Rola tlenku azotu, siarkowodoru oraz tlenku węgla w regulacji układu krążenia i ich potencjał farmakoterapeutyczny

In the eighties of the twentieth century nitric oxide (NO) was identified as the endothelium-derived relaxing factor. This discovery has triggered an interest in gaseous transmitters and their role in the regulation of the circulatory system. Recently, it has become evident that hydrogen sulfide (H2S) and carbon monoxide are also involved in physiological and pathological processes in the cardiovascular system. Nitrates that have been used for over a century and nebivolol, a third-generation b-blocker with vasodilating properties by increasing bioavailability of NO, provide convincing arguments that the compounds acting via NO pathway will remain an important class of cardiovascular drugs. A rapidly growing number of publications on functions of H2S in the circulatory system suggests that the gaseous transmitter may become a promising target for new treatment strategies in cardiovascular diseases. This review is focused on the role of gaseous transmitters in the regulation of the cardiovascular system and their pharmacotherapeutic potential. Kardiol Pol 2010; 68, supl. V: 436-440Wzmożone zainteresowanie udziałem transmiterów gazowych w regulacji układu krążenia pojawiło się w latach 80. XX wieku, kiedy wykazano, że napięcie mięśniówki naczyń jest kontrolowane przez uwalniany ze śródbłonka tlenek azotu (NO). Obecnie wiadomo, że także dwa inne transmitery gazowe, siarkowodór (H2S) oraz tlenek węgla, biorą udział w fizjologicznych i patologicznych procesach zachodzących w układzie krążenia. Doświadczenia kliniczne ze stosowaną od ponad 100 lat nitrogliceryną oraz bardzo korzystny profil działania nebiwololu, beta-adrenolityku trzeciej generacji zwiększającego biodostępność NO, pozwalają przypuszczać, że leki oddziałujące za pośrednictwem NO będą nadal odgrywać istotną rolę w farmakoterapii chorób układu krążenia. Lawinowo rosnąca liczba publikacji dotyczących działań sercowo-naczyniowych H2S świadczy o tym, że w najbliższych latach zostaną podjęte badania nad związkami modulującymi stężenie H2S w układzie krążenia i ich zastosowaniem klinicznym. W niniejszej pracy zostaną przedstawione zarys funkcji transmiterów gazowych w regulacji układu krążenia w zdrowiu i chorobie oraz ich potencjał farmakoterapeutyczny. Kardiol Pol 2010; 68, supl. V: 436-44

Blood pressure and glaucoma: At the crossroads between cardiology and ophthalmology

Glaucoma is an optic nerve neuropathy of undetermined cause. Although many mechanisms are thought to be involved in the development and progression of the disease, only an increased intraocular pressure has been established as a clinically significant modifiable risk factor. Nevertheless, up to 40% of patients develop glaucoma without evidence of increased intraocular pressure.  Ample evidence suggests that alterations in the control of arterial blood might negatively affect optic nerve function. However, evidence-based guidelines on the management of arterial blood pressure in glaucoma patients are lacking. Regrettably, intraocular pressure is generally not included as a secondary end-point in clinical trials on arterial hypertension. Considering the relative simplicity of intraocular pressure measurements and large number of patients included in hypertension studies, the benefits of including intraocular pressure as a secondary end-point could be of a great value for improving care for glaucoma patients. Therefore, closer collaboration between cardiologists and ophthalmologists is needed.

Heart Failure Disturbs Gut–Blood Barrier and Increases Plasma Trimethylamine, a Toxic Bacterial Metabolite

Trimethylamine (TMA) is a gut bacteria product oxidized by the liver to trimethylamine-N-oxide (TMAO). Clinical evidence suggests that cardiovascular disease is associated with increased plasma TMAO. However, little headway has been made in understanding this relationship on a mechanistic and molecular level. We investigated the mechanisms affecting plasma levels of TMAO in Spontaneously Hypertensive Heart Failure (SHHF) rats. Healthy Wistar Kyoto (WKY) and SHHF rats underwent metabolic, hemodynamic, histopathological and biochemical measurements, including tight junction proteins analysis. Stool, plasma and urine samples were evaluated for TMA and TMAO using ultra performance liquid chromatography-mass spectrometry. SHHF presented disturbances of the gut–blood barrier including reduced intestinal blood flow, decreased thickness of the colonic mucosa and alterations in tight junctions, such as claudin 1 and 3, and zonula occludens-1. This was associated with significantly higher plasma levels of TMA and TMAO and increased gut-to-blood penetration of TMA in SHHF compared to WKY. There was no difference in kidney function or liver oxidation of TMA to TMAO between WKY and SHHF. In conclusion, increased plasma TMAO in heart failure rats results from a perturbed gut–blood barrier and increased gut-to-blood passage of TMAO precursor, i.e., TMA. Increased gut-to-blood penetration of bacterial metabolites may be a marker and a mediator of cardiovascular pathology

Spontaneously hypertensive rats exhibit increased liver flavin monooxygenase expression and elevated plasma TMAO levels compared to normotensive and Ang II-dependent hypertensive rats

