Biomedical subjects

Xiaoqiang Yao

Publications and source records attributed to Xiaoqiang Yao.

At least 19 recordsLinked to original sources

PubMed2006

Endothelium-independent relaxation to raloxifene in porcine coronary artery.

Although the vascular action of raloxifene has been studied in several vascular beds, the underlying mechanisms are still incompletely understood. The role of endothelium in raloxifene-induced vascular responses was controversial. The present study was designed to examine endothelium-independent effects of raloxifene in isolated porcine left circumflex coronary arteries. Arterial rings were suspended in organ baths and changes in isometric tension were measured. The large-conductance Ca2+-activated K+(BK(Ca)) currents were recorded using a whole-cell patch-clamp technique. Treatment with raloxifene (1-10 micromol/l) reduced the contractions to 9,11-dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin F2alpha (U46619), serotonin (5-HT), endothelin-1 in normal Krebs solution and to CaCl2 in a Ca2+-free, high K+-containing solution. In endothelin-1-contracted rings, raloxifene (0.3 to 50 micromol/l) caused relaxations which were comparable in rings with and without endothelium. The raloxifene-induced relaxation was reduced by putative K+ channel blockers, iberiotoxin and tetraethyl ammonium chloride (TEA+) in rings with and without endothelium, or by elevated extracellular K+ ions (30 mmol/l K+ and 60 mmol/l K+). 13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-7,8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta[a] phenanthrene-3,17-diol (ICI 182,780) did not affect raloxifene-induced relaxation. Raloxifene enhanced the outward BK(Ca) currents, which were sensitive to inhibition by iberiotoxin. In summary, the present study shows that raloxifene acutely relaxes porcine coronary arteries via an endothelium-independent mechanism without involving the ICI 182,780-sensitive estrogen receptors. Raloxifene mainly acts on the vascular smooth muscle cells to induce vasorelaxation by the inhibition of Ca2+ channels and the activation of BK(Ca) channels. The former mechanism appears to play a more significant role.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2006

Mechanism of non-capacitative Ca2+ influx in response to bradykinin in vascular endothelial cells.

Bradykinin is a potent vasoactive nonapeptide. It elicits a rise in cytosolic Ca(2+) (Ca(2+))(i) in endothelial cells, resulting in Ca(2+)-dependent synthesis and release of endothelial vasodilators. In the present study, we investigated the mechanism of bradykinin-induced Ca(2+) influx in primary cultured rat aortic endothelial cells and in a mouse heart microvessel endothelial cell line (H5V). Bradykinin-induced Ca(2+) influx was resolved into capacitative Ca(2+) entry (CCE) and non-CCE. The non-CCE component was inhibited by a B2 receptor antagonist (HOE140; 1 microM) and a phospholipase C (PLC) inhibitor (U73122; 10 microM). The action of bradykinin could be mimicked by 1-oleoyl-2-acetyl-glycerol, an analogue of diacylglycerol (DAG), and by RHC80267, a DAG-lipase inhibitor. Immunoblots showed that TRPC6 was one of the main TRPC channels expressed in endothelial cells. Transfection of H5V cells with two siRNA constructs against TRPC6 both markedly reduced the TRPC6 protein level and, at the same time, decreased the percentage of cells displaying bradykinin-induced non-CCE. siRNA transfection also reduced the magnitude of non-CCE among the cells responding to bradykinin. Taken together, our data suggest that bradykinin-induced non-CCE is mediated via the B2-PLC pathway, and that DAG may be involved in this process. Further, TRPC6 is one of the important channels participating in bradykinin-induced non-CCE in endothelial cells.

Animals↗

PubMed2006

Raloxifene prevents endothelial dysfunction in aging ovariectomized female rats.

