UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Vascular contractions induced by K(+)-free solution and relaxation responses following the return of K+ to the organ bath were studied in mesenteric arterial rings from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with particular focus on the role of vascular adrenergic nerve-endings and endothelium. 2. In endothelium-denuded rings the omission of K+ from the incubation medium resulted in gradual contractions, the rate of which was slower in SHR than WKY. Nifedipine (1 microM) inhibited the contractions more effectively in SHR than WKY. 3. Adrenergic denervation in vitro with 6-hydroxydopamine reduced the contractions induced by the K(+)-free medium in endothelium-denuded rings. The remaining contractions after denervation were markedly greater in SHR than WKY. 4. The presence of intact vascular endothelium attenuated the K(+)-free contractions in both strains, the attenuation being smaller in SHR than WKY. NG-nitro-L-arginine methyl ester (L-NAME, 0.1 mM) and methylene blue (10 microM), but not indomethacin (10 microM), abolished the attenuating effect of endothelium on the K(+)-free contractions. L-Arginine (1 mM) reversed the effect of L-NAME in WKY but not in SHR. 5. The re-addition of K+ after full K(+)-free contractions dose-dependently relaxed the rings. The rate of this K(+)-induced relaxation was significantly slower in SHR than WKY at all K+ concentrations (0.1-5.9 mM) studied, whether the endothelium or functioning adrenergic nerve-endings were present or not. Ouabain (1 mM) totally inhibited the K+ relaxation in SHR but only partially in WKY.6. Vascular smooth muscle contractions induced by high concentrations of potassium were comparable between the strains. The EC50 for noradrenaline-induced contractions was lower in SHR than WKY, but the maximal forces did not differ significantly.7. In conclusion, the contractile response in K+-free solution more clearly differentiates vascular rings from SHR and WKY than the responses induced by the classical contractile agents noradrenaline and high concentrations of potassium. The depressant effect of the presence of intact endothelium on the K+-free contractions, which was smaller in SHR than WKY, is mediated via the endothelium-derived relaxing factor. Neurotransmitter release from vascular adrenergic nerve-endings participates less in the K+-free contractile response in SHR than WKY. Moreover, the contractile response is more dependent on calcium entry through nifedipine-sensitive calcium channels in SHR than WKY. The greater K+-free contractions of denervated endothelium-denuded rings and the reduced K+ relaxation rate in SHR when compared to WKY suggest increased cell membrane permeability and decreased activity of vascular Na+, K+-ATPase, respectively, in this type of genetic hypertension.
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PMID:Contractions induced by potassium-free solution and potassium relaxation in vascular smooth muscle of hypertensive and normotensive rats. 150 24

In the present study, basal and stimulated production of endothelium-derived relaxing factor (EDRF) were examined in young (4-5 week-old) and mature (10-12 week-old) spontaneously hypertensive rats (SHR) and were compared with those of age-matched Wistar Kyoto (WKY) normotensive rats. Nw-nitro-L-arginine methyl ester (L-NAME) was used as a probe for basal EDRF production in vivo. We also determined the dose-response effects of acetylcholine (Ach, 10(-9)-10(-5) M), sodium nitroprusside (NP, 10(-9)-10(-5) M), and norepinephrine (NE, 3 x 10(-10)-10(-6) M), on third-order arterioles (3A) in the two age groups. Relaxation of 3A vessels in response to Ach was significantly lower (p < 0.01) in mature SHR than in WKY rats. No significant differences were observed in responses to Ach in young animals or in responses to NP in either age groups. Preincubation with L-NAME (2 x 10(-4) M) shifted the dose-response curves of NE to the left in mature WKY rats (n = 6), but not in mature SHR (n = 6). These data indicate that both basal and stimulated production of EDRF are decreased in small arterioles in the striated muscle microcirculation at an established stage of genetic hypertension. These data suggest that a diminished EDRF response by arterioles may be in part responsible for the elevated microvascular reactivity observed in genetic hypertension.
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PMID:Decreased arteriolar endothelium-derived relaxing factor production during the development of genetic hypertension. 849 May 94

