Restini, Carolina Baraldi A.
Fink, Gregory D.
Watts, Stephanie W.
Total Authors: 3
 Michigan State Univ, Dept Pharmacol & Toxicol, 44575 Garfield Rd, Bldg UC4, E Lansing, MI 48824 - USA
 Michigan State Univ, Coll Osteopath Med, 44575 Garfield Rd, Bldg UC4, Clinton Township, MI 48038 - USA
Total Affiliations: 2
Web of Science Citations:
Trimethylamine (TMA), formed by intestinal microbiota, and its Flavin-Monooxygenase 3 (FMO3) product Trimethylamine-N-Oxide (TMAO), are potential modulators of host cardiometabolic phenotypes. High circulating levels of TMAO are associated with increased risk for cardiovascular diseases. We hypothesized that TMA/TMAO could directly change the vascular tone. Perivascular adipose tissue (PVAT) helps to regulate vascular homeostasis and may also possess FMO3. Thoracic aorta with(+) or without(-) PVAT, also + or - the endothelium (E), of male Sprague Dawley rats were isolated for measurement of isometric tone in response to TMA/TMAO (1nM-0.5 M). Immunohistochemistry (IHC) studies were done to identify the presence of FMO3. TMA and TMAO elicited concentration-dependent arterial contraction. However, at a maximally achievable concentration (0.2 M), contraction stimulated by TMA was of a greater magnitude (141.5 +/- 16% of maximum phenylephrine contraction) than that elicited by TMAO (19.1 +/- 4.03%) with PVAT and endothelium intact. When PVAT was preserved, TMAO-induced contraction was extensively reduced the presence (19.1 +/- 4.03%) versus absence of E (147.2 +/- 20.5%), indicating that the endothelium plays a protective role against TMAO-induced contraction. FMO3 enzyme was present in aortic PVAT, but the FMO3 inhibitor methimazole did not affect contraction stimulated by TMA in aorta + PVAT. However, the L-type calcium channel blocker nifedipine reduced TMA-induced contraction by similar to 50% compared to the vehicle. Though a high concentration of these compounds was needed to achieve contraction, the findings that TMA-induced contraction was independent of PVAT and E and mediated by nifedipine-sensitive calcium channels suggest metabolite-induced contraction may be physiologically important. (AU)