Lack of an appropriate animal model has delayed the better understanding of mechanisms related to higher cardiovascular risk in women after menopause. The aging female rat may share some menopausal changes observed in women. However, most studies have attempted to mimic menopause by ovariectomizing young (6-12 weeks old) animals without taking into accounts the influence of aging and of declining ovarian function. Therefore, the present study examined changes in vascular reactivity in the aging (15 months old) female rat after ovariectomy and the effects of chronic raloxifene therapy on vascular reactivity and eNOS protein expression. Aortic rings were prepared from the three experimental groups of rats: sham-operated control, ovariectomized and ovariectomized aging rats receiving daily oral administration of raloxifene for 3 months. Aortic rings were suspended in organ baths for the measurement of isometric tension. Rings with endothelium contracted significantly more to phenylephrine after inhibition of nitric oxide/cyclic GMP-signaling pathway by L-NAME or ODQ (as an index of basal nitric oxide release) in control and raloxifene-treated ovariectomized rats than in ovariectomized rats. This effect was abolished upon mechanical removal of the endothelium. Phenylephrine induced greater contractions only in rings with endothelium from ovariectomized rats as compared with control rats and raloxifene treatment normalized this response. In the presence of L-NAME or ODQ, phenylephrine-induced contraction was similar in rings from the three groups. Rings relaxed more to thapsigargin and acetylcholine in raloxifene-treated ovariectomized rats than in ovariectomized rats. There was no significant difference in aortic eNOS protein contents among the different groups. These results suggest that chronic oral administration of raloxifene to aging ovariectomized female rats augmented the bioavailability of endothelial nitric oxide in isolated aortic rings without altering eNOS protein levels.

Acetylcholine↗

PubMed2006

Endothelial mediators of the acetylcholine-induced relaxation of the rat femoral artery.

This study examined endothelium-derived mediators of acetylcholine-induced relaxation in male rat femoral arteries. Arterial rings were suspended in a myograph for the measurement of isometric force. The generation of hydrogen peroxide (H2O2) in endothelial cells was detected using the fluorescent probe, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester. N(G)-nitro-L-arginine methyl ester (L-NAME, NOS inhibitor) and 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ, guanylate cyclase inhibitor) alone or in combination with indomethacin (cycloxygenase inhibitor) diminished acetylcholine-induced endothelium-dependent relaxation to a similar extent. A small relaxation to acetylcholine in 60 mM KCl-constricted rings was abolished by L-NAME. Acetylcholine-induced relaxation was reduced by charybdotoxin plus apamin (intermediate- and small-conductance Ca2+-activated K+ channel blockers, respectively) or by 30 mM KCl. Both ouabain (Na+/K+ ATPase inhibitor) and BaCl2 (K(IR) channel blocker) also inhibited the relaxation albeit to a lesser degree. In the presence of L-NAME, ODQ plus indomethacin, charybdotoxin plus apamin or ouabain plus BaCl2 produced further inhibition. Catalase attenuated acetylcholine-induced relaxations and this attenuation was prevented by 3-amino-1,2,4-triazole (catalase inhibitor). Catalase did not affect acetylcholine-induced relaxations in rings treated with L-NAME or ODQ. Acetylcholine increased the dichlorofluorescein fluorescence intensity in native endothelial cells and this effect was abolished by catalase and by L-NAME. Exogenous H2O2 caused endothelium-independent relaxation that was slightly inhibited by iberiotoxin, ODQ or significantly reduced by elevated KCl, and abolished by catalase. The present results indicate that in addition to nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF, sensitive to charybdotoxin plus apamin, ouabain, and BaCl2), the endothelium of rat femoral artery can release H2O2 in response to acetylcholine, which was sensitive to L-NAME. Thus, the eNOS-dependent H2O2 is likely to be the third mediator of acetylcholine-mediated relaxations in rat femoral arteries.

Acetylcholine↗

PubMed2006

Protein kinase C can inhibit TRPC3 channels indirectly via stimulating protein kinase G.

