High concentration of uric acid failed to affect endothelial function of small mesenteric arteries, femoral arteries and aortas from aged Wistar-Kyoto rats.

It is known that a high level of uric acid (UA) in plasma, hyperuricemia (HU), is associated with the increased risk of cardiovascular diseases (CVDs). Endothelial damage has been suggested as a potential mechanism involved in HU-induced CVDs, especially in patients with the accumulation of other cardiovascular risk factors. However, the role of UA in the pathogenesis of endothelial dysfunction is still a matter of debate. It is unclear whether UA is a causative risk factor in endothelial dysfunction, an inert marker or an endothelium-protective molecule with respect to its antioxidant properties. Of note, only a few studies have been conducted to investigate the effect of UA on vascular endothelium-dependent relaxation. Therefore, we have studied the acute in vitro effects of high UA concentrations on the endothelial function of arteries isolated from aged rats. Experiments were performed in small mesenteric arteries (SMAs), femoral arteries and thoracic aortas isolated from 68-week-old and 57-week-old male Wistar-Kyoto rats. Vascular reactivity was investigated in isometric conditions using the wire myograph and organ chamber. Acetylcholine (ACh) was used to investigate endothelium-dependent vasorelaxation. Then, UA was added to the myograph or organ chamber at 600 µmol/l (arteries from 68-week-old rats) or 1200 µmol/l (arteries from 57-week-old rats) and incubated for 1 h, and this was followed by determining the ACh concentration-response curve. UA had no significant effect on ACh-induced vasorelaxation and pD2 values in all investigated groups. Likewise, no significant differences in noradrenaline- (SMAs), serotonin- (femoral arteries) and phenylephrine-induced (aortas) vasoconstriction were observed after UA pre-incubation. In conclusion, high concentrations of UA administered acutely failed to affect endothelial function and did not provoke endothelial dysfunction in resistant mesenteric arteries, medium-sized and large arteries from aged rats.

Chronic NOS Inhibition Affects Oxidative State and Antioxidant Response Differently in the Kidneys of Young Normotensive and Hypertensive Rats.

Deficiency of nitric oxide (NO) and oxidative stress can be a cause, a consequence, or, more often, a potentiating factor for hypertension and hypertensive renal disease. Both NO and superoxide anions are radical molecules that interact with each other, leading to oxidative damage of such organs as the kidney. In the present study, we investigated the effect of chronic-specific (neuronal NOS inhibition) and nonspecific NOS inhibition on the oxidative state and antioxidant response and associated oxidative damage of the kidney of young normotensive and hypertensive rats. Young male normotensive Wistar rats (WRs, age 4 weeks) and spontaneously hypertensive rats (SHRs, age 4 weeks) were divided into three groups for each strain by the type of administered compounds. The first group was treated with 7-nitroindazole (WR+7-NI; SHR+7-NI), the second group was treated with N(G)-nitro-L-arginine-methyl ester (WR+L-NAME; SHR+L-NAME), and the control group was treated with pure drinking water (WR; SHR) continuously for up to 6 weeks. Systolic blood pressure increased in WR+L-NAME after the first week of administration and increased slightly in SHR+L-NAME in the third week of treatment. 7-NI had no effect on blood pressure. While total NOS activity was not affected by chronic NOS inhibition in any of the WR groups, it was attenuated in SHR+7-NI and SHR+L-NAME. Nitration of proteins (3-nitrotyrosine expression) was significantly reduced in WR+7NI but not in WR+L-NAME and increased in SHR+7-NI and SHR+L-NAME. Immunoblotting analysis of SOD isoforms showed decreased SOD2 and SOD3 expressions in both WR+7-NI and WR+L-NAME followed by increased SOD activity in WR+L-NAME. Conversely, increased expression of SOD2 and SOD3 was observed in SHR+L-NAME and SHR+7-NI, respectively. SOD1 expression and total activity of SOD did not change in the SHR groups. Our results show that the antioxidant defense system plays an important role in maintaining the oxidative state during NO deficiency. While the functioning antioxidant system seeks to balance the oxidation state in the renal cortex of normotensive WRs, the impaired antioxidant activity leads to the development of oxidative damage of proteins in the kidney induced by peroxynitrite in SHRs.

The role of perivascular adipose tissue and endogenous hydrogen sulfide in vasoactive responses of isolated mesenteric arteries in normotensive and spontaneously hypertensive rats.