Background: Flavin monooxygenases (FMOs) are enzymes responsible for the oxidation of a broad spectrum of exogenous and endogenous amines. There is increasing evidence that trimethylamine (TMA), a compound produced by gut bacteria and also recognized as an industrial pollutant, contributes to cardiovascular diseases. FMOs convert TMA into trimethylamine oxide (TMAO), which is an emerging marker of cardiovascular risk. This study hypothesized that blood pressure phenotypes in rats might be associated with variations in the expression of FMOs.Methods: The expression of FMO1, FMO3, and FMO5 was evaluated in the kidneys, liver, lungs, small intestine, and large intestine of normotensive male Wistar-Kyoto rats (WKY) and two distinct hypertensive rat models: spontaneously hypertensive rats (SHRs) and WKY rats with angiotensin II-induced hypertension (WKY-ANG). Plasma concentrations of TMA and TMAO were measured at baseline and after intravenous administration of TMA using liquid chromatography-mass spectrometry (LC-MS).Results: We found that the expression of FMOs in WKY, SHR, and WKY-ANG rats was in the descending order of FMO3 > FMO1 >> FMO5. The highest expression of FMOs was observed in the liver. Notably, SHRs exhibited a significantly elevated expression of FMO3 in the liver compared to WKY and WKY-ANG rats. Additionally, the plasma TMAO/TMA ratio was significantly higher in SHRs than in WKY rats.Conclusion: SHRs demonstrate enhanced expression of FMO3 and a higher plasma TMAO/TMA ratio. The variability in the expression of FMOs and the metabolism of amines might contribute to the hypertensive phenotype observed in SHRs

Trimethylamine, a gut bacteria metabolite and air pollutant, increases blood pressure and markers of kidney damage including proteinuria and KIM-1 in rats

BACKGROUND: Trimethylamine oxide (TMAO) is a biomarker in cardiovascular and renal diseases. TMAO originates from the oxidation of trimethylamine (TMA), a product of gut microbiota and manufacturing industries-derived pollutant, by flavin monooxygenases (FMOs). The effect of chronic exposure to TMA on cardiovascular and renal systems is undetermined. METHODS: Metabolic, hemodynamic, echocardiographic, biochemical and histopathological evaluations were performed in 12-week-old male SPRD rats receiving water (controls) or TMA (200 or 500 µM/day) in water for 18 weeks. TMA and TMAO levels, the expression of FMOs and renin-angiotensin system (RAS) genes were evaluated in various tissues. RESULTS: In comparison to controls, rats receiving high dose of TMA had significantly increased arterial systolic blood pressure (126.3 ± 11.4 vs 151.2 ± 19.9 mmHg; P = 0.01), urine protein to creatinine ratio (1.6 (1.5; 2.8) vs 3.4 (3.3; 4.2); P = 0.01), urine KIM-1 levels (2338.3 ± 732.0 vs. 3519.0 ± 953.0 pg/mL; P = 0.01), and hypertrophy of the tunica media of arteries and arterioles (36.61 ± 0.15 vs 45.05 ± 2.90 µm, P = 0.001 and 18.44 ± 0.62 vs 23.79 ± 2.60 µm, P = 0.006; respectively). Mild degeneration of renal bodies with glomerulosclerosis was also observed. There was no significant difference between the three groups in body weight, water-electrolyte balance, echocardiographic parameters and RAS expression. TMA groups had marginally increased 24 h TMA urine excretion, whereas serum levels and 24 h TMAO urine excretion were increased up to 24-fold, and significantly increased TMAO levels in the liver, kidneys and heart. TMA groups had lower FMOs expression in the kidneys. CONCLUSIONS: Chronic exposure to TMA increases blood pressure and increases markers of kidney damage, including proteinuria and KIM-1. TMA is rapidly oxidized to TMAO in rats, which may limit the toxic effects of TMA on other organs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03687-y

Hypertensive rats show increased renal excretion and decreased tissue concentrations of glycine betaine, a protective osmolyte with diuretic properties

Hypertension leads to water-electrolyte disturbances and end-organ damage. Betaine is an osmolyte protecting cells against electrolyte imbalance and osmotic stress, particularly in the kidneys. This study aimed to evaluate tissue levels and hemodynamic and renal effects of betaine in normotensive and hypertensive rats. Betaine levels were assessed using highperformance liquid chromatography-mass spectrometry (HPLC-MS) in normotensive rats (Wistar-Kyoto, WKYs) and Spontaneously Hypertensive rats (SHRs), a model of genetic hypertension. Acute effects of IV betaine on blood pressure, heart rate, and minute diuresis were evaluated. Gene and protein expression of chosen kidney betaine transporters (SLC6a12 and SLC6a20) were assessed using real-time PCR and Western blot. Compared to normotensive rats, SHRs showed significantly lower concentration of betaine in blood serum, the lungs, liver, and renal medulla. These changes were associated with higher urinary excretion of betaine in SHRs (0.20 ± 0.04 vs. 0.09 ± 0.02 mg/ 24h/ 100g b.w., p = 0.036). In acute experiments, betaine increased diuresis without significantly affecting arterial blood pressure. The diuretic response was greater in SHRs than in WKYs. There were no significant differences in renal expression of betaine transporters between WKYs and SHRs. Increased renal excretion of betaine contributes to decreased concentration of the protective osmolyte in tissues of hypertensive rats. These findings pave the way for studies evaluating a causal relation between depleted betaine and hypertensive organ damage, including kidney injury