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

Many diseases of the heart and circulatory system have been linked with both dysfunction of vascular endothelium and insufficient deformability of erythrocytes. Using shear stress laser diffractometry we investigated whether deformability of erythrocytes would be regulated endogenously by generation of two endothelial secretogogues: prostacyclin and nitric oxide. Experiments were performed in rats ex vivo and with whole blood or isolated erythrocytes in vitro. Iloprost--a stable analogue of prostacyclin (10 microg/kg i.v.) and SIN-1 (NO-donor) at a dose of 2 mg/kg/min i.v induced a significant improvement of deformability of erythrocytes ex vivo. Improvements of deformability by these two compounds were also evident in vitro when they were applied at a range of concentrations of 1 microM and 3 microM, respectively. Cyclooxygenase (indomethacin 20 mg.kg i.v.) and nitric oxide synthase (L-NAME 10 mg/kg i.v.) inhibitors while worsening deformability ex vivo, they did not affect (3 mM and 10 microM, respectively) rheological functions of erythrocytes in vitro. Aggravating effects of these inhibitors on erythrocyte deformability ex vivo were reversed by prostacyclin and nitric oxide supplemented exogenously. Aspirin at a low (1 mg/kg i.v.) and high dose (50 mg/kg i.v.), contrary to indomethacin and L-NAME, aggravated erythrocyte deformability either ex vivo or in vitro. It is concluded that autocrine function of vascular endothelium plays an important role in regulation of rheology of red blood cells in flowing blood. The mechanism of this phenomenon is unclear but some possible explanations are discussed. In addition, in our experiments aspirin revealed unique erythrocyte damaging properties, possibly independent of inhibition of cyclooxygenase, but related to a direct protein acetylation.
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PMID:Endothelial secretogogues and deformability of erythrocytes. 1251

Dual increases in nitric oxide ((*)NO) and superoxide anion (O(2)(*-)) production are one of the hallmarks of endothelial cell proliferation. Increased expression of endothelial nitric oxide synthase (eNOS) has been shown to play an important role in maintaining high levels of (*)NO generation to offset the increase in O(2)(*-) that occurs during proliferation. Although recent reports indicate that heat shock protein 90 (hsp90) associates with eNOS to increase (*)NO generation, the role of hsp90 association with eNOS during endothelial cell proliferation remains unknown. In this report, we examine the effects of endothelial cell proliferation on eNOS expression, hsp90 association with eNOS, and the mechanisms governing eNOS generation of (*)NO and O(2)(*-). Western analysis revealed that endothelial cells not only increased eNOS expression during proliferation but also hsp90 interactions with the enzyme. Pretreatment of cultures with radicicol (RAD, 20 microM), a specific inhibitor that does not redox cycle, decreased A23187-stimulated (*)NO production and increased L(omega)-nitroargininemethylester (L-NAME)-inhibitable O(2)(*-) generation. In contrast, A23187 stimulation of controls in the presence of L-NAME increased O(2)(*-) generation, confirming that during proliferation eNOS generates (*)NO. Our findings demonstrate that hsp90 plays an important role in maintaining (*)NO generation during proliferation. Inhibition of hsp90 in vascular endothelium provides a convenient mechanism for uncoupling eNOS activity to inhibit (*)NO production. This study provides new understanding of the mechanisms by which ansamycin antibiotics inhibit endothelial cell proliferation. Such information may be useful in the development and design of new antineoplastic agents in the future.
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PMID:Inhibition of heat shock protein 90 (hsp90) in proliferating endothelial cells uncouples endothelial nitric oxide synthase activity. 1252 8

