Endothelin‐1 plasma levels and hypertension in cyclosporine‐treated renal transplant patients

Abstract

Experimental models suggest that endothelin-1 (ET-1) has a significant role in the pathogenesis of cyclosporin A (CyA)-induced hypertension. However, its serum levels evaluated in different studies, including patients who received solid organ transplants, exhibited controversial results. Our study population consisted of 43 renal transplant patients: 33 were taking CyA as a component of their immunosuppressive regimen (CyA group) and 10 that were not taking CyA (control group). Baseline laboratory data, blood pressure and ET-1 levels were taken at baseline and 3 and 4 h after the ingestion of CyA. In the control group samples were collected in the corresponding periods of time. Blood pressure was significantly higher in the CyA group (mean blood pressure: 101.2 +/- 9.5 vs. 91.1 +/- 10.7 mmHg; p < 0.001), who also presented higher serum creatinine (1.2 +/- 0.28 vs. 0.97 +/- 0.13 mg/dL; p < 0.001) and ET-1 levels. In the CyA group an ET-1 peak was evident by the third hour after CyA ingestion that showed its maximum concentration after 1-2 h; the control group exhibited significantly lower levels of ET-1 (p = 0.044). ET-1 levels compared between patients with and without hypertension showed a non-statistically significant difference (1.54 +/- 0.76 vs. 1.27 +/- 0.62 ng/mL; p = 0.27, respectively). In conclusion, in the present study chronic CyA ingestion was associated with higher blood pressure and plasma ET-1 levels.

Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: Role of endothelin signaling

“…Although ET and its receptor sites have been implicated in the CSAevoked hypertension (Phillips et al, 1994;Bartholomeusz et al, 1996;Cauduro et al, 2005), no attempts were made to investigate the relative contributions of ET receptor subtypes (ET A and ET B ) in CSA hypertension. In fact, either nonselective ET A/B or selective ET A receptor antagonists were employed in previous studies including ours in order to verify the role of ET receptors in CSA hemodynamics (Phillips et al, 1994;Bartholomeusz et al, 1996;Nasser et al, 2014).…”

“…The clinical use of cyclosporine is often associated with serious cardiovascular disorders such as hypertension (Cauduro et al, 2005;Riva et al, 2013). The mechanisms of the hypertensive effect of CSA include sympathoexcitation (Zhang and Victor, 2000), enhanced reninangiotensin activity (Nishiyama et al, 2003), arterial baroreflex impairment (El-Mas et al, 2002, 2012b, oxidative stress (El-Mas et al, 2012b), vascular endothelium dysfunction (El-Mas et al, 2003, and interruption of brainstem nitric oxide synthase/heme oxygenase pathway and downstream guanylate cyclase activity (El-Mas et al, 2012c).…”

“…The mechanisms of the hypertensive effect of CSA include sympathoexcitation (Zhang and Victor, 2000), enhanced reninangiotensin activity (Nishiyama et al, 2003), arterial baroreflex impairment (El-Mas et al, 2002, 2012b, oxidative stress (El-Mas et al, 2012b), vascular endothelium dysfunction (El-Mas et al, 2003, and interruption of brainstem nitric oxide synthase/heme oxygenase pathway and downstream guanylate cyclase activity (El-Mas et al, 2012c). Moreover, experimental (Nasser et al, 2014) and clinical (Cauduro et al, 2005) studies suggest the involvement of endothelin (ET) in the pathogenesis of CSA hypertension. Nonselective blockade of ET receptors with bosentan (Bartholomeusz et al, 1996) or selective blockade of endothelin ET A receptors with BQ-123 (Phillips et al, 1994) abrogates the hypertensive response elicited by CSA.…”

Systems biology modeling of omics data: effect of cyclosporine a on the Nrf2 pathway in human renal cells

“…Other ROS scavenging mechanisms are present in RPTECs and could be involved during CsA exposure. On the other hand, CsA nephrotoxicity involves several mechanism [31-35] and it is possible that ROS generation is not alone in causing critical damages.…”

Therapeutic Targets in the Treatment of Allograft Fibrosis

“…In addition to its vasoconstrictive properties, which can result in ischemia damage, ET-1 promotes fibrosis by upregulating TGFb but also can directly stimulate collagen synthesis and limit collagen degradation. In kidney grafts with arteriosclerosis, ET receptor expression is upregulated in smooth muscle cells of the media (65) and systemic levels of ET-1 are elevated in cyclosporine treated kidney transplant recipients with hypertension (66). Use of a non-selective ET receptor antagonist after ischemic injury in the rat limited the fall in GFR (67).…”