Trimethylamine-<i>N</i>-oxide (TMAO) Selectively Disrupts Endothelium-Dependent Hyperpolarization-Type Relaxations in a Time-Dependent Manner in Rat Superior Mesenteric Artery

Abstract

The vascular action of trimethylamine-N-oxide (TMAO)-the gut microbiota-derived metabolite-in contributing cardiovascular disease is a controversial topic. A recent study has shown that acute exposure of TMAO at moderate concentrations inhibits endothelium-dependent hyperpolarization (EDH)-type relaxations selectively in rat isolated femoral arteries, but not in mesenteric arteries. Here we determined the efficacy of higher TMAO concentrations with longer exposure times on vascular reactivity in rat isolated superior mesenteric arteries. Acetylcholine-induced EDH-type relaxations were examined before and after incubation with TMAO (0.1-10 mM) at increasing exposure times (1-24 h). One-and 4-h-incubations with TMAO at 0.1-3 mM did not cause any change in EDH-type relaxations. However, when the incubation time was increased to 24 h, responses to acetylcholine were reduced in arteries incubated with 1-3 mM TMAO. In addition, at higher TMAO concentration (10 mM) the decrease in EDH relaxations could be detected both in 4-h-and 24-h-incubations. The EDH-relaxations were preserved in rings incubated with 10 mM TMAO for 24 h in the presence of SKA-31 (10 µM), the small (SKCa)-and intermediate (IKCa)-conductance calciumactivated potassium channel activator. Contractile responses to phenylephrine increased in arteries exposed to 10 mM TMAO for 24 h. Interestingly, nitric oxide (NO)-mediated relaxations remained unchanged in arteries treated for 24 h at any TMAO concentration. Our study revealed that TMAO selectively disrupted EDH-type relaxations time-dependently without interfering with NO-induced vasodilation in rat isolated mesenteric arteries. Disruption of these relaxations may help explain the causal role of elevated TMAO levels in certain vascular diseases.

Contractile effect of trimethylamine and trimethylamine‐n‐oxide on isolated human umbilical arteries

“…Moreover, other in vitro studies investigating the direct effect of TMA and TMAO on vascular tissues have used similar dose ranges. 23,38 Despite the lower plasma concentrations of TMAO in umbilical cord blood compared to maternal plasma, the maternal cardiovascular system plays a crucial role in the maternal manifestations of hypertensive disorders during pregnancy. Therefore, it is essential to understand the mechanisms underlying the effects of TMAO on human vascular structures, which is the main objective of our study.…”

“…Concentrations of TMAO reported in the aforementioned study were within the dose range used in our study. Moreover, other in vitro studies investigating the direct effect of TMA and TMAO on vascular tissues have used similar dose ranges 23,38 …”