The pharmacological effects of BDPBI (7-bromo-1,4-dihydro-2-phenyl-4,4-bis(4-pyridinylmethyl)2H-isoquinolin-3-one dihydrochloride) were tested on isolated endothelium-containing or denuded aorta of the guinea pig. BDPBI with the formula C(27)H(24)BrCl(2)N(3)O was synthesized starting with 3-isochromanone. In the endothelium-containing preparations of the aortic rings, phenylephrine (PHE; 10 micromol/l) elicited contracture and acetylcholine (ACh; 10 micromol/l) or BDPBI (0.01-10 micromol/l) elicited relaxation effects on the PHE-precontracted preparations. The BDPBI-elicited effect on the PHE-precontracted aortic rings was not altered in the presence of adrenergic blockers (propranolol or yohimbine; 1 micromol/l) or pretreated preparations with aspirin, indomethacin (10 micromol/l) or L-NAME (1 mmol/l). However, the relaxation effects of BDPBI were blocked if the preparations were pretreated with diphenhydramine (10 micromol/l) or chloropheniramine maleate (10 micromol/l). In contrast to lower concentrations of atropine (1 micromol/l), higher concentrations of atropine (30 micromol/l) did block the effects of BDPBI on the PHE-precontracted aortic rings. HTMT dimaleate (0.01-10 micromol/l), a histamine H(1) receptor agonist, also elicited relaxation effects on the PHE-precontracted preparation, and the effects were blocked if the preparations were pretreated with diphenhydramine or chloropheniramine maleate. On isolated denuded aorta of the guinea pig, BDPBI did not elicit relaxation effects on the PHE-precontracted aortic rings. These results demonstrated that the vasorelaxation effect of BDPBI on PHE-precontracted aortic rings is partly dependent on the activation of a histaminergic receptor from the vascular endothelium. We suggested that BDPBI would be an effective vasorelaxant for cardiovascular systems.
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PMID:A new isoquinolinone derivative with noble vasorelaxation activity. 1259 51

The compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine-like head pain in some subjects, was evaluated for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role for nitric oxide (NO) and the trigeminal system, respectively. NO release has been linked to activation of the 5-HT2B receptor on the vascular endothelium. However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal ganglion. These data are consistent with activation of peripheral 5-HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists might be effective prophylactic therapies for migraine.
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PMID:Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine (mCPP) involves nitric oxide and 5-HT2B receptor activation. 1260 68

In experimental and human diabetes mellitus, evidence for an impaired function of the vascular endothelium has been found and has been suggested to contribute to the development of vascular complications in this disease. The aim of the study was to evaluate possible regional hemodynamic in vivo differences between healthy and diabetic rats which would involve nitric oxide (NO). Central hemodynamics and regional blood flow (RBF) were studied using radioactive microspheres in early streptozotocin (STZ)-diabetic rats and compared to findings in healthy control animals. This method provides a possibility to study the total blood flow and vascular resistance (VR) in several different organs simultaneously. L-NAME iv induced widespread vasoconstriction to a similar extent in both groups. In the masseter muscle of both groups, acetylcholine 2 microg/kg per min, induced a RBF increase, which was abolished by pretreatment with L-NAME, suggesting NO as a mediator of vasodilation. In the heart muscle of both groups, acetylcholine alone was without effect while the combined infusion of acetylcholine and L-arginine induced an L-NAME-sensitive increase in RBF. The vasodilation induced by high-dose acetylcholine (10 microg/kg per min) in the kidney was more pronounced in the STZ-diabetic rats. The results indicate no reduction in basal vasodilating NO-tone in the circulation of early diabetic rats. The sensitivity to vasodilating effects of acetylcholine at the level of small resistance arterioles vary between tissues but was not impaired in the diabetic rats. In the heart muscle the availability of L-arginine was found to limit the vasodilatory effect of acetylcholine in both healthy and diabetic rats. In conclusion, the results indicate a normal action of NO in the investigated tissues of the early STZ-diabetic rat.
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PMID:Involvement of nitric oxide in the regulation of regional hemodynamics in streptozotocin-diabetic rats. 1267 58

Previously, it was reported that red blood cells (RBCs) are required to demonstrate participation of nitric oxide (NO) in the regulation of rabbit pulmonary vascular resistance (PVR). RBCs do not synthesize NO; hence, we postulated that ATP, present in millimolar amounts in RBCs, was the mediator, which evoked NO synthesis in the vascular endothelium. First, we found that deformation of RBCs, as occurs on passage across the pulmonary circulation with increasing flow rate, evoked increments in ATP release. Here, ATP (300 nM), administered to isolated, salt solution-perfused (PSS) rabbit lungs, decreased total and upstream (arterial) PVR, a response inhibited by NG-nitro-L-arginine methyl ester (L-NAME, 100 microM). In lungs perfused with PSS containing RBCs, L-NAME increased total and upstream PVR. In lungs perfused with PSS containing glibenclamide-treated RBCs, which inhibits ATP release, L-NAME was without effect. Apyrase grade VII (8 U/ml), which degrades ATP to AMP, was without effect on PVR in PSS-perfused lungs. These results are consistent with the hypothesis that ATP, released from RBCs as they traverse the pulmonary circulation, evokes endogenous NO synthesis.
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PMID:Extracellular ATP signaling in the rabbit lung: erythrocytes as determinants of vascular resistance. 1268 60