The arterioles of young spontaneously hypertensive rats (SHR) are purported to have an enhanced sensitivity to nitric oxide (NO)-dependent vasodilators, relative to normotensive animals, while NO-related arteriolar responses are diminished in both mature SHR as well as hypercholesterolemic normotensive rats. Because endothelial production of NO relaxes vascular smooth muscle and inhibits platelet adhesion and aggregation, hypercholesterolemia may synergistically affect the development of genetic hypertension. The NO-mediated baseline vascular tone, acetylcholine-induced dilation, and inhibition of platelet thrombus formation were studied over time (10 weeks) in SHR and hypercholesterolemic SHR (HC-SHR). The in vivo microcirculation of the cremaster muscle was used to quantitate all observations. The HC-SHR became significantly hypercholesterolemic after 1 week on the cholesterol-supplemented diet, with serum cholesterol concentrations remaining elevated for the 10 weeks studied. However, the serum cholesterol concentrations of HC-SHR were significantly less than those of Sprague-Dawley and Wistar-Kyoto rats fed the same diet. Dietary hypercholesterolemia did not exacerbate the development of genetic hypertension. Second- and third-order arterioles of SHR and age-matched HC-SHR constricted to the same extent when the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was applied. The third order arterioles of both groups also dilated the same amount to acetylcholine and sodium nitroprusside. Platelet thrombus formation induced by light/dye photochemistry was not different between the SHR and HC-SHR groups either at 1 or 10 weeks of diet, and L-NAME decreased the time to thrombus occlusion of blood flow equally in both groups. This is in marked contrast to the previously reported hypercholesterolemia-induced decreases in vascular reactivity in Sprague-Dawley rats. These current findings demonstrate that SHR are resistant to the development of hypercholesterolemia and that NO-mediated vascular responses in SHR are not attenuated by hypercholesterolemia.
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PMID:Spontaneously hypertensive rats are resistant to the development of hypercholesterolemia. 884 68

Possible impairment of the L-arginine-nitric oxide (NO) pathway in the rostral ventrolateral medulla of adult spontaneously hypertensive rats (SHR) was investigated by microinjecting N(G)-nitro-L-arginine methyl ester (L-NAME), NOC 18 (an NO donor), or L-arginine. Unilateral injection of L-NAME (10 nmol/50 nL) into the rostral ventrolateral medulla significantly increased mean arterial pressure (MAP) in both SHR and Wistar-Kyoto rats (WKY). The increases in MAP did not differ significantly between the two strains (15+/-3 versus 10+/-2 mm Hg, respectively; n=8). In contrast, microinjection of L-arginine elicited significant (P<.05) dose-dependent decreases in MAP in both strains, and these depressor responses were significantly greater in SHR than in WKY (in 10 nmol of L-arginine: -29+/-2 versus -15+/-2 mm Hg, respectively; n=8, P<.01). Similarly, microinjection of NOC 18 (10 nmol/50 nL) reduced MAP in both strains, and the depressor response was also significantly greater in SHR than in WKY (-38+/-7 versus -22+/-3 mm Hg, respectively; n=8, P<.05). These results suggest that the L-arginine-NO pathway in the rostral ventrolateral medulla is impaired in SHR and that this impairment may contribute to the increase in arterial pressure in this animal model of genetic hypertension.
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PMID:Enhanced depressor response to nitric oxide in the rostral ventrolateral medulla of spontaneously hypertensive rats. 953 31

