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.

Different structural alterations in individual conduit arteries of SHRs compared to Wistar rats from the prehypertensive period to late adulthood.

Structural changes of thoracic aorta (TA), carotid (CA) and iliac artery (IA) were assessed in Wistar and spontaneously hypertensive rats (SHR) aged 3, 17, and 52 weeks. Systolic blood pressure (sBP) was measured by plethysmography weekly. After perfusion fixation the arteries were processed for electron microscopy. The wall thickness (WT), cross-sectional area (CSA), inner diameter (ID), and WT/ID in all arteries and volume densities of endothelial cells (ECs), muscle cells (SMCs), and extracellular matrix (ECM) in TA were measured and their CSAs were calculated. In 3-week-old SHR compared to Wistar rats, sBP did not differ; in the TA, all parameters (WT, CSA, ID, WT/ID, CSA of SMCs, CSA of ECs, and CSA of ECM) were decreased; in CA, WT and CSA did not differ, ID was decreased, and WT/ID was increased; in IA, WT, CSA, and ID were increased. In 17- and 52-week-old SHRs, sBP and all parameters in all arteries were increased, only ID in IE in 52-week-old SHRs and CSA of ECs in the TA in 17-week-old SHRs did not change. Disproportionality between BP increase and structural alterations during ontogeny in SHR could reflect the flexibility of the arterial tree to the different needs of supplied areas.

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.

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.

Different effects of 7-nitroindazole and L-NAME administered both individually and together on the cardiovascular system of the rat.

We evaluated the effects of N(G)-nitro-L-arginine methylester (L-NAME) (50 mg/kg/day) and 7-nitroindazole (7NI) (10 mg/kg/day) administered from 10th-16th week of age either individually or together on cardiovascular system of Wistar rats and SHR. Systolic blood pressure (sBP) was measured weekly by the plethysmographic method. For morphological studies, the animals (n=10) were perfused with a fixative (120 mm Hg), and thoracic aorta and carotid and coronary arteries were processed for electron microscopy. For functional investigation (n=10), aortic rings were used in an organ bath. In Wistar rats, L-NAME evoked an increase of sBP; hypertrophy of the heart and arterial walls; an increase in cross-sectional areas (CSA) of endothelial cells (EC), muscle cells (SMC), extracellular matrix (ECM), and a decrease in acetylcholine-induced endothelial-dependent relaxation (EDR). 7NI evoked sBP-independent hypotrophy of the heart and arterial walls, a decrease in CSA of EC and SMC without affecting the CSA of ECM, and a mild decrease in acetylcholine-induced EDR. 7NI and L-NAME administered together evoked lower effect on BP and trophicity of the heart and all arteries, and a similar decrease in acetylcholine-induced EDR compared to L-NAME alone. In SHR, 7NI did not evoke any effect on the studied parameters.

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.

[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.).

The role of oxidative stress in acetylcholine-induced relaxation of endothelium-denuded arteries.

Nitric oxide (NO) is produced in the endothelium in response to vasorelaxants, such as acetylcholine, and acts on vascular smooth muscle cells to induce vasorelaxation. Previously, we found that the smooth muscle of endothelium-denuded arteries expresses functional NO synthase. We hypothesized that the destruction of arterial anatomical integrity induced by denuding arteries of their endothelial layers causes the vessels to become insensitive to vasodilators as a consequence of oxidative stress. In this study, we examined whether the acetylcholine-induced vasorelaxation observed in deendothelialized arteries is mediated by NO and/or affected by oxidative stress. For functional relaxation studies, the isolated thoracic aorta and pulmonary artery of male Wistar rats were used. Vessel superoxide production was assessed in preserved and endothelium-denuded arteries by the lucigenin chemiluminescence method. In all arteries with intact endothelia, acetylcholine evoked vasorelaxation; this effect was inhibited in endothelium-denuded rings. Pretreatment of denuded rings with the free-radical scavenger tempol improved acetylcholine-induced relaxation. This effect was inhibited by the coadministration of 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ), an inhibitor of guanylate cyclase, or N(G)-nitro-L-arginine methylester (L-NAME), an inhibitor of NO synthase. The chemiluminescent assay revealed that endothelial denudation of both vessel types increased the production of superoxide radicals which has been decreased after tempol administration. Our results show that non-endothelial NO could represent an additional source of physiologically active NO and that the insensitivity of endothelium-denuded vessels to vasodilators could be a consequence of oxidative stress. These findings question the concept that endothelial cells play an obligatory role in vasorelaxation.

