Asymmetrical Dimethylarginine in Idiopathic Pulmonary Arterial Hypertension

Abstract

Objective-We explored the potential role of the endogenous NO synthase inhibitor asymmetrical dimethylarginine (ADMA) in patients with idiopathic pulmonary arterial hypertension (IPAH). Method and Results-We correlated plasma ADMA levels and cardiovascular indices from right heart catheterization in 57 patients with IPAH. Predictors of survival in patients with IPAH were studied. Furthermore, the effect of systemic ADMA infusion on pulmonary ventricular resistance and stroke volume was investigated in healthy volunteers using right heart catheterization. Mean plasma ADMA concentrations were significantly higher in patients with IPAH than in control subjects (0. Key Words: idiopathic pulmonary arterial hypertension Ⅲ ADMA Ⅲ nitric oxide I diopathic pulmonary arterial hypertension (IPAH) is a disease of unknown etiology that is characterized by progressive obliteration of small and medium-size pulmonary arteries, elevation in pulmonary arterial pressure, and increase in pulmonary vascular resistance, eventually leading to right heart failure and death. 1 Without appropriate medical treatment, mean survival of patients experiencing IPAH is Ͻ3 years. 2 In the current understanding of the pathogenesis of IPAH, it is thought that a combination of genetically determined predisposition coupled with ill-defined exogenous factors may contribute to damage of the pulmonary vessels, resulting in endothelial dysfunction with proliferation of vascular endothelial and smooth muscle cells. [3][4][5] Endothelial dysfunction attributable to reduced bioavailability of endogenous vasodilator substances such as NO is thought to play an important role in the development of pulmonary hypertension. 6,7 NO is synthesized in the endothelium from the amino acid L-arginine by the action of NO synthase (NOS). Endogenous guanidino-substituted analogues of L-arginine that can selectively inhibit NOS have been implicated in the pathogenesis of various cardiovascular diseases. The most potent of these endogenous NOS inhibitors is asymmetrical dimethylarginine (ADMA). Elevated ADMA levels and low L-arginine/ADMA ratios not only correlate with the severity of atherosclerotic disease 8 -11 but also predict cardiovascular outcome and overall mortality. 12, 13 We demonstrated recently that pathophysiologically relevant ADMA blood concentrations inhibited NO production and reduced cardiac output and renal perfusion in healthy subjects. 14 Experimental data from a rat model of chronic hypoxia-induced pulmonary hypertension revealed that increased pulmonary concentrations of ADMA contributes to pulmonary hypertension. 15 On the basis of these observations, it seems possible that increased plasma ADMA concentrations may also contribute to endothelial dysfunction in patients with pulmonary vascular disease. 16 The present study was undertaken to evaluate a potential role of ADMA in IPAH.53Ϯ0 Subjects and Methods Participants and ProtocolsThe study protocol was approved by the local Ethics committee, and all participants gave informed consent. 17 For comp...

Biomarkers in pulmonary hypertension

“…In IPAH, plasma levels are significantly higher than in healthy, matched controls [71]. In such patients, plasma ADMA correlates positively with right atrial pressure, and negatively with mixed venous oxygen saturation, stroke volume, cardiac index and survival.…”

Symmetrical Dimethylarginine

“…In our study, however, patients with CKD stage 5 were excluded. Other studies on mortality and dimethylarginines in nonrenal patients (9) or patients with CKD 1 through 4 (34) failed to quantify SDMA. A recent study by Wanby et al (35), involving 363 patients, reported that there was a significant positive multivariate relationship between SDMA and cardioembolic infarction.…”

Chronic pulmonary hypertension and nitric oxide

“…У больных с идиопатической (а не только гипо ксической) легочной артериальной гипертонией уровень ADMA также был существенно выше, чем у здоровых лиц [9]. Недавно J. Leiper et al [10] устано вили исключительно важную роль DDAН в регуля ции тонуса легочных сосудов.…”