control studies, 5 μM TG produced a biphasic response: [Ca2+]i peaked with a 60-s lag, and it then declined to a plateau of elevated [Ca2+]i, which remains above basal. However, it became evident that CsA strengthened the Ca2+ response to TG because the addition of 5 μM TG to cells exposed to 400 nM CsA did not affect the peak response to TG, but it markedly affected the subsequent sustained phase ([Ca2+]i = 156 ± 4.84 versus 130 ± 3.28 nmol, mean ± SEM, n = 6, P < 0.001). In membrane preparations, 200 nM CsA brought about, in the presence of 10 μM calmodulin (CaM), a significant decrease of plasma membrane Ca2+ pump (PMCA) activity (46.96 ± 0.26 versus 53.48 ± 1.96 nmol · mg of protein−1 · min−1, n = 6, P < 0.02), a value similar to that obtained in the presence of equimolar amounts of cyclosporine H (CsH), a non-immunosuppressive analogue of CsA. These findings suggest that in this cell line CsA affects the Ca2+ export pathway through the reduction of the PMCA activity with consequent amplification and strengthening of [Ca2+]i response after exposure to agents that trigger intracellular Ca2+ release. The increased cell sensitivity during Ca2+ signaling events ensuing from the impairment of this “defense system” may be regarded as one of the basic mechanisms involved in the development of the side effects induced by CsA. E-mail: vincenzo.calderaro@unina2.it

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Mechanisms of the endothelial toxicity of cyclosporin A. Role of nitric oxide, cGMP, and Ca2+.

Cited by 86 publications

References 17 publications

Role of Nitric Oxide in Cyclosporine A–Induced Hypertension

Role of Nitric Oxide in Cyclosporine A–Induced Hypertension

Sevoflurane reduces endothelium-dependent vasorelaxation: role of Superoxide anion and endothelin

Cyclosporine A Amplifies Ca2+ Signaling Pathway in LLC-PK1 Cells through the Inhibition of Plasma Membrane Ca2+ Pump

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