Perivascular adipose tissue (PVAT) and hydrogen sulfide (H2S) play important roles in the modulation of vasoactive responses and can interfere with the ethiopathogenesis of essential hypertension. The aim of this study was to evaluate the mutual relationship between PVAT and H2S (endogenously produced, exogenous) in vasoactive responses of isolated mesenteric arteries (MA) in adult normotensive (Wistar) and spontaneously hypertensive rats (SHR). In SHR, hypertension was associated with cardiac hypertrophy and increased contractility; however, there were no differences in the amount of retroperitoneal fat between strains. PVAT revealed the anti-contractile effect on vasoconstriction induced by exogenous noradrenaline in both strains, but surprisingly, this effect was stronger in SHR. Concurrently; PVAT exhibited a pro-contractile effect on contractions to endogenous noradrenaline released from arterial sympathetic nerves in SHR, but not in Wistar rats. We confirmed the anti-contractile effect of H2S in both, the vascular wall and PVAT of Wistar rats because the pre-treatment with propargylglycine (PPG), an inhibitor of H2S producing enzyme, significantly increased the noradrenaline-induced contraction. In SHR, H2S in the vascular wall exhibited a pro-contractile effect that was eliminated by the presence of PVAT; however, the pre-treatment with PPG did not affect noradrenaline contraction farther. Nevertheless, unlike in Wistar rats, the presence of PVAT potentiated the vasorelaxant effect of exogenously applied H2S in SHR. Our results confirmed that PVAT of MA and endogenously produced H2S could manifest as pro-contractile or as anti-contractile. In SHR, unlike in Wistar rats, the pro-contractile effect of PVAT associated with the stimulation of perivascular nerves, and the pro-contractile effect of H2S in the arterial wall could represent pathologic features. On the other hand, PVAT of SHR is endowed with compensatory vasoactive mechanisms, which include stronger anti-contractile action of an unknown factor (other than H2S) and potentiation of the vasorelaxant effect of exogenous H2S.

Changes in the vasoactive effects of nitric oxide, hydrogen sulfide and the structure of the rat thoracic aorta: the role of age and essential hypertension.

Several studies have already confirmed the specific vasomotor effect of hydrogen sulfide (H2S) and its interaction with the nitric oxide (NO) system in normotensive rats, but results in spontaneously hypertensive rats (SHRs) are limited. the aim of this study was to describe the age- and blood pressure-dependent effects of endogenous NO and exogenous Na2S and their interaction in vasomotor responses of the thoracic aorta (TA) in normotensive Wistar rats and SHRs. the systolic blood pressure (sBP), vasoactivity, NO-synthase (NOS) expression and activity, cystathionine gamma-lyase (CSE) expression, and geometry of the isolated TA were evaluated at 4 and 16 weeks of age. Although hypertrophy of the heart was observed in young and adult SHRs, the sBP was increased only in adulthood. the contractile responses were decreased in young as in adult SHRs with the key participation of the endogenous NO system. however, the hypotrophy in the young and the hypertrophy (mainly at the expense of extracellular matrix) in the adult SHRs were found in the TA. While unchanged in young SHRs, in adult SHRs, partially impaired endothelial function was confirmed. Nevertheless, the NO-dependent component of acetylcholine-induced relaxation was higher in both young and adult SHRs. Consistently, even though there was an age-dependent decrease in NOS activity in both strains, NOS activity was higher in both young and adult SHRs compared to age-matched normotensive rats. Application of exogenous Na2S evoked a concentration-dependent dual vasoactive effect of TAs in both strains, regardless of age. Increased sensitivity in favor of vasorelaxant responses of Na2S in prehypertensive SHRs, and an enhanced maximal vasorelaxation in adult SHR was observed. the acute NO inhibition generally increased the relaxant phase of Na2S responses; nevertheless, the development of hypertension potentiated this effect. the TA of the SHRs is endowed with a unique inherent predisposition of vasoactive mechanisms, which serve as compensatory processes during the developed stage of hypertension: the NO component and H2S signaling pathways are implicated. the decreased contractility seems to be a deleterious effect. the increased participation of the H2S system on vasorelaxation after acute NO inhibition could be considered a reserved mechanism in case of endogenous NO deficiency.

Nitroso-sulfide coupled signaling triggers specific vasoactive effects in the intrarenal arteries of patients with arterial hypertension.