There are two known phosphorylation-mediated inactivation mechanisms for TRPC3 channels. Protein kinase G (PKG) inactivates TRPC3 by direct phosphorylation on Thr-11 and Ser-263 of the TRPC3 proteins, and protein kinase C (PKC) inactivates TRPC3 by phosphorylation on Ser-712. In the present study, we explored the relationship between these two inactivation mechanisms of TRPC3. HEK cells were first stably transfected with a PKG-expressing construct and then transiently transfected with a TRPC3-expressing construct. Addition of 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analog of diacylglycerol (DAG), elicited a TRPC3-mediated [Ca2+]i rise in these cells. This OAG-induced rise in [Ca2+]i could be inhibited by phorbol 12-myristate 13-acetate (PMA), an agonist for PKC, in a dose-dependent manner. Importantly, point mutations at two PKG phosphorylation sites (T11A-S263Q) of TRPC3 markedly reduced the PMA inhibition. Furthermore, inhibition of PKG activity by KT5823 (1 microM) or H8 (10 microM) greatly reduced the PMA inhibition of TRPC3. These data strongly suggest that the inhibitory action of PKC on TRPC3 is partly mediated through PKG in these PKG-overexpressing cells. The importance of this scheme was also tested in vascular endothelial cells, in which PKG plays a pivotal functional role. In these cells, OAG-induced [Ca2+]i rise was inhibited by PMA, which activates PKC, and by 8-BrcGMP and S-nitroso-N-acetylpenicillamine (SNAP), both of which activate PKG. Importantly, the PMA inhibition on OAG-induced [Ca2+]i rise was significantly reduced by PKG inhibitor KT5823 (1 microM) or DT-3 (500 nM), suggesting an important role of PKG in the PMA-induced inhibition of TRPC channels in native endothelial cells.

Animals↗

PubMed2006

Cilnidipine, a slow-acting Ca2+ channel blocker, induces relaxation in porcine coronary artery: role of endothelial nitric oxide and [Ca2+]i.

Cilnidipine is a dual blocker of L-type voltage-gated Ca(2+) channels in vascular smooth muscle and N-type Ca(2+) channels in sympathetic nerve terminals that supply blood vessels. However, the clinical benefits of cilnidipine and underlying mechanisms are incompletely understood. This study was designed to compare the time course of relaxant responses to cilnidipine and nifedipine, and to examine the role of endothelial NO and [Ca(2+)](i) in the vasorelaxation. Porcine left circumflex coronary arteries were isolated and isometric tension was measured with Grass force transducers. Endothelial [Ca(2+)](i) in intact arteries was determined by a calcium fluorescence imaging technique. The free radical scavenging capacity was also assayed. Cilnidipine and nifedipine induced concentration-dependent relaxations in high KCl-precontracted artery rings, while the former-induced relaxation was slower as compared to the latter. Treatment with L-NAME or ODQ reduced relaxations to cilnidipine or nifedipine to the same extent as in rings without endothelium. Indomethacin or omega-conotoxin had no effects. L-Arginine antagonized the effect of L-NAME on cilnidipine-induced relaxations. Cilnidipine did not affect sodium nitroprusside-induced relaxation in rings with and without endothelium. Cilnidipine and nifedipine caused extracellular Ca(2+)-dependent increases in endothelial [Ca(2+)](i) in intact arteries and cilnidipine's action had a slower onset, similar to that of cilnidipine-induced relaxation. Neither cilnidipine nor nifedipine exhibited a free radical scavenging property. The present results demonstrate that cilnidipine can produce endothelium-dependent relaxation in porcine coronary arteries in vitro in addition to blocking Ca(2+) channels. Like short-acting nifedipine, cilnidipine-dependent relaxation, albeit to a slower onset, is partly mediated by endothelial NO but not by prostacyclin. The increased release or bioavailability of NO may causally result from elevated endothelial [Ca(2+)](i) in arteries. The Ca(2+) channel-independent effect suggests the usefulness of cilnidipine in the treatment of cardiovascular diseases associated with diminished NO release, such as atherosclerosis.