Blood pressure-independent hypotrophy of the heart, kidneys and conduit arteries after 7-nitroindazole administration to Wistar rats from the prenatal period to adulthood.

The aim of this study was to investigate the long-term effects of 7-nitroindazole on the heart, kidneys, thoracic aorta, and carotid arteries from the progeny of mothers that had been treated with 7-nitroindazole (7NI) (10 mg/kg/day in drinking water) during gestation and nursing. The offspring were also treated with 7NI (10 mg/kg/day in drinking water) until 10 weeks of age. Mean arterial pressure (BP) was measured by tail-cuff plethysmography starting at 4 weeks of age. After perfusion fixation with glutaraldehyde at 120 mmHg, the heart and kidneys were weighed and the thoracic aorta and carotid arteries were processed for morphological investigation. The BP and body weight of treated rats did not differ from age-matched control rats during the course of the experiment. In the experimental group, at the end of the experiment, the heart weight/body weight and kidney weight/body weight ratios were decreased. In addition, the wall thickness (intima + media), cross sectional area (intima + media), and wall thickness/inner diameter ratio were significantly decreased in both the thoracic aorta and carotid arteries without a change in the inner vessel diameter. Circumferential wall tension was increased in both arteries. The data clearly indicate that long-term inhibition of neuronal nitric oxide (NO) synthase with the specific inhibitor 7NI evokes BP-independent hypotrophy of the heart, kidneys, and conduit arterial walls in normotensive Wistar rats.

Effects of chronic neuronal nitric oxide-synthase inhibition on arterial function and structure in spontaneously hypertensive rats.

While the effect of chronic non-specific NO-synthase inhibition in the cardiovascular system has been recognized under normotensive and hypertensive conditions, there are no data relating the long-term inhibition of neuronal NO-synthase (nNOS) in essential hypertension. The aim of this study was to investigate the long-term effect of nNOS inhibitor 7-nitroindazole (7-NI) administration on arterial function and structure in spontaneously hypertensive rats (SHR). Ten weeks old SHR were divided in two groups: control group and group administered 7-NI (10 mg/kg/day) for six weeks in drinking water. Systolic blood pressure (SBP) was measured using the plethysmographic method. The vasoactivity of isolated thoracic aorta (TA) and mesenteric artery (MA) was recorded via changes in isometric tension, and the geometry of both arteries was measured using light microscopy. Chronic treatment with 7-NI did not affect either SBP or heart/body weight ratio. Acetylcholine-induced relaxation of both arteries was unchanged after 7-NI. 7-NI administration did not affect the sensitivity and contraction to exogenous noradrenaline in TA, whereas both parameters were augmented in MA. The contractile response of MA induced by transmural nerve stimulation (endogenous noradrenaline) was unaffected after 7-NI. The mass of TA wall was unchanged, whereas hypertrophy was observed in MA after 7-NI. In summary, although SBP and endothelial function were not changed after chronic nNOS inhibition, the contractile and structural properties of TA and MA were affected differently. The data suggest that nNOS triggers original and tissue-specific regulatory pathways in essential hypertension.

Hypotrophic effect of long-term neuronal NO-synthase inhibition on heart and conduit arteries of the Wistar rats.

We demonstrate the effect of long-term nNOS inhibition with 7-nitroindazole (7NI) on the heart and conduit arteries. Ten weeks old Wistar rats were used: two groups of controls and rats receiving 7-NI (10 mg/kg b.w./day) for 6 weeks in drinking water. Blood pressure (BP) was measured by the plethysmographic method. In first group mesenteric, carotid and coronary arteries were excised after perfusion fixation (120 mmHg) for morphological study, in second group mesenteric artery was taken for functional investigation. 7NI did not affect BP, heart/body weight was decreased. In all arteries inner diameter (ID) did not changed, wall thickness (WT) (intima+media), cross sectional area (CSA) (intima+media), and WT/ID decreased. In carotid artery volume density (VD) (percentual proportion) of intima and media did not change; VD and CSAs of endothelial and smooth muscle cells decreased, CSAs of extracellular matrix in intima and media did not change. No difference was found in relaxation of mesenteric artery to acetylcholine (10(-9)-10(-5) mol/L). Contraction induced by transmural nerve stimulation (8 Hz) augmented and contraction to exogennous noradrenaline (10(-9)-10(-5) mol/L) attenuated. Long-term 7NI administration evoked pressure independent cardiac hypotrophy and due to decrease of endothelial and smooth muscle cell mass arterial wall hypotrophy associated with decreased contractile efficiency.

