Impact of ADMA (asymmetric dimethylarginine) on physiology with respect to diabetes mellitus and respiratory system BEAS-2B cells (human bronchial epithelial cells)

Abstract

Objectives Asymmetric dimethylarginine (ADMA) is a non-selective nitric oxide (NO) synthase inhibitor associated with cardiovascular and metabolic disorders. This study aimed to investigate ADMA with respect to both diabetes and respiratory disease. Methods Glucose was determined by hexokinase method, insulin by a radioimmunoassay. Griess test was used for NO assay and cytokinines were assayed by ELISA. Ciliary beat frequency was determined by high speed video using a microscope. Key findings ADMA induced an increase in blood glucose and plasma insulin levels in rats; the ratio of these effects indicates the induction of a diabetic situation (insulin resistance). l-arginine increased blood glucose and initially slightly decreased plasma insulin. A pretreatment with ADMA abolished these effects. ADMA shows similar effects in vitro (insulin-secreting cell line, INS-1 cells). l-arginine increased production of NO, which was reversed by ADMA (INS-1 cells). ADMA also reduced NO production positively modulated by various substances, namely metformin, ciglitazone, losartan and nateglinide, but nevertheless inhibited insulin release induced by these compounds. ADMA stimulated the production of cytokines such as interleukin (IL-6) and macrophage inflammatory protein-2 (MIP-2) (rat IL-8 analogue) from INS-1 cells. 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), a direct adenosine monophosphate protein kinase (AMPK) activator and anti-inflammatory agent, induced NO production and reduced cytokine release. In contrast to diabetes parameters, ADMA had no effect of on the respiratory system (cytokine secretion from BEAS-2B cells (IL-8, regulated on activation, normal T cell expressed and secreted, and tumour necrosis factor-α), ciliary beat frequency and smooth muscle contraction of rat trachea). Conclusions ADMA has a pathophysiological impact leading to a diabetic situation but has no impact on the respiratory system. © 2012 Royal Pharmaceutical Society.