Animals↗

PubMed2006

Depletion of intracellular Ca2+ stores enhances flow-induced vascular dilatation in rat small mesenteric artery.

The effect of depleting intracellular Ca2+ stores on flow-induced vascular dilatation and the mechanism responsible for the vasodilatation were examined in rat isolated small mesenteric arteries. The arteries were pressurized to 50 mmHg and preconstricted with phenylephrine. Intraluminal flow reversed the effect of phenylephrine, resulting in vasodilatation. Flow dilatation consisted of an initial transient peak followed by a sustained plateau phase. The magnitude of dilatation was markedly reduced by removing Ca2+ from the intraluminal flow medium. Depletion of intracellular Ca2+ stores with either cyclopiazonic acid (CPA, 2 microM) or 1,4-dihydroxy-2,5-di-tert-butylbenzene (BHQ, 10 microM) significantly augmented the magnitude of flow dilatation. Flow-induced endothelial cell Ca2+ influx was also markedly enhanced in arteries pretreated with CPA or BHQ.Flow-induced dilatation was insensitive to Nw-nitro-L-arginine methyl ester (100 microM) plus indomethacin (3 microM) or to oxyhemoglobin (3 microM), but was markedly reduced by 30 mM extracellular K+ or 2 mM tetrabutylammonium (TBA), suggesting an involvement of EDHF. Catalase at 1200 U ml-1 abolished the flow-induced dilatation, while the application of exogenous H2O2 (90-220 microM) induced relaxation in phenylephrine-preconstricted arteries. Relaxation to exogenous H2O2 was blocked in the presence of 30 mM extracellular K+, and H2O2 (90 microM) hyperpolarized the smooth muscle cells, indicating that H2O2 can act as an EDHF. In conclusion, flow-induced dilatation in rat mesenteric arteries can be markedly enhanced by prior depletion of intracellular Ca2+ stores. Furthermore, these data are consistent with a role for H2O2 as the vasodilator involved.

Adenosine Triphosphate↗

PubMed2006

Reactive oxygen species in vascular wall.

Reactive oxygen species (ROS) contribute to the pathogenesis of cardiovascular diseases including hypertension, atherosclerosis, cardiac hypertrophy, heart failure and diabetes mellitus. Oxidative stress is resulted from excessive generation of ROS that outstrips the antioxidant system. Various agonists, pathological conditions and therapeutic interventions lead to modulated expression and function of oxidant and antioxidant enzymes, including NAD(P)H oxidase, endothelial nitric oxide synthase, xanthine oxidase, myeloperoxidase, superoxide dismutases, catalase and glutathione peroxidase. ROS formed in vascular wall target a wide range of signaling molecules and cellular pathways in both endothelium and vascular smooth muscle, such as transcription factors, protein tyrosine phosphatase, protein tyrosine kinase, mitogen-activated protein kinase, Ca(2+)-transporting system and protein modification. ROS also have distinct physiological and pathophysiological impacts on vascular cells. ROS contribute to vascular dysfunction and remodeling through oxidative damage by (1) reducing the bioavailability of NO, (2) impairing endothelium-dependent vasodilatation and endothelial cell growth, (3) causing apoptosis or anoikis, (4) stimulating endothelial cell migration, and (5) activating adhesion molecules and inflammatory reaction, leading to endothelial dysfunction, an initial episode progressing toward hypertension and atherosclerosis. Cellular events underlying these processes involve changes in vascular smooth muscle cell growth, apoptosis/anoikis, cell migration, inflammation, and vasoconstriction. The present communication focuses on the biology of ROS signaling in vascular cells, discusses how oxidative stress contributes to vascular damage, and the therapeutic strategies/biotic factors that can prevent or treat ROS-associated cardiovascular disorders.

Animals↗

PubMed2005

Recent developments in vascular endothelial cell transient receptor potential channels.