The effects of pertussis toxin-treatment on integrated vasoactive response of vascular system in spontaneously hypertensive rats.

We investigated the effect of pertussis toxin (PTX) on hypotensive response induced by acetylcholine (ACh) and bradykinin (BK) and on noradrenaline (NA)-induced pressor response in spontaneously hypertensive rats (SHR). Fifteen-week-old Wistar rats and age-matched SHR were used. Half of SHR received PTX (10 microg/kg/i.v.) and the experiments were performed 48 h later. After the anesthesia the right carotid artery was cannulated in order to record blood pressure (BP). The hypotensive response to ACh was enhanced in SHR compared to Wistar rats. After pretreatment of SHR with PTX the hypotensive response to ACh was reduced compared to untreated SHR and it was also diminished in comparison to Wistar rats. Similarly, the hypotensive response to BK was also decreased after PTX pretreatment. The pressor response to NA was increased in SHR compared to Wistar rats. NA-induced pressor response was considerably decreased after PTX pretreatment compared to untreated SHR. In conclusion, the enhancement of hypotensive and pressor responses in SHR was abolished after PTX pretreatment. Our results suggested that the activation of PTX-sensitive inhibitory G(i) proteins is involved in the regulation of integrated vasoactive responses in SHR and PTX pretreatment could be effectively used for modification of BP regulation in this type of experimental hypertension.

Hereditary hypertriglyceridemic rat: a suitable model of cardiovascular disease and metabolic syndrome?

Hypertriglyceridemia and hypertension seem to be very important cardiovascular risk factors. The Prague hereditary hypertriglyceridemic (hHTG) rat was developed as a model of human hypertriglyceridemia. It was demonstrated that these rats are not obese, they are hypertensive and insulin resistant and they have some disturbances in glucose metabolism. Several QTLs were identified for blood pressure, its particular components (dependent on major vasoactive systems) and plasma triglycerides throughout the genome of hHTG rats by using of F(2) hybrids strategy. It is evident that hHTG rats are a suitable model for the study of metabolic disturbances in relation to blood pressure as well as for the search of genetic determinants of these abnormalities. Numerous abnormalities of blood pressure regulation as well as alterations in the structure and function of cardiovascular apparatus (heart, conduit and resistance arteries) were found in hHTG rats. A special attention was paid to possible changes in the efficiency of various vasoactive systems such as nitric oxide, renin-angiotensin-aldosterone system and sympathetic nervous system, which seem to contribute substantially to cardiovascular and/or metabolic abnormalities observed in Prague hereditary hypertriglyceridemic rats.

Comparison of vascular function and structure of iliac artery in spontaneously hypertensive and hereditary hypertriglyceridemic rats.

The aim of this study was to compare the vascular reactivity and morphology of iliac artery (IA) in adult spontaneously hypertensive rats (SHR) and hereditary hypertriglyceridemic (hHTG) rats. The isolated rings of iliac artery (IA) from Wistar rats (controls), SHR and hHTG rats were used for measurement of relaxant responses to acetylcholine (ACh) and contractile responses to noradrenaline (NA). Morphological changes of IA were measured using light microscopy. Systolic blood pressure (BP) measured by plethysmographic method was increased in SHR approximately by 88 % and in hHTG rats by 44 % compared to controls. BP increase was accompanied by cardiac hypertrophy. In both SHR and hHTG groups (experimental groups) reduced relaxation to ACh and enhanced maximal contraction and sensitivity to adrenergic stimuli were observed. The sensitivity to NA in SHR was higher also in comparison with hHTG. Geometry of IA in both experimental groups revealed increased wall thickness and wall cross-sectional area, in SHR even in comparison with hHTG. Inner diameter was decreased in both experimental groups. Thus, independently of etiology, hypertension in both models was connected with impaired endothelial function accompanied by structural alterations of IA. A degree of BP elevation was associated with arterial wall hypertrophy and increased contractile sensitivity.

