Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis.
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PMID:Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits. 925 81

We report on the modulatory effects of chronic subcutaneous or oral estrogen and LY117018, a selective estrogen receptor modulator, on the release of nitric oxide in rings of rat aorta studied under isometric conditions. Dilator responses to acetylcholine (ACh; 10[8] to 10[-5] M) were obtained in phenylephrine (PE; 2 microM)-contracted aorta, and constrictor dose-response curves to PE (10[-8] to 10[-5] M) were generated before and after pretreatment with N omega-nitro-L-arginine methyl ester (L-NAME; 200 microM), an inhibitor of nitric oxide synthase. Tissue segments were obtained from five groups of rats implanted with a subcutaneous pellet delivery system for 21 days: (1) male, (2) sham-operated placebo-treated female, (3) ovariectomized placebo-treated, (4) ovariectomized, 17beta-estradiol treated (0.5 mg/pellet) and (5) ovariectomized, progesterone (15 mg/pellet) and 17beta-estradiol (0.5 mg/pellet)-treated. Aortic rings from sham rats and ovariectomized rats receiving estrogen relaxed more to ACh (10[-6] to 10[-5] M) than did the rings from ovariectomized, progesterone plus estrogen-treated and male rats (P < .05). They were also characterized by a greater potentiation of the PE responses after L-NAME compared with male, progesterone plus estrogen-treated and ovariectomized rats (P < .05) and a similar sensitivity to PE. In addition, ACh-induced relaxation and L-NAME-induced potentiation of PE contractions in aortic rings from rats dosed orally with LY117018 were similar to responses of aortic rings from rats dosed orally with estrogen. These results demonstrate that chronically administered estrogen and LY117018 enhance the release of nitric oxide from endothelium in rat aortic rings.
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PMID:Estrogen and selective estrogen receptor modulator LY117018 enhance release of nitric oxide in rat aorta. 933 15

The JCR:LA-cp rat is obese and insulin resistant and develops a major vasculopathy, with associated ischemic damage to the heart. Male rats were treated with 17alpha-ethinylestradiol (EE), LY117018, and/or the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). LY117018 decreased plasma cholesterol esters, with a 40% reduction in total cholesterol. EE increased triglyceride levels and modestly decreased cholesterol esters. L-NAME increased blood pressure and aortic contractile sensitivity to phenylephrine and inhibited acetylcholine-induced relaxation. LY117018 decreased the force of contraction. The L-NAME-mediated increase in force of contraction and decrease in response to acetylcholine was inhibited by LY117018. L-NAME-induced hypertension was prevented by LY117018. Platelet aggregation was not different between obese and lean rats and was unaffected by L-NAME. LY117018, both in the absence and presence of L-NAME, inhibited platelet aggregation. The effects of LY117018 are apparently mediated through both NO-dependent and -independent mechanisms. The changes induced by EE and LY117018 may reflect the activation of multiple mechanisms, both estrogen receptor-dependent and -independent. The changes induced by LY117018 are significant and may prove to be cardioprotective in the presence of the insulin resistance syndrome.
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PMID:Effects of LY117018 and the estrogen analogue, 17alpha-ethinylestradiol, on vascular reactivity, platelet aggregation, and lipid metabolism in the insulin-resistant JCR:LA-cp male rat: role of nitric oxide. 1115 69

By perfusing isolated carotid sinus, the effect of 17beta-estradiol (E(2)) on carotid sinus baroreflex was observed in anesthetized male rats. The results obtained are as follows. (1) By perfusing with E(2) (10 micromol/L), the functional curve of baroreflex was shifted to the right and upward, with a peak slope (PS) decrease from 0.49+/-0.03 to 0.25+/-0.01 (P<0.01) and a reflex decrease in mean arterial pressure (reflex decrease, RD) from 7.37+/-0.42 kPa to 3.49+/-0.20 kPa (P<0.001), while the threshold pressure (TP) and saturation pressure (SP) were significantly increased from 9.52+/-0.68 kPa to 13.3+/-0.11 kPa (P<0.001) and 24.53+/-0.48 kPa to 27.52+/-0.20 kPa (P<0.01) respectively. Among the functional parameters of carotid baroreflex, the changes of RD, PS, TP and SP were dose-dependent. (2) Pretreatment with different doses of tamoxifen (1, 5, 10, 30 micromol/L), an inhibitor of estrogen receptor, did not block the effect of E(2) on carotid baroreflex. (3) Preperfusion with an inhibitor of NO synthase L-NAME (100 micromol/L) could completely abolish the effect of E(2) on carotid baroreflex. It is concluded that the inhibitory effect of E(2)on carotid sinus baroreflex may be mediated by NO release from endothelial cells, but not by a genomic mechanism.
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PMID:[17beta -estradiol inhibits carotid sinus baroreflex in male rats]. 1194 4