Among the 28 identified and unique mammalian TRP (transient receptor potential) channel isoforms, at least 19 are expressed in vascular endothelial cells. These channels appear to participate in a diverse range of vascular functions, including control of vascular tone, regulation of vascular permeability, mechanosensing, secretion, angiogenesis, endothelial cell proliferation, and endothelial cell apoptosis and death. Malfunction of these channels may result in disorders of the human cardiovascular system. All TRP channels, except for TRPM4 and TRPM5, are cation channels that allow Ca2+ influx. However, there is a daunting diversity in the mode of activation and regulation in each case. Specific TRP channels may be activated by different stimuli such as vasoactive agents, oxidative stress, mechanical stimuli, and heat. TRP channels may then transform these stimuli into changes in the cytosolic Ca2+, which are eventually coupled to various vascular responses. Evidence has been provided to suggest the involvement of at least the following TRP channels in vascular function: TRPC1, TRPC4, TRPC6, and TRPV1 in the control of vascular permeability; TRPC4, TRPV1, and TRPV4 in the regulation of vascular tone; TRPC4 in hypoxia-induced vascular remodeling; and TRPC3, TRPC4, and TRPM2 in oxidative stress-induced responses. However, in spite of the large body of data available, the functional role of many endothelial TRP channels is still poorly understood. Elucidating the mechanisms regulating the different endothelial TRP channels, and the associated development of drugs selectively to target the different isoforms, as a means to treat cardiovascular disease should, therefore, be a high priority.

Animals↗

PubMed2005

Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure.

The kidney not only regulates fluid and electrolyte balance but also functions as an endocrine organ. For instance, it is the major source of circulating erythropoietin and renin. Despite currently available therapies, there is a marked increase in cardiovascular morbidity and mortality among patients suffering from end-stage renal disease. We hypothesized that the current understanding of the endocrine function of the kidney was incomplete and that the organ might secrete additional proteins with important biological roles. Here we report the identification of a novel flavin adenine dinucleotide-dependent amine oxidase (renalase) that is secreted into the blood by the kidney and metabolizes catecholamines in vitro (renalase metabolizes dopamine most efficiently, followed by epinephrine, and then norepinephrine). In humans, renalase gene expression is highest in the kidney but is also detectable in the heart, skeletal muscle, and the small intestine. The plasma concentration of renalase is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects. Renalase infusion in rats caused a decrease in cardiac contractility, heart rate, and blood pressure and prevented a compensatory increase in peripheral vascular tone. These results identify renalase as what we believe to be a novel amine oxidase that is secreted by the kidney, circulates in blood, and modulates cardiac function and systemic blood pressure.

Animals↗

PubMed2005

Raloxifene relaxes rat intrarenal arteries by inhibiting Ca2+ influx.

Raloxifene may confer vascular benefits without causing estrogen-related side effects. However, its action on renal vascular circulation is unknown. This study aimed to examine the sex difference and roles of the endothelium and Ca(2+) channels in rat renovascular relaxation to raloxifene. On isolated intralobar renal artery rings mounted in a myograph and contracted by U-46619, concentration-relaxation curves were constructed for raloxifene and contractions to CaCl(2) were studied. Changes in intracellular Ca(2+) concentration levels ([Ca(2+)](i)) of vascular smooth muscle (VSM) were measured by fura 2 fluorescence. Raloxifene or 17beta-estradiol was equally effective in relaxing renal arteries from both sexes, with raloxifene being more potent than 17beta-estradiol. Endothelial denudation did not affect raloxifene- or 17beta-estradiol-induced relaxation. N(G)-nitro-l-arginine methyl ester, charybdotoxin plus apamin, indomethacin, or ICI-182, 780 did not modify the effect of raloxifene. Raloxifene caused similar relaxations in rings contracted by U-46619 and high K(+). Nifedipine attenuated the potency of raloxifene. Raloxifene reduced CaCl(2)-induced contractions. K(+) (80 mM) stimulated an increase in VSM [Ca(2+)](i), and raloxifene attenuated this effect. Raloxifene-induced reduction of contraction and increase in VSM [Ca(2+)](i) were insensitive to ICI-182, 780. In summary, raloxifene causes relaxation in rat renal arteries; this effect is independent of a functional endothelium and is not mediated by ICI 182, 780-sensitive estrogen receptors. Raloxifene inhibited both contractions and VSM [Ca(2+)](i) in response to CaCl(2), indicating that raloxifene relaxes rat renal arteries primarily through inhibiting Ca(2+) influx via Ca(2+) channels. There is little sex difference in raloxifene-induced relaxation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2005

