Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A

Perico, Norberto; Benigni, Ariela; Zoja, Carla; Delaini, Federica; Remuzzi, Giuseppe

doi:10.1152/ajprenal.1986.251.4.f581

Cited by 77 publications

(50 citation statements)

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“…Nitric oxide-mediated relaxations induced by sodium nitroprusside are not altered in arteries from cyclosporine-treated rats, suggesting that alterations in endothelial cell rather than vascular smooth muscle cell function are more important in cyclosporine-induced vasoconstriction. The enhanced production of vasoconstricting prostanoids 23 and of endothelin 24 described in subjects treated with cyclosporine may arise as a consequence of a loss of EDNO-mediated inhibition of the production of these agents. 25 Equally important, a decrease in EDNO activity predictably will lead to enhanced vasoconstriction induced by angiotensin II.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporine produces endothelial dysfunction by increased production of superoxide.

et al. 1994

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Vasoconstriction and hypertension are major side effects of cyclosporine therapy. The mechanism or mechanisms responsible for the vascular effects of cyclosporine are unclear. The vascular effects of cyclosporine may arise as a consequence of endothelial dysfunction induced by the agent. To test this possibility, we compared in vessels prepared in myographs endothelium-mediated relaxations of mesenteric resistance arteries of Wistar-Kyoto rats treated for 21 to 28 days with subcutaneous injections of cyclosporine (25 mg/kg per day) or vehicle. Endothelium-dependent relaxations in response to acetylcholine were impaired in arteries from cyclosporine-treated rats; the concentrations of acetylcholine required to produce 50% relaxation of norepinephrine activation (pD 2 ) were 31.6±0.1 versus 5±0.1 nmol/L in control arteries (P<.05). Nitro-L-arginine produced comparable 10-fold decreases in sensitivity to acetylcholine in arteries from both rat groups, indicating that the relaxations were mediated by endothelium-derived nitric oxide. Acetylcholine-induced H ypertension and nephrotoxicity are major side effects of cyclosporine-induced vasoconstriction. Vasoconstriction induced by cyclosporine is both acute in onset and persistent during chronic administration of the agent.12 Administration of a single dose of cyclosporine to healthy individuals produces an abrupt 20% to 30% decrease in renal blood flow and glomerular filtration rate over the course of 2 hours. 1 Similarly, renal blood flow and glomerular filtration rate increase after cyclosporine is stopped in subjects who have received the drug for more than a year.3 The mechanism or mechanisms responsible for cyclosporineinduced vasoconstriction remain poorly understood. Three mechanisms have received the most attention: (1) an increase in intracellular calcium with enhancement of vasoconstrictor responses, 4 -5 (2) activation of the sympathetic nervous system, 6 and (3) cyclosporine-induced endothelial dysfunction. 79 Studies described in this report will focus on the effects of cyclosporine on endothelial function. Endothelial cells modulate vascular smooth muscle tone in large part by regulated production of endothelium-derived nitric oxide (EDNO) and to a lesser extent of vasodilating prostaglandins. relaxations in cyclosporine-treated arteries were normalized by pretreatment of the arteries with superoxide dismutase (150 IU/mL; pD 2 , 3.6±0.1; P<.Q5); superoxide dismutase had no effect on relaxations in control arteries. SQ 29,548, an inhibitor of prostaglandin H 2 /thromboxane A, receptors; H-7, an inhibitor of protein kinase C; and indomethacin did not alter relaxations in response to acetylcholine in either group of arteries. Cyclosporine-treated arteries were more sensitive than control arteries to nitroprusside, an agent that induces relaxation via nitric oxide (pD 2 , 1.3 and 6.2 /unol/L, respectively; P<.05). Thus, cyclosporine impairs relaxations mediated by endothelium-derived nitric oxide in mesenteric arteries via enhanced production of f...