Acetylcholine and bradykinin enhance hypotension and affect the function of remodeled conduit arteries in SHR and SHR treated with nitric oxide donors.

Discrepancy was found between enhanced hypotension and attenuated relaxation of conduit arteries in response to acetylcholine (ACh) and bradykinin (BK) in nitric oxide (NO)-deficient hypertension. The question is whether a similar phenomenon occurs in spontaneously hypertensive rats (SHR) with a different pathogenesis. Wistar rats, SHR, and SHR treated with NO donors [molsidomine (50 mg/kg) or pentaerythritol tetranitrate (100 mg/kg), twice a day, by gavage] were studied. After 6 weeks of treatment systolic blood pressure (BP) was increased significantly in experimental groups. Under anesthesia, the carotid artery was cannulated for BP recording and the jugular vein for drug administration. The iliac artery was used for in vitro studies and determination of geometry. Compared to control, SHR showed a significantly enhanced (P < 0.01) hypotensive response to ACh (1 and 10 microg, 87.9 +/- 6.9 and 108.1 +/- 5.1 vs 35.9 +/- 4.7 and 64.0 +/- 3.3 mmHg), and BK (100 microg, 106.7 +/- 8.3 vs 53.3 +/- 5.2 mmHg). SHR receiving NO donors yielded similar results. In contrast, maximum relaxation of the iliac artery in response to ACh was attenuated in SHR (12.1 +/- 3.6 vs 74.2 +/- 8.6% in controls, P < 0.01). Iliac artery inner diameter also increased (680 +/- 46 vs 828 +/- 28 microm in controls, P < 0.01). Wall thickness, wall cross-section area, wall thickness/inner diameter ratio increased significantly (P < 0.01). No differences were found in this respect among SHR and SHR treated with NO donors. These findings demonstrated enhanced hypotension and attenuated relaxation of the conduit artery in response to NO activators in SHR and in SHR treated with NO donors, a response similar to that found in NO-deficient hypertension.

Acetylcholine and bradykinin enhance hypotension and affect the function of remodeled conduit arteries in SHR and SHR treated with nitric oxide donors

Discrepancy was found between enhanced hypotension and attenuated relaxation of conduit arteries in response to acetylcholine (ACh) and bradykinin (BK) in nitric oxide (NO)-deficient hypertension. The question is whether a similar phenomenon occurs in spontaneously hypertensive rats (SHR) with a different pathogenesis. Wistar rats, SHR, and SHR treated with NO donors [molsidomine (50 mg/kg) or pentaerythritol tetranitrate (100 mg/kg), twice a day, by gavage] were studied. After 6 weeks of treatment systolic blood pressure (BP) was increased significantly in experimental groups. Under anesthesia, the carotid artery was cannulated for BP recording and the jugular vein for drug administration. The iliac artery was used for in vitro studies and determination of geometry. Compared to control, SHR showed a significantly enhanced (P < 0.01) hypotensive response to ACh (1 and 10 æg, 87.9 ± 6.9 and 108.1 ± 5.1 vs 35.9 ± 4.7 and 64.0 ± 3.3 mmHg), and BK (100 æg, 106.7 ± 8.3 vs 53.3 ± 5.2 mmHg). SHR receiving NO donors yielded similar results. In contrast, maximum relaxation of the iliac artery in response to ACh was attenuated in SHR (12.1 ± 3.6 vs 74.2 ± 8.6 percent in controls, P < 0.01). Iliac artery inner diameter also increased (680 ± 46 vs 828 ± 28 æm in controls, P < 0.01). Wall thickness, wall cross-section area, wall thickness/inner diameter ratio increased significantly (P < 0.01). No differences were found in this respect among SHR and SHR treated with NO donors. These findings demonstrated enhanced hypotension and attenuated relaxation of the conduit artery in response to NO activators in SHR and in SHR treated with NO donors, a response similar to that found in NO-deficient hypertension.