An angiotensin (ANG) receptor homologous to the type 1 receptor (AT1) has been cloned in chickens (cAT1). We investigated whether cAT1 expression in various tissues shows maturation/age-dependent changes. cAT1 mRNA levels detected in renal glomeruli [in situ hybridization (ISH)] and kidney extract (RT-PCR) are significantly (P < 0.01) higher in 19-day embryos (EB) than in chicks (CH, 2-3 wk) and pullets/cockerels (PL/CK, 14-16 wk). The levels in adrenal glands (concentrated in subcapsular regions) are high in EB and further increased in CH and PL/CK. cAT1 mRNA is also detectable in smooth muscle (SM)/adventitia of EB and CH aorta and in the adventitia, but not SM, from PL/CK aortas. The endothelia from small arteries and arterioles, but not from aorta, express cAT1 mRNA (ISH). In all age groups, ANG II induces profound endothelium-dependent relaxation of abdominal aorta, partly (37-47%) inhibitable (P < 0.01) by Nomega-nitro-l-arginine methyl ester (l-NAME, 10(-4) M), suggesting the presence of ANG receptor in endothelium. l-NAME-resistant ANG II relaxation, examined in a limited number of EB or CH aortas, was reduced by 125 mM K+ or apamin plus charybdotoxin. The results suggest that 1) cAT1 is present in kidney, adrenal gland, and vascular endothelium (heterogeneity exists among arteries) of EB, CH, and PL/CK, and in aortic SM/adventitia of EB/CH but only in adventitia of PL/CK; 2) levels of cAT1 gene expression change during maturation in a tissue-specific manner; and 3) ANG II-induced relaxation may be partly attributable to nitric oxide and potassium channel activation.
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PMID:Maturation-dependent changes of angiotensin receptor expression in fowl. 1279 89

Using automatic erythrocyte aggregometer type MA-1 (Myrenne gmbh, Germany), we investigated the hypothesis that therapeutic effectiveness of quinapril--angiotensin converting enzyme inhibitor (ACEI)--in the treatment of hypertension would correlate with improvement of red blood cell (RBC) aggregability. Experiments were performed on commercially available inbred strain of spontaneously hypertensive male rats (SHR) aged 19-21 weeks. Age-matched normotensive Wistar-Kyoto (WKY) rats genetically related to SHR were used as a control. Aggregability of RBC in hypertensive rats was significantly higher than in control WKY animals. Quinapril (100 microg/kg) administered i.p. for 8 days improved RBC aggregability in normotensive rats but surprisingly not in SHR animals. Beneficial effect of quinapril on RBC aggregation observed in normotensive animals did not occur when this drug was injected in combination with aspirin (1 or 50 mg/kg) or with indomethacin (20 mg/kg) or with L-NAME (10 mg/kg). However, much the same damaging effects on RBC aggregability were observed when aspirin, indomethacin or L-NAME were each administered into normotensive animals without quinapril. In contrast with normotensive rats, aggregability of RBC in SHR was not affected either by quinapril or by indomethacin and by L-NAME, given separately or in combination. The only compound significantly worsening RBC aggregability in SHR was aspirin but this effect was not dose-dependent. Quinapril-induced improvement of RBC aggregability in normotensive rats (but not in SHR) was completely abolished by simultaneous administration of B2 receptor antagonist icatibant and successfully mimicked by 8 days of treatment with bradykinin. In vitro aggregability of RBC isolated from WKY was not affected by previous incubation (30 min at 37 degrees C) with quinapril, indomethacin or L-NAME. Only aspirin (3 mM) significantly increased RBC aggregability as compared to placebo. It is concluded that under physiological conditions quinapril efficiently inhibits RBC aggregability and this effect is modulated by secretion of endothelial mediators, mainly prostacyclin and nitric oxide. In hypertension quinapril, in spite of lowering of arterial blood pressure, is unable to display its beneficial effects on RBC aggregability possibly due to the hypertension-induced/accompanied dysfunction of vascular endothelium. Aspirin revealed unique erythrocyte damaging properties, presumably independent of inhibition of cyclooxygenase but related to a direct membrane protein acetylation.
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PMID:Secretory dysfunction of vascular endothelium limits the effect of angiotensin converting enzyme inhibitor quinapril on aggregation of erythrocytes in experimental hypertension. 1456 78