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Section: Discussionmentioning

confidence: 99%

Cyclosporine produces endothelial dysfunction by increased production of superoxide.

et al. 1994

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“…Glomerular filtration rate and renal plasma flow were measured by inulin and para-aminohippuric acid clearance methods, respectively, 10 and blood pressure was measured by 24-hour ambulatory blood pressure monitoring (A&A Medical, TM-2430).…”

Section: Methodsmentioning

confidence: 99%

Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy

et al. 2010

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Abstract-The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria Ͼ0.5 and Ͻ3.0 g, systolic blood pressure Ͼ135 and Ͻ170 mm Hg, and/or diastolic blood pressure Ͼ85 and Ͻ110 Key Words: diabetic nephropathy Ⅲ urotensin antagonist Ⅲ RAAS blockade Ⅲ hypertension Ⅲ albuminuria Ⅲ palosuran U rotensin II, initially described as the most potent vasoconstrictor known in mammals, 1,2 is upregulated in hypertension and diabetic nephropathy and, therefore, has been hypothesized to be involved in the development of albuminuria. 3-5 Palosuran (ACT-058362) is an oral, selective, competitive, nonpeptidic antagonist of the human urotensin receptor and has been extensively studied in experimental models of renal failure. In these models, palosuran displayed renoprotective potential by beneficial effects on renal blood flow, proteinuria, and development of glomerular and tubulointerstitial damage. 6,7 Thus far, no controlled data in humans are available. This multicenter, randomized, doubleblind, placebo-controlled, 2-period crossover, proof-ofconcept study was designed to assess whether palosuran would reduce urinary albumin excretion (UAE) and/or systemic blood pressure in hypertensive patients with type 2 diabetic nephropathy on stable treatment with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II-receptor type 1 antagonist. MethodsPatients of both sexes, age Ͼ30 to Ͻ75 years, with type 2 diabetes mellitus (with or without insulin treatment) and hemoglobin A1c Ͻ10%, hypertension (systolic/diastolic blood pressure Ն135 to Ͻ170 mm Hg and/or Ն85 to Ͻ110 mm Hg), macroalbuminuria (UAE Ն0.5 and Ͻ3.0 g/24 hours), and a measured creatinine clearance Ն30 mL/min per 1.73 m 2 were recruited. Diabetic nephropathy was defined as the presence of macroalbuminuria. Renal biopsy for confirmation was not required. All of the patients gave their written informed consent. The study was conducted in full adherence to the principles of the Declaration of Helsinki. Patients had to be on stable single renin-angiotensin-aldosterone system (RAAS) blockade for Ն3 months. Any treatment with other antihypertensives, statins, and nonsteroidal antiinflammatory drugs had to be stable. Patients had stable renal function in the last 6 months. Exclusion criteria included combined angiotensin II-receptor type 1 antagonist and angiotensin-

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“…The precise mechanism by which CsA induced renal vasoconstriction has not been clearly established. Results from several studies indicate that vascular dysfunction induced by CsA results from an increase in vasoconstrictor factors that include endothelin (28), thromboxane (46), and angiotensin II (45,65) as well as a reduction of vasodilator factors such as prostacyclin (45) and nitric oxide (NO) (10,11,17,34,69). Thus an imbalance in the release of vasoactive substances seems to be responsible for renal vasoconstriction.…”

Section: Mechanisms Of Csa Nephrotoxicitymentioning

confidence: 99%

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Bobadilla¹,

Gamba²

2007

American Journal of Physiology-Renal Physiology

117

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Cyclosporine A (CsA), a calcineurin inhibitor, has improved allograft survival in solid organ transplantation and has been increasingly applied in the management of autoimmune diseases. While marked progress has been made in patient and allograft survival rates, clinical use of CsA is often limited by its nephrotoxic effect, which can be presented as two distinct and well-characterized forms: acute and chronic nephrotoxicity. The acute form is characterized by renal vasoconstriction, induced by an imbalance of vasoactive substances release, which leads to renal dysfunction. This form is reversible. The chronic toxicity, in contrast, is characterized by the vasoconstriction plus the development of structural damage that includes arteriolopathy and tubulointerstitial fibrosis that are often not reversible. The exact mechanisms of these deleterious effects are not fully understood, but major advances have occurred over the last few years. Here we review the current literature regarding the pathogenesis and strategies that have been used to ameliorate renal injury in chronic CsA nephrotoxicity. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CsA nephrotoxicity and that spironolactone could be a useful agent to prevent it. These studies and the use of mineralocorticoid receptor blockade are discussed.

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Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A

Cited by 77 publications

References 0 publications

Cyclosporine produces endothelial dysfunction by increased production of superoxide.

Cyclosporine produces endothelial dysfunction by increased production of superoxide.

Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

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