In normotensive conditions, it has been confirmed that S-nitrosothiols (RSNO), can interact with hydrogen sulfide (H2S) and create new substances with specific vasoactive effects. This interaction could also represent a new regulator signaling pathway in conditions of hypertension. Until now, these effects were studied only in normotensive rats, and they have not been carried out in humans yet. We investigated the vasoactive effects of the products of the H2S/S-nitrosoglutathione (S/GSNO) interaction in lobar arteries (LA) isolated from the nephrectomized kidneys of patients suffering from arterial hypertension and in renal arteries (RA) of spontaneously hypertensive rats (SHR). The changes in the isometric tension of pre-contracted arteries were evaluated. Acetylcholine-induced vasorelaxation of LA was reduced compared to the effect induced by an NO donor, sodium nitroprusside suggesting an endothelium dysfunction. While 1 µmol/L Na2S had a minimal effect on the vascular tone, the concentration 20 µmol/L evoked a slight vasorelaxation. GSNO at 0.1 µmol/L induced vasorelaxation, which was less pronounced compared to the effect induced by 1 µmol/L. The S/GSNO products (final concentration 0.1 µmol/L) prepared as the mixture of GSNO (0.1 µmol/L) + Na2S (1 µmol/L) induced a higher vasorelaxation compared to GSNO (0.1 µmol/L) alone only in the 5th minute and without the differences in the speed. On the other hand, the S/GSNO products (final concentration 1 µmol/L) prepared as the mixture of GSNO (1 µmol/L) + Na2S (10 µmol/L) induced a higher and faster vasorelaxation compared to the effect induced by GSNO (1 µmol/L) alone. In RA of SHR this S/GSNO products induced similar vasorelaxation (higher and faster than GSNO) with involvement of HNO (partially) and cGMP as mediators. However, the products of the H2S/NO donor (DEA NONOate) manifested differently than S/GSNO indicating the unique interaction between GSNO and H2S. In this study, we confirmed for the first time that specific vasoactive effects of coupled nitroso-sulfide signaling were also triggered in human arterial tissue. We suggest that in hypertension, H2S in interaction with GSNO regulated a vasoconstrictor-induced increase in arterial tone towards a stronger vasorelaxation compared to GSNO alone or H2S alone.

Corrigendum to "(-)-Epicatechin Prevents Blood Pressure Increase and Reduces Locomotor Hyperactivity in Young Spontaneously Hypertensive Rats".

[This corrects the article DOI: 10.1155/2016/6949020.].

(-)-Epicatechin Prevents Blood Pressure Increase and Reduces Locomotor Hyperactivity in Young Spontaneously Hypertensive Rats.

This study investigated the effects of subchronic (-)-epicatechin (Epi) treatment on locomotor activity and hypertension development in young spontaneously hypertensive rats (SHR). Epi was administered in drinking water (100 mg/kg/day) for 2 weeks. Epi significantly prevented the development of hypertension (138 ± 2 versus 169 ± 5 mmHg, p < 0.001) and reduced total distance traveled in the open-field test (22 ± 2 versus 35 ± 4 m, p < 0.01). In blood, Epi significantly enhanced erythrocyte deformability, increased total antioxidant capacity, and decreased nitrotyrosine concentration. In the aorta, Epi significantly increased nitric oxide (NO) synthase (NOS) activity and elevated the NO-dependent vasorelaxation. In the left heart ventricle, Epi increased NOS activity without altering gene expressions of nNOS, iNOS, and eNOS. Moreover, Epi reduced superoxide production in the left heart ventricle and the aorta. In the brain, Epi increased nNOS gene expression (in the brainstem and cerebellum) and eNOS expression (in the cerebellum) but had no effect on overall NOS activity. In conclusion, Epi prevented the development of hypertension and reduced locomotor hyperactivity in young SHR. These effects resulted from improved cardiovascular NO bioavailability concurrently with increased erythrocyte deformability, without changes in NO production in the brain.

The role of hydrogen sulphide in blood pressure regulation.

Cardiovascular studies have confirmed that hydrogen sulphide (H(2)S) is involved in various signaling pathways in both physiological and pathological conditions, including hypertension. In contrast to nitric oxide (NO), which has a clear vasorelaxant action, H(2)S has both vasorelaxing and vasoconstricting effects on the cardiovascular system. H(2)S is an important antihypertensive agent, and the reduced production of H(2)S and the alterations in its functions are involved in the initiation of spontaneous hypertension. Moreover, cross-talk between H(2)S and NO has been reported. NO-H(2)S interactions include reactions between the molecules themselves, and each has been shown to regulate the endogenous production of the other. In addition, NO and H(2)S can interact to form a nitrosothiol/s complex, which has original properties and represents a novel nitroso-sulphide signaling pathway. Furthermore, recent results have shown that the interaction between H(2)S and NO could be involved in the endothelium-regulated compensatory mechanisms that are observed in juvenile spontaneously hypertensive rats. The present review is devoted to role of H(2)S in vascular tone regulation. We primarily focus on the mechanisms of H(2)S-NO interactions and on the role of H(2)S in blood pressure regulation in normotensive and spontaneously hypertensive rats.

