Inhibitory effects of meta-iodo-benzylguanidine (MIBG) on endothelial histamine receptor binding

Abstract

Meta-iodo-benzylguanidine (MIBG), a selective inhibitor of mono-ADP-ribosylation, has been shown to inhibit histamine induced inositol–trisphosphate and prostacyclin production. The purpose of this study was to evaluate the effect of MIBG on the binding of histamine to the H 1-receptor and to study its effects on phospholipid metabolism in human endothelial cells. The effects of MIBG and MIBA (meta-iodo-benzylamine), which does not affect cellular ADP-ribosylation, on agonist induced cGMP production in cultured HUVEC's were measured by RIA and a binding study carried out to evaluate their effects on the binding of [ 3H]mepyramine to membrane fractions. MIBG (0.3 mM) reduced histamine induced cGMP production by 90.8% but did not inhibit the cGMP production induced by other agonists. MIBA had no effect. MIBG also reduced the binding of [ 3H]mepyramine (1.0 nM) to membrane fractions with IC 50 at 0.094 mM and maximal inhibition (83%) at 0.22 mM MIBG. The calculated K i was 0.076 mM. MIBG and MIBA altered phospholipid metabolism in a similar way as the cationic amphiphilic drug propranolol. MIBA caused up to 42% reduction in [ 3H]mepyramine binding, probably due to its inhibition of nonspecific binding. These results indicate that MIBG reduces histamine induced cGMP production by inhibiting its binding to H 1-receptors and alters phospholipid metabolism in cultured endothelial cells in a similar way as known cationic amphiphilic drugs.