Regulation of TRP channels by phosphorylation.

The transient receptor potential (TRP) channels are a group of Ca2+-permeable cation channels (except TRPM4 and TRPM5) that function as cellular sensors of various internal and external stimuli. Most of these channels are expressed in the nervous system and they play a key role in sensory physiology. They may respond to temperature, pressure, inflammatory agents, pain, osmolarity, taste and many other stimuli. Recent development indicates that the activity of these channels is regulated by protein phosphorylation and dephosphorylation of serine, threonine, and tyrosine residues. In this review, we present a comprehensive summary of the literature regarding the TRP channel regulation by different protein kinases.

Animals↗

PubMed2005

Biological properties of baicalein in cardiovascular system.

The dried roots of Scutellaria baicalensis (S. baicalensis) Georgi (common name: Huangqin in China) have been widely employed for many centuries in traditional Chinese herbal medicine as popular antibacterial and antiviral agents. They are effective against staphylococci, cholera, dysentery, pneumococci and influenza virus. Baicalein, one of the major flavonoids contained in the dried roots, possesses a multitude of pharmacological activities. The glycoside of baicalein, baicalin is a potent anti-inflammatory and anti-tumor agent. This review describes the biological properties of baicalein (Table 1), which are associated with the prevention and treatment of cardiovascular diseases. Baicalein is a potent free radical scavenger and xanthine oxidase inhibitor, thus improving endothelial function and conferring cardiovascular protective actions against oxidative stress-induced cell injury. Baicalein lowers blood pressure in renin-dependent hypertension and the in vivo hypotensive effect may be partly attributed to its inhibition of lipoxygenase, resulting in reduced biosynthesis and release of arachidonic acid-derived vasoconstrictor products. On the other hand, baicalein enhances vasoconstricting sensitivity to receptor-dependent agonists such as noradrenaline, phenylephrine, serotonin, U46619 and vasopressin in isolated rat arteries. The in vitro effect is likely caused by inhibition of an endothelial nitric oxide-dependent mechanism. The anti-thrombotic, anti-proliferative and anti-mitogenic effects of the roots of S. baicalensis and baicalein are also reported. Baicalein inhibits thrombin-induced production of plasminogen activator inhibitor-1, and interleukin-1beta- and tumor necrosis factor-alpha-induced adhesion molecule expression in cultured human umbilical vein endothelial cells. The pharmacological findings have highlighted the therapeutic potentials of using plant-derived baicalein and its analogs for the treatment of arteriosclerosis and hypertension.

Animals↗

PubMed2004

Raloxifene relaxes rat pulmonary arteries and veins: roles of gender, endothelium, and antagonism of Ca2+ influx.

