Selective impairment of endothelium-mediated vasodilation in liver transplant recipients with cyclosporin A -induced hypertension

Abstract

Arterial hypertension is commonly observed in orthotopic liver transplantation (OLT) recipients receiving cyclosporin A (CsA), but the precise pathogenetic mechanisms remain partially unknown. The aim of this study was to investigate endothelium-dependent and -independent dilation and adrenergic constriction of resistance vessels of OLT recipients treated with CsA. Vascular reactivity was examined in 22 OLT patients, 10 with and 12 without arterial hypertension, and in 10 control subjects by assessing the forearm blood flow response to the brachial artery infusion of increasing concentrations of methacholine chloride, sodium nitroprusside, and phenylephrine. In 10 OLT patients, the response to methacholine was also examined after acetylsalicylate. The ratio of serum nitrite and nitrate to serum creatinine was lower (P F .05) in OLT patients with hypertension than in nonhypertensive patients and controls. Basal forearm flow was similar in the three groups. Methacholine vasodilation was impaired in the hypertensive patients as shown by a lower maximum forearm vasodilator response and a shift in the dose response curve to methacholine to the right compared with the nonhypertensive OLT patients and the controls. The response to methacholine was not modified after salicylate. Forearm flow response to nitroprusside was similar in the three groups. No differences between the patients and the controls were found in the maximum forearm flow contraction in response to phenylephrine. An impairment in endothelium-dependent vasodilation could mediate arterial hypertension in OLT patients immunosuppressed with CsA. (HEPATOLOGY 1998;27:332-338.)Arterial hypertension is a side-effect commonly observed in patients with an allogeneic solid organ graft receiving an immunosuppressive regimen based on cyclosporin A (CsA). 1,2 Published reports show that between 60% and 85% of transplant recipients treated with CsA develop hypertension. 3 The precise pathogenetic pathways underlying CsA-induced hypertension remain partially unknown. This problem is further hindered by the frequent discrepancy between the results obtained in humans and in animal models, and the relative resistance of rats that receive CsA to develop systemic hypertension. These facts make it difficult to extrapolate data from the experimental to the human setting. 4 Recent lines of evidence point to a disturbance in the local mechanisms of vascular regulation as the most likely cause of hypertension after transplantation. In this regard, several studies that have focused on the effects of CsA on arachidonic acid metabolites and endothelium-dependent and -independent vasodilation suggest that the arterial hypertension developed during CsA therapy reflects a shift in favor of vasoconstriction through an impairment of vasodilating mechanisms. [5][6][7][8][9][10][11] These studies have been performed in animal models, in vessels from healthy humans incubated with CsA, or in vessels from CsA-treated patients. However, no study to date has investigated the pattern of reacti...

Lack of endothelial dysfunction in patients under tacrolimus after orthotopic liver transplantation

“…Both ET‐1 and NO levels were normal in these patients. This is in line with previous data (16, 37). Together with the fact that other vasodilatory mediators such as adrenomodulin and atrial natriuretic peptide were increased after OLT (38), this suggests that the vasodilatory capacities of OLT patients are normal.…”

“…After organ transplantation, an impaired balance between vasodilatory and vasoconstrictive mediators has been reported, with decreased endothelial NO bioavailability, enhanced sensitivity to ET-1 and significantly impaired FMD (8)(9)(10)(11)(12)(13)(14)(15). Few data are available concerning endothelial function after OLT (16,17), but cardiovascular complications are more prevalent in liver transplant recipients than in the general population (18). Among other etiologies, the use of calcineurin inhibitors (CNI) such as tacrolimus (TAC) has been cited as a cause of altered endothelial function (19,20).…”

Comparative effects of sirolimus and cyclosporin on conduit arteries endothelial function in kidney recipients

“…Nevertheless, the doses of CsA we used were not particularly high and were reduced after the 4th month of transplantation (C0 M7: 139 ± 10 ng/ml) [34,35]. Therefore, because CsA is not always associated with endothelial dysfunction [5,51,52] and conversion to CNI‐free regimen may be insufficient to restore endothelial function [6,45], additional mechanisms may be involved. This includes a direct beneficial effect of SRL on vascular endothelium [17,28], although controversial [30–32], or a vascular synergistic effect of SRL and MMF preventing endothelin‐1 release and oxidative stress [53,54].…”

Plasma total homocysteine and cardiovascular risk in patients submitted to liver transplantation

“…The association of Hcy with hypertension is more intriguing. Renal artery vasoconstriction has been proposed as the main cause of posttransplantation hypertension,35 and recent studies have demonstrated a defect in post‐OLT endothelial‐mediated vasodilation,36 that could also be produced by Hcy 15. Drugs may be involved as well.…”