Ephedrine is a mixed adrenergic agonist, stimulating both alpha- and beta-adrenergic receptors. The effects of ephedrine use include increases in heart rate, cardiac output, peripheral resistance, and blood pressure, and its use is associated with serious cardiovascular events such as stroke, arrhythmias, and myocardial infarction. The vascular endothelium plays a fundamental role in the regulation of vascular tone by releasing vasoactive factors such as nitric oxide (NO). The loss of NO bioactivity, often referred to as endothelial dysfunction, is characterized by the loss of endothelium-dependent vasodilation and is thought to be a common pathway for cardiovascular events such as vasospasm, hypertension, and myocardial infarction. Since endothelial dysfunction is characterized by loss of NO activity, and since ephedrine and endothelial dysfunction may be associated with similar cardiovascular events, the current study was undertaken to determine the effect of inhibition of NO production on responses to ephedrine in the rat. A sodium nitroprusside (SNP) infusion procedure was used to restore baseline vascular parameters to pre-L-NAME levels, allowing for direct comparison of agonist responses before and after NOS inhibition. The results demonstrate that the vascular response to ephedrine in the rat is modulated by NO and that NO production in response to ephedrine may be secondary to beta 2-receptor stimulation.
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PMID:Effect of inhibition of nitric oxide synthase on the vasopressor response to ephedrine. 1460 14

The antihypertensive effect of vanylidilol, a new alpha/beta-adrenoceptor antagonist with endothelium-dependent and K(+)-channel-opening activities, was investigated in normotensive and hypertensive Wistar rats. Vanylidilol competitively antagonized (-)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in isolated rat right atria, left atria, and guinea pig tracheal strips in a concentration-dependent manner. Vanylidilol's apparent pA(2) values were 6.36 +/- 0.08 (right atria), 6.41 +/- 0.07 (left atria), and 6.31 +/- 0.06 (trachea). Vanylidilol also produced a competitive antagonism of phenylephrine-induced contraction in the isolated rat aorta with pA(2) values of 6.79 +/- 0.18. In the radioligand binding assay, vanylidilol inhibited [(3)H]CGP-12177 binding to rat ventricle and lung tissues and [(3)H]prazosin binding to brain membranes with Ki values of 535.17, 2,066.69, and 431.11, respectively. In isolated rat thoracic aorta, vanylidilol's vasorelaxant effects on phenylephrine (10 micromol/l)-induced contractions were attenuated by removing endothelium and by the presence of L-N(G)-nitro arginine methyl ester (L-NAME; 100 micromol/l), methylene blue (10 micromol/l), 1H-[1,2,4]oxadiazolol[4,3,-a] quinoxalin-1-one (ODQ; 10 micromol/l), tetraethylammonium (10 mmol/l), glibenclamide (1 micromol/l), apamin (1 micromol/l), and charybdotoxin (0.1 micromol/l). In addition, vanylidilol, in an equally antagonistic activity, inhibited phenylephrine-induced phasic and tonic contractions. Intravenous vanylidilol further reduced mean blood pressure in pentobarbital-anesthetized normotensive Wistar rats in a dose-dependent manner. The oral administration of vanylidilol to conscious spontaneously hypertensive rats had a long-lasting hypotensive effect on the heart rate and decreased it in a dose-dependent manner. Furthermore, vanylidilol's vasodilator effect can be attributed in part to the release of NO or NO-related substance from vascular endothelium, while the endothelium-independent mechanism involved in vanylidilol's relaxation is probably linked to the activation of the K(+) channels and the alpha-adrenoceptor blocking activity in these vessels.
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PMID:Anti-hypertension effect of vanylidilol: a phenylaldehyde alpha/beta-adrenoceptor blocker with endothelium-dependent and K+ channels opening-associated vasorelaxant activities. 1475 34


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