Endothelins (ET) are 21-aminoacid peptides produced ubiquitously, which were discovered originally as endothelial products. These peptides may play important roles in cardiovascular physiology and pathophysiology. As the pathophysiologic roles of endothelins in cardiovascular disease become increasingly apparent, the potential therapeutic use of endothelin antagonists or endothelin converting enzyme inhibitors is recognized. The main endothelin produced by the endothelium is ET-1. Endothelin-1 is overexpressed in the vascular wall of salt-dependent models of hypertension, such as DOCA-salt hypertensive rats, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, and in stroke-prone SHR, angiotensin II-infused rats and 1-kidney 1 clip Goldblatt hypertensive rats, but not in SHR, 2-K 1C hypertensive rats or L-NAME-treated rats. The vasoconstrictor effect of ET-1 may contribute to blood pressure elevation and its growth-promoting action to vascular hypertrophy in the hypertensive models which overexpress ET-1 in blood vessels. In rats without generalized activation of the endothelin system, expression of ET-1 is often enhanced in coronary arteries, which suggests a role for ET-1 in myocardial ischemia in hypertension. In rats overexpressing ET-1, ETA/B and ETA-selective antagonists lowered blood pressure slightly, and significantly reduced vascular growth, particularly of small arteries, suggesting that ET-1 has a direct effect on growth. Protection from renal injury and from stroke has also been demonstrated in hypertensive rats treated with endothelin antagonists. In normotensive human subjects endothelin-dependent tone can be shown in the forearm. In a study of mild hypertensive patients, the ETA/B antagonist bosentan reduced blood pressure similarly to an ACE inhibitor. Moderate to severe hypertensive patients presented enhanced expression of ET-1 mRNA in the endothelium of subcutaneous resistance arteries. In blacks with familial hypertension increased plasma levels of endothelin have been found. Thus, ET-1 may play a role in some experimental hypertensive models and in human hypertension. In summary, endothelial ET-1 may be overexpressed in the more severe forms of hypertension, and in certain special populations which may respond particularly well to endothelin antagonism. Endothelin antagonists may prove to be effective disease-modifying agents if in future clinical trials they are shown clinically to blunt vascular growth and endothelial dysfunction, reduce stroke and exert the cardioprotective and renal protective effects already reported in experimental hypertension. These agents could contribute to reduce the long-term complications of hypertension, which remains to be demonstrated in humans.
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PMID:Endothelin: role in hypertension. 983 May 7

The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O2-) was examined. O2- generation, measured by lucigenin chemiluminescence, was studied in 12- to 16-week male and female Wistar-Kyoto rats (WKY) and SHRSP. In addition, expression of the gene encoding endothelial NO synthase, the enzyme involved in NO generation, was investigated. O2- generation was increased in male and female SHRSP (4.11+/-0.24 and 3. 84+/-0.28 nmol O2-. min-1. mg-1 respectively) compared with their WKY counterparts and was significantly higher in male than female WKY (1.22+/-0.08 in males and 0.8+/-0.08 nmol O2-. min-1. mg-1 respectively) (SHRSP versus WKY P<0.0001, 95% CI -3.39, -2.51; male versus female WKY P=0.0029, 95% CI -0.67, -0.17). Removal of the endothelium by rubbing or addition of NO synthase inhibitors attenuated O2- generation in SHRSP but not WKY. In males, removal of the endothelium reduced O2- generation from 3.86+/-0.12 to 1.35+/-0. 08 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.29, 2.81), whereas addition of L-NAME caused a reduction from 4.13+/-0.17 to 1.32+/-0.16 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.36, 2.83). Similar reductions were observed in females. L-arginine had no significant effect, but tetrahydrobiopterin significantly decreased O2- generation in SHRSP from 4.04+/-0.11 to 2.36+/-0.40 nmol. min-1. mg-1 (P=0.0026, 95% CI 0.89, 2.44). Endothelial NO synthase mRNA expression was significantly greater in SHRSP than in WKY and in WKY males than in WKY females. These results show that O2- generation is increased in SHRSP and that the tissue and enzymatic sources of this excess O2- appear to be the endothelium and eNOS, respectively. The increase in O2- generation could explain the decreased availability of basal NO observed in this model of genetic hypertension.
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PMID:Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium. 1037 15