Effects of raloxifene have been documented in the systemic circulation. However, its impact on the pulmonary circulation is unclear. The present study investigated the role of gender, endothelial modulation, and Ca(2+) channel in relaxations evoked by raloxifene in rat pulmonary arteries and veins. Vascular responses were studied on isolated pulmonary blood vessels mounted in a myograph and constricted by U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha)). Constrictions to CaCl(2) were studied in Ca(2+)-free, 60 mM K(+) solution. Changes in the intracellular calcium ion concentration ([Ca(2+)](i)) in vascular smooth muscle were measured using a calcium fluorescence imaging method. Raloxifene was more effective in relaxing U46619-constricted pulmonary arteries from male than female rats. Raloxifene-induced relaxation was unaffected by ICI 182,780 [7alpha-[9-[(4,4,5,5,5,-pentafluoropentyl)-sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol], inhibition of the nitric oxide (NO) pathway, or removal of the endothelium. In arteries without endothelium, raloxifene attenuated CaCl(2)-induced constriction and CaCl(2)-stimulated increase in [Ca(2+)](i) with similar potencies. Raloxifene caused endothelium-independent relaxations in pulmonary veins, albeit to a lesser degree than in pulmonary arteries. The venous responses showed a gender difference because raloxifene was more potent in male veins. In summary, raloxifene relaxed rat pulmonary arteries, and this effect did not involve the endothelium/NO or ICI 182,780-sensitive estrogen receptors. Raloxifene, like nifedipine, reduced constriction and [Ca(2+)](i) increase in response to CaCl(2) in high K(+) solution. Raloxifene also relaxed high K(+)-constricted pulmonary veins. Our data indicate that raloxifene acutely relaxes rat pulmonary blood vessels primarily via inhibition of Ca(2+) influx through voltage-sensitive Ca(2+) channels. Finally, raloxifene induced more relaxation in blood vessels isolated from male than female rats.

Animals↗

PubMed2004

Expression of TRPC homologs in endothelial cells and smooth muscle layers of human arteries.

TRPC channels are a group of Ca(2+)-permeable nonselective cation channels that mediate store-operated and/or agonist-stimulated Ca(2+) influx in a variety of cell types. In this study, we extensively examined the expression patterns of TRPC homologs in human vascular tissues. RT-PCR amplified cDNA fragments of TRPC1 (505 bp), TRPC3 (372 bp), TRPC4 (499 bp), TRPC5 (325 bp), TRPC6 (509 bp), and TRPC7 (187 bp) from RNA isolated from cultured human coronary artery endothelial cells. In situ hybridization yielded strong labeling of TRPC1,3-6 in the endothelial and smooth muscle cells of human coronary and cerebral arteries. TRPC7 labeling was exclusively found in endothelial cells but not in smooth muscle cells. Results from immunohistochemical staining were consistent with those from in situ hybridization. Similar expression patterns of TRPC homologs were also observed in arterioles and vaso vasora. In conclusion, our study indicates that TRPC homologs are widely expressed in human vessels of all calibers, including medium-sized coronary arteries and cerebral arteries, smaller-sized resistance arteries, and vaso vasora. These results suggest a ubiquitous role of TRPC homologs in regulating blood supply to different regions and in controlling arterial blood pressure.

Adolescent↗

PubMed2004

Attenuated endothelium-mediated relaxation by acteoside in rat aorta: Role of endothelial [Ca2+]i and nitric oxide/cyclic GMP pathway.

Acteoside and other phenylethanoid glycoside are contained in many plants that are widely used in traditional Chinese herbal medicine. Acteoside possesses multiple biological actions. Its effect on the vascular system is, however, incompletely understood. This study was aimed to investigate the role of endothelial [Ca2+]i, nitric oxide (NO), and cyclic GMP in acteoside-induced inhibition of endothelial NO-mediated relaxation in rat aorta. Acteoside reduced endothelial NO-dependent relaxation induced by acetylcholine (Ach) or A23187. Acteoside inhibited Ach-stimulated increase in tissue content of cyclic GMP in endothelium-intact rings. L-NNA abolished the stimulatory effect of Ach. Treatment with acteoside significantly suppressed bradykinin-induced increase in [Ca2+]i of cultured rat aortic endothelial cells. Acute exposure to acteoside (30 microM) did not affect the expression of eNOS mRNA in endothelium-intact rings. In summary, acteoside impairs endothelial NO-mediated aortic relaxation partially through inhibition of agonist-induced endothelial Ca2+ mobilization and Ca2+-dependent NO production and subsequent suppression of cyclic GMP formation. This novel pharmacological action if occurring in small vessels in vivo, may contribute to the reported anti-inflammatory effect of acteoside against NO-mediated vascular permeability-related acute edema.