Bovine aortic endothelial cells (BAECs) were used to study the effect of 17beta -estradiol (E(2)) on nitric oxide (NO) release, nitric oxide synthase (eNOS) mRNA expression and intracellular free calcium con~cen~tration ([Ca(2+)](I)) and modulation of the effect of E(2) by estrogen receptor (ER) antagonist tamoxifen and NOS inhibitor L-NAME. E(2) (10(-12) 10(-8) mol/L) induced NO release of BAECs in a concentration-dependent manner and the abundant expression of eNOS mRNA in BAECs increased obviously after treatment with E(2) (10(-8)mol/L) for 48 h. These effects were evidently inhibited by tamoxifen (10(-7)mol/L) and L-NAME (10(-6) mol/L). Furthermore treatment with E(2) (10(-8) mol/L) for 48 h significantly increased the resting [Ca(2+)](I) and the rise of [Ca(2+)](I) induced by ATP in BAECs. These results suggest that E(2)-induced NO release and eNOS mRNA expression in BAECs may be mediated by ER and related to calcium mobilization.
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PMID:[17beta -estradiol induced nitric oxide release in vascular endothelial cells]. 1194 11

Estrogens could play a cardiovascular protective role not only by means of systemic effects but also by means of direct effects on vascular structure and function. We have studied the acute effects and mechanisms of action of 17-beta-estradiol on vascular tone of rabbit isolated carotid artery. 17-Beta-estradiol (10, 30, and 100 microM) elicited concentration-dependent relaxation of 50 mM KCl-induced active tone in male and female rabbit carotid artery. The stereoisomer 17-alpha-estradiol showed lesser relaxant effects in male rabbits. Endothelium removal did not modify relaxation induced by 17-beta-estradiol. The NO synthase inhibitor L-NAME (100 microM) only reduced significantly relaxation produced by 30 microM 17-beta-estradiol. Relaxation was not modified by the estrogen receptor antagonist ICI 182,780 (1 microM), the protein synthesis inhibitor cycloheximide (1 microM), and the selective K(+) channel blockers charybdotoxin (0.1 microM) and glibenclamide (1 microM). CaCl(2) (30 microM -10 mM) induced concentration-dependent contraction in rabbit carotid artery depolarized by 50 mM KCl in Ca(2+) free medium. Preincubation with 17-beta-estradiol (3, 10, 30, or 100 microM) or the L-type Ca(2+) channel blocker nicardipine (0.01, 0.1, 1, or 10 nM) produced concentration-dependent inhibition of CaCl(2)-induced contraction. In conclusion, 17-beta-estradiol induces endothelium-independent relaxation of rabbit carotid artery, which is not mediated by classic estrogen receptor and protein synthesis activation. The relaxant effect is due to inhibition of extracellular Ca(2+) influx to vascular smooth muscle, but activation of K(+) efflux is not involved. Relatively high pharmacological concentrations of estrogen causing relaxation preclude acute vasoactive effects of plasma levels in the carotid circulation.
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PMID:Acute relaxant effects of 17-beta-estradiol through non-genomic mechanisms in rabbit carotid artery. 1195 89

Selective estrogen receptor modulators are estrogen-like compounds that lack the deleterious effects of estrogen. The present study was designed to determine whether idoxifene, a new selective estrogen receptor modulator, may have a vasodilatory effect on aortic vessels from male animals, and if so, to investigate the mechanism (i.e., endothelium-independent, direct vasorelaxation vs. endothelium-dependent, nitric oxide mediated vasorelaxation) by which idoxifene may exert its vasodilatory effect. Superior mesenteric arterial rings from adult male Sprague-Dawley rats were suspended in Krebs-Henseleit ring baths. Rings were contracted with 50 nM U-46619 (9,11-epoxymethano-PGH(2)), a thromboxane A(2) mimetic. Cumulative dose-response vasorelaxation to idoxifene (0.01 to 3 microM) was studied in the presence and absence of 200 microM N(omega)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase (NOS) inhibitor). The results obtained from idoxifene were compared with those from 17beta-estradiol. Our experimental results demonstrated that addition of idoxifene to superior mesenteric arterial rings isolated from male rats resulted in a dose-dependent vasorelaxation in the range of 0.1 microM (minimal vasodilatory concentration) to 3 microM (maximal vasodilatory concentration). Pre-treatment with L-NAME to block nitric oxide (NO) production virtually abolished idoxifene-induced vasodilatation, indicating that idoxifene caused an NO-mediated vasorelaxation in vessels from male animals. Addition of 17beta-estradiol also resulted in an endothelium-dependent vasorelaxation in aortic rings from male rats. However, these vessels were 30-fold less sensitive to 17beta-estradiol than to idoxifene in their vasorelaxation responses. Taken together, these results demonstrate that selective estrogen receptor modulators are superior to traditional estrogen in their vascular protection and may thus have potential therapeutic use in protection against cardiovascular disease, especially in male patients.
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PMID:Idoxifene causes endothelium-dependent, nitric oxide-mediated vasorelaxation in male rats. 1209 95