Changes in the lipid composition of the membrane affect its fluidity and function. These variables are altered in various forms of hypertension. Our hypothesis was that the rapid increase in blood pressure (BP) caused by inhibition of nitric oxide production would lead to alterations in membrane fluidity similar to those observed in genetic hypertension. We used Nomega-nitro L-arginine methyl ester (L-NAME) and vehicle-treated (3 weeks) Wistar-Kyoto rats to study the effects of nitric oxide synthase (NOS) inhibition on membrane fluidity and lipid composition. Erythrocyte membrane fluidity was measured by fluorescence anisotropy. Membrane lipids were separated using Sep-Pak and thin-layer chromatography. Fatty acid methyl esters were produced and analyzed by gas chromatography-mass spectrometry. Nomega-nitro L-arginine methyl ester treatment increased BP and erythrocyte membrane fluidity. The phospholipid and unsaturated fatty acid levels in the membranes from the L-NAME-treated rats were consistent with the increase in fluidity (ie, more unsaturated fatty acid, in particular, arachidonic and docosahexaenoic acid) and a reduction in membrane sphingomyelin content. Fatty acid analysis of individual lipid groups suggested the changes in membrane fatty acid composition may be asymmetric, with the majority of the changes occurring in the outer leaflet. Inhibition of NOS results in changes in membrane composition that may explain the concurrent changes in fluidity. The increased membrane fluidity observed here contrasts with the reduced fluidity observed in genetic hypertension or unchanged fluidity in secondary hypertension. The effects could be related to NOS inhibition or may be a direct effect of L-NAME.
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PMID:Inhibition of nitric oxide synthesis increases erythrocyte membrane fluidity and unsaturated fatty acid content. 1107 80

The precise role of nitric oxide (NO) in hypertension is still not fully understood, although this vasodilator system represents the main counterbalance of major pressor systems. The aim of our study was to determine the contributions of superoxide anions, the renin-angiotensin system (RAS), the sympathetic nervous system (SNS) and NO to the maintenance of blood pressure (BP) in Prague hereditary hypertriglyceridaemic (HTG) rats with genetic hypertension. Conscious chronically cannulated rats were subjected to the consecutive blockade of the RAS (losartan, 10 mg/kg), the SNS (pentolinium, 5 mg/kg) and NO synthase [N(omega)-nitro-L-arginine (L-NAME), 30 mg/kg]. Some additional rats were pretreated with tempol (a membrane-permeable mimetic of superoxide dismutase). A subsequent genetic study in HTG x Lewis F(2) hybrid rats (n=284) was designed to reveal potential associations of particular BP components with baseline BP. The progenitor study indicated that BP elevation was more pronounced in male than female HTG rats (as compared with normotensive Lewis controls). Higher BP in HTG rats was due to the increased residual BP (measured after combined RAS and SNS blockade) and the augmentation of BP responses to tempol or losartan. In contrast, BP responses to pentolinium or l-NAME were similar in all experimental groups. It should, however, be noted that the baseline BP of progenitor animals was correlated positively with both residual BP and the magnitude of the BP response to pentolinium, but not with BP response to L-NAME. Similarly, the baseline BP of F(2) hybrid rats was positively associated with residual BP, the BP response to pentolinium and the relative SNS contribution to BP maintenance [expressed as a percentage of baseline mean arterial pressure (MAP) values], as well as with the ratio of BP changes elicited by ganglion blockade and NO synthase inhibition (Delta MAP(pentolinium)/Delta MAP(L-NAME) ratio), reflecting the balance of main vasopressor and vasodepressor systems. Thus our studies, performed in progenitor and F(2) hybrid rats, revealed that changes in BP induced by L-NAME do not keep pace with the progressive augmentation of pentolinium-induced changes in BP occurring over a wide range of increasing BP. The altered balance between enhanced SNS-dependent vasoconstriction and unchanged NO-dependent vasodilation ('relative NO deficiency' in rats with high BP) might result in BP elevation in this form of genetic hypertension.
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PMID:Altered balance of main vasopressor and vasodepressor systems in rats with genetic hypertension and hypertriglyceridaemia. 1186 67