Animals↗

PubMed2004

Estrogen and tamoxifen modulate cerebrovascular tone in ovariectomized female rats.

Postmenopausal estrogen deficiency increases the incidence of cerebrovascular disease. However, hormone replacement therapy is associated with an increased cardiovascular risk. Tamoxifen is a selective estrogen receptor modulator with estrogenic effects on cardiovascular risk factors, but its long-term impacts on cerebral vasculature are unknown. We hypothesized that chronic 17beta-estradiol or tamoxifen treatment exerted similar effects in reducing cerebrovascular tension in ovariectomized rats. We therefore determine whether (1) chronic 17beta-estradiol treatment could influence vasomotor activities, (2) chronic tamoxifen therapy could exert an estrogen-like or estrogen-antagonistic effect, and (3) acute exposure to estrogen could mimic the effect of 17beta-estradiol. Isometric tension was measured in cerebral arteries from female rat groups: control, ovariectomy, ovariectomy plus 17beta-estradiol treatment, ovariectomy plus tamoxifen treatment, and ovariectomized rats treated with tamoxifen and 17beta-estradiol. Ovariectomy enhanced cerebrovascular contractions to endothelin-1 or CaCl2, but not to U46619 or phenylephrine. 17beta-Estradiol therapy reversed these effects. Chronic tamoxifen treatment exerted estrogen-like actions by reversing ovariectomy-induced enhancement of vessel tone without antagonizing the effect of chronic 17beta-estradiol treatment. Ovariectomy enhanced the relaxing potency of nicardipine, and 17beta-estradiol treatment prevented this effect. Acute exposure to 10(-9) mol/L 17beta-estradiol or 10(-8) mol/L tamoxifen did not modulate contractions in rings from nonoperated female rats. In conclusion, ovariectomy differentially enhances agonist-induced cerebrovascular tone, an effect that was reversed by estrogen therapy. Tamoxifen does not act as an estrogen antagonist; instead, it functions as an estrogen agonist during estrogen deficiency. Thus, tamoxifen may confer beneficial effects similar to estrogen in cerebrovascular vessels.

Animals↗

PubMed2004

Raloxifene relaxes rat cerebral arteries in vitro and inhibits L-type voltage-sensitive Ca2+ channels.

BACKGROUND AND PURPOSE: Because of their mixed estrogen-agonist and estrogen-antagonist properties, selective estrogen receptor modulators (SERMs) are considered promising substitutes for hormone replacement therapy. Raloxifene and other SERMs confer estrogen-like cardiovascular protective effects but lack the carcinogenic activity of exogenous estrogen. However, little is known about the cerebrovascular action of raloxifene. Therefore, we studied the effects of raloxifene on the mechanisms regulating rat cerebral artery tone. METHODS: Ring segments of the isolated rat posterior communicating cerebral arteries were mounted in a microvessel myograph for measurement of isometric tension. Whole-cell L-type voltage-sensitive Ca2+ currents were recorded using the perforated patch-clamp technique. Raloxifene (0.1 to 10 micromol/L) reduced the contractile responses to U46619, phenylephrine, and endothelin-1 in normal Krebs solution or to CaCl2 in Ca2+-free, high K+-containing solution. Raloxifene-induced relaxation was identical in endothelium-intact and endothelium-denuded rings. ICI 182780 had no effect on raloxifene-induced relaxation. Raloxifene reduced L-type Ca2+ currents with a pD2 of 5.98+/-0.06, close to that (6.44+/-0.09) for raloxifene-induced relaxation of 60 mmol/L K+-contracted rings. CONCLUSIONS: This study demonstrates that raloxifene acutely relaxes rat cerebral arteries largely via an endothelium-independent mechanism, involving inhibition of Ca2+ influx through L-type Ca2+ channels.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