An increased blood trimethylamine N-oxide (TMAO) has emerged as a marker of cardiovascular mortality, however, the mechanisms of the increase are not clear. We evaluated if hypertension was associated with changes in the colon permeability to trimethylamine (TMA), a TMAO precursor. We did experiments on male, 24-26-week-old normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and SHR treated with enalapril, an antihypertensive drug (SHR-E). To check the colon permeability and liver TMA clearance, blood was collected from the portal vein and hepatic veins confluence, at baseline and after the intracolonic administration of TMA. Arterial blood pressure (BP) and intestinal blood flow (IBF) recordings and histological assessment of the colon were performed. SHR showed an increased gut-blood barrier permeability to TMA. Namely, at baseline SHR had a higher BP and portal blood TMA, but a lower IBF than WKY. After the intracolonic administration of TMA, SHR had a significantly higher portal blood TMA and higher TMA liver clearance than WKY. In SHR the arteriolar walls of the colon mucosa were significantly thicker than in WKY. Furthermore, SHR showed a significant decrease in the height of the mucosa. In contrast, SHR-E had lower portal blood TMA, lower BP and smaller thickness of arteriolar walls, but higher IBF than SHR, which indicates improved function of the gut-blood barrier in SHR-E. All groups had similar immunostaining of occludin and zonula occludens-1, markers of tight junctions. In conclusion, hypertensive rats show an increased permeability of the colon to TMA, which is accompanied by morphological and hemodynamic alterations in the colon. Therefore, cardiovascular diseases may be characterized by an increased permeability of the gut-blood barrier to bacterial metabolites such as TMA.

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This study compared the vasoconstrictor action of angiotensin II (ANG II) and norepinephrine (NE) with different levels of nitric oxide (NO) in the kidney of anesthetized rats. In one series of experiments, the drugs were infused intravenously, and systemic NO content was reduced by a NO synthase inhibitor, nitro-L-arginine methyl ester (L-NAME). L-NAME significantly enhanced the renal blood flow (RBF) reduction produced by ANG II from 26 to 49%, but it had no significant effect on the change in RBF induced by NE. Medullary blood flow was not influenced by either ANG II or NE given alone or given after L-NAME. In the second series of experiments, all drugs were infused into the renal artery to avoid their systemic and, hence, extrarenal effects. In these experiments, renal content of NO was increased by the NO donor sodium nitroprusside (SNP), decreased by L-NAME, or restored by replacing endogenous NO by exogenous NO (L-NAME + SNP). Effects of both ANG II and NE on RBF were similarly and significantly attenuated by SNP (60% of control), enhanced by L-NAME (200% of control), and restored by L-NAME + SNP (90% of control, not significant). Our results indicate that NO attenuates the renal vasoconstriction due to ANG II or NE and that the antagonism between vasoconstrictors and NO is not due to a constrictor-induced production of NO because exogenous and endogenous NO were equally effective.