Using spontaneously hypertensive rats (SHR) fed a standard or a Zn-deficient diet for 4 weeks, we examined whether Zn deficiency affects systemic blood pressure (BP) levels in a genetically hypertensive state through a fall in the activity of Cu/Zn-superoxide dismutase (SOD). SHR fed a Zn-deficient diet had a progressive increase in systolic BP during the dietary conditioning. Consequently, SHR fed a Zn-deficient diet exhibited significantly increased levels of systolic BP by 2 weeks after the start of dietary treatment when compared with SHR fed a standard diet. Similarly, levels of basal mean arterial pressure (MAP) observed at the end of dietary treatment were SHR fed a Zn-deficient diet > SHR fed a standard diet. Administration of the nitric oxide synthase (NOS) inhibitor, L-NAME, caused an increase in MAP levels in the two groups of rats, demonstrating the involvement of the vasodilator, nitric oxide (NO), in the regulation of systemic BP in a genetically hypertensive state. The expression of endothelial (e) NOS mRNA and protein in the thoracic aorta paralleled basal MAP levels in the two groups of rats, suggesting the counter-regulation of eNOS against the developed hypertensive state in SHR fed a Zn-deficient diet. On the other hand, administration of the superoxide scavenger, tempol (a SOD mimetic compound), led to a decrease in MAP levels in the two groups of rats, indicating the participation of the oxygen free radical, superoxide, in an increase in systemic BP in a genetically hypertensive state. As reported recently, the mechanism involved is due likely to a decrease in the action of the vasodilator, NO, based on the formation of peroxynitrite coming from the non-enzymatic reaction of superoxide and NO. In addition, tempol treatment completely restored MAP levels in SHR fed a Zn-deficient diet to levels comparable to those observed in SHR fed a standard diet, indicating that a further increase in systemic BP levels seen in SHR fed a Zn-deficient vs. a standard diet is presumably brought by a reduction in the action of the vasodilator, NO, resulting from an increase in the action of superoxide. The activity of the superoxide scavenger, Cu/Zn-SOD, in the thoracic aorta was significantly decreased in SHR fed a Zn-deficient diet relative to SHR fed a standard diet. It appears that a decrease in the activity of Cu/Zn-SOD observed in the thoracic aorta of SHR fed a Zn-deficient diet at least in part plays a role in an increase in the action of superoxide in this model. Thus, Zn deficiency may be a factor to develop genetic hypertension presumably through the oxidative stress caused by superoxide.
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PMID:Zn deficiency aggravates hypertension in spontaneously hypertensive rats: possible role of Cu/Zn-superoxide dismutase. 1210 76

Antioxidant vitamins C and E have protective properties in genetic hypertension associated with enhanced oxidative stress. This study investigated whether vitamins C and/or E modulate vascular function by regulating enzymatic activities of endothelial nitric oxide synthase (eNOS) and NAD(P)H oxidase using thoracic aortas of 20- to 22-week-old male spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar-Kyoto rats (WKY). SHR aortas had impaired relaxant responses to acetylcholine but not to sodium nitroprusside, despite an approximately 2-fold increase in eNOS activity and NO release. The levels of superoxide anion (O2-), a potent NO scavenger, and NAD(P)H oxidase activity were also 2-fold higher in SHR aortas. Mechanical but not pharmacological inactivation of endothelium (by rubbing and 100 micromol/L L-NAME, respectively) significantly abrogated O2- in both strains. Treatments of SHR aortas with NAD(P)H oxidase inhibitors, namely diphenyleneiodinium and apocynin, significantly diminished O2- production. The incubation of SHR aortas with different concentrations of vitamin C (10 to 100 micromol/L) and specifically with high concentrations of vitamin E (100 micromol/L) improved endothelial function, reduced superoxide production as well as NAD(P)H oxidase activity, and increased eNOS activity and NO generation in SHR aortas to the levels observed in vitamin C- and E-treated WKY aortas. Our results reveal endothelial NAD(P)H oxidase as the major source of vascular O2- in SHR and also show that vitamins C and E are critical in normalizing genetic endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities.
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PMID:Vitamins reverse endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities. 1262 55

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