The adaptive role of nitric oxide and hydrogen sulphide in vasoactive responses of thoracic aorta is triggered already in young spontaneously hypertensive rats.

The aorta plays an important role in blood pressure control so the early determination of its vasoactive properties could predict pathological changes in hypertension. The aim of study was to compare vasoactive properties and geometry of thoracic aorta (TA) and the participation of two vasoactive transmitters, nitric oxide (NO) and hydrogen sulphide (H2S), in TA tone regulation in young Wistar rats (WR) and spontaneously hypertensive rats (SHR). Four-weeks-old WR and SHR were used. Systolic blood pressure (sBP) was measured by plethysmography. The vasoactivity of TA was evaluated by changes in isometric tension. For morphological study the geometry of TA was measured using light microscopy. Decomposition of NO donor (nitrosoglutathione, GSNO) induced by H2S donor (Na2S) was studied by UV-VIS spectroscopy. In SHR the sBP was not increased in spite of cardiac hypertrophy compared to WR. Vasoconstriction to noradrenaline (NA) was decreased in SHR compared to WR which correlated with arterial wall hypotrophy. Acetylcholine (Ach)-induced vasorelaxation was increased and NO component participated in vasorelaxation and basal tone regulation significantly more in SHR. Na2S induced biphasic effect in both experimental groups, however, the shift towards vasorelaxation was demonstrated in SHR. Pretreatment with NO-synthase inhibitor, NG-nitro-L-arginine methylester (L-NAME), diminished the contractile part of vasoactive Na2S effects in both strains, moreover, an increased sensitivity in behalf of vasorelaxation was observed in SHR. Pretreatment with Na2S did not affect Ach-induced vasorelaxation in WR, but an inhibition was demonstrated in SHR. On the other hand, pretreatment with Na2S increased the release of NO from GSNO which corresponded with increased GSNO-induced vasorelaxation in both groups. However, this effect was stronger in SHR. The study showed that TA of prehypertensive SHR disposed by decreased contractility and strengthened endothelium-regulated vasorelaxant mechanisms involving of NO and H2S interaction which could serve as adaptive mechanisms in the adulthood.

[Role of NO signaling pathway in regulation of vascular tone--new aspects]. / Uloha NO signalizacnej dráhy v regulácii cievneho tonusu--nové aspekty.

Nitric oxide (NO) participates in the control of the cardiovascular system where two constitutive isoforms of NO-synthase were discovered: endothelial and neuronal. Both isoforms were observed in various cells, however, endothelial NO-synthase is predominantly present in the endothelium. Injury of the endothelium disturbs the balance between vasodilation and vasoconstriction and triggers different pathological alterations. In addition, whereas the intact endothelium protects vascular smooth muscle from oxidative attack, intervention in the vascular wall integrity increases the concentration of vascular superoxides, thus disturbing the effects of NO. Morphological evidence demonstrated that both isoforms of NO-synthase were expressed also in smooth muscle cells and functional studies revealed that different pathological interventions in endothelial function (such as oxidative stress or hypertension) were associated with NO generation in the vascular media. In this case, the generation of NO by vascular smooth muscle may represent a physiologically relevant compensation of endothelial NO deficiency. Whereas long-term inhibition of endothelial NO-synthase resulted in an unequivocal pattern of cardiovascular changes, inhibition of neuronal NO-synthase led to opposite effects, suggesting a specific position of neuronal NO-synthase in the regulation of cardiovascular tone. The specificity of endothelial or neuronal NO function seems to be related to a particular circulatory area and it is presumably determined by mutual interactions with other regulatory systems (sympathoadrenergic, renin-angiotensin, etc.).

Captopril partially decreases the effect of H(2)S on rat blood pressure and inhibits H(2)S-induced nitric oxide release from S-nitrosoglutathione.

We studied the effects of the H(2)S donor Na(2)S on the mean arterial blood pressure (MAP) and heart and breathing rates of anesthetized Wistar rats in the presence and absence of captopril. Bolus administration of Na(2)S (1-4 micromol/kg) into the right jugular vein transiently decreased heart and increased breathing rates; at 8-30 micromol/kg, Na(2)S had a biphasic effect, transiently decreasing and increasing MAP, while transiently decreasing heart rate and increasing and decreasing breathing rate. These results may indicate independent mechanisms by which H(2)S influences MAP and heart and breathing rates. The effect of Na(2)S in decreasing MAP was less pronounced in the presence of captopril (2 micromol/l), which may indicate that the renin-angiotensin system is partially involved in the Na(2)S effect. Captopril decreased H(2)S-induced NO release from S-nitrosoglutathione, which may be related to some biological activities of H(2)S. These results contribute to the understanding of the effects of H(2)S on the cardiovascular system.