Endothelial and vascular smooth muscle cells express both estrogen receptor (ER) alpha and beta. Recent findings indicate that vascular ER beta and ER alpha may substitute for one another. Here, we investigate vascular morphology, contractility and protein expression in intact aorta from adult (4 months old) female mice lacking both ER alpha and ER beta (DERKO). The body weights were 17% higher ( P<0.01) in DERKO than in wild-type mice. Vascular morphology, investigated in paraffin sections from aorta stained with hematoxylin-eosin or van Gieson, was identical in DERKO and wild-type mice. Endothelial cells were clearly visible in aorta of both DERKO and wild-type animals. Morphometric analysis of media thickness and wall to lumen ratio using a computerized image analyzing system demonstrated no differences between the two groups of mice. The vascular expression of endothelial nitric oxide synthase (eNOS, NOS III) and inducible nitric oxide synthase (iNOS, NOS II) was investigated using Western blotting. Aorta from both DERKO and wild-type mice expressed iNOS protein, but the iNOS expression was 3 times lower ( P<0.05) in DERKO compared to wild-type mice. No difference in eNOS protein level between the two groups of animals was observed. Force responses to noradrenaline, determined either in the absence or in the presence of the nitric oxide synthase inhibitor l-NAME and the cyclo-oxygenase inhibitor indomethacin, were unaffected by the lack of functional ER alpha/ER beta. In summary, combined lack of functional ER alpha and ER beta lowers the vascular expression of iNOS but has no effects on morphology, eNOS expression, and noradrenaline sensitivity in the intact aorta.
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PMID:Combined lack of estrogen receptors alpha and beta affects vascular iNOS protein expression. 1282 94

This study investigated the mechanisms responsible for the estrogen-dependent, cytochrome P450 (CYP)-mediated dilator responses to shear stress in arterioles of NO-deficient female rats and mice. Flow-induced dilation (FID) was assessed in isolated arterioles from N(G)-nitro-L-arginine methyl ester (L-NAME)-treated male and ovariectomized female rats before and after overnight incubation with 17beta-estradiol (17beta-E2, 10(-9) mol/L). In control conditions, prostaglandins (PGs) mediated FID, because indomethacin (INDO) abolished the responses. After incubation of the vessels with 17beta-E2, the basal tone of arterioles was significantly reduced and FID was augmented. INDO did not affect the dilation of the vessels incubated with 17beta-E2. Dilations of these vessels, however, were eliminated by PPOH and miconazole, inhibitors of CYP/epoxygenase. Simultaneous incubation of the vessels with 17beta-E2 plus ICI, 182,780, an estrogen receptor antagonist, or wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K) phosphorylation or the transcriptional inhibitor DRB, prevented the reduced arteriolar tone and the enhanced CYP-mediated FID caused by incubation of vessels with 17beta-E2. Western blot analysis indicated a significantly increased phospho-Akt level in arterioles incubated with 17beta-E2 compared with those without 17beta-E2. The enhanced phospho-Akt in response to 17beta-E2 was localized, by immunohistochemistry, to arteriolar endothelial cells. Moreover, GC-MS analysis indicated a significantly increased production of epoxyeicosatrienoic acids, vasodilator metabolites of CYP/epoxygenase, in arterioles incubated with 17beta-E2, a response that was prevented by ICI 182780 and wortmannin, respectively. Thus, estrogen, via a receptor-dependent, PI3K/Akt-mediated pathway, transcriptionally upregulates CYP activity, leading to an enhanced arteriolar response to shear stress.
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PMID:Estrogen elicits cytochrome P450--mediated flow-induced dilation of arterioles in NO deficiency: role of PI3K-Akt phosphorylation in genomic regulation. 1467 Aug 45

17beta-estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [3H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.
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PMID:Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice. 1467 19


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