Effect of bis[curcumino]oxovanadium complex on non-diabetic and streptozotocin-induced diabetic rats

The effect of the vanadium complex bis[curcumino]oxovanadium (BCOV) on blood glucose level, serum lipid levels, blood pressure and vascular reactivity were studied in non-diabetic and streptozotocin-induced diabetic (STZ-diabetic) rats and compared to that of vanadyl sulfate. Blood glucose level, serum lipid levels, and blood pressure were significantly increased in STZ-diabetic rats. Vascular reactivity to various agonists such as noradrenaline and acetylcholine were significantly increased in STZ-diabetic rats. Blood glucose and serum lipid levels were restored to normal in STZ-diabetic animals treated with vanadyl sulfate at a concentration of 0.5 mmol/kg/day (p.o.). However, vanadyl sulfate at a concentration of 0.2 mmol/kg/day (p.o.) did not produce any significant change in blood glucose and lipid levels. There was no significant effect of vanadyl sulfate (0.2 or 0.5 mmol/kg/day) treatment on blood pressure and vascular reactivity in STZ-diabetic rats. Vanadyl sulfate significantly reduced the body weight of non-diabetic and STZ-diabetic rats. Moreover, it also caused severe diarrhea in both groups of animals. Treatment with BCOV (0.05, 0.1 and 0.2mmol/kg/day, p.o.) significantly decreased blood glucose level and serum lipids in STZ-diabetic rats. Furthermore, administration of BCOV to STZ-diabetic rats restored the blood pressure and vascular reactivity to agonists to normal. There was no significant change in the body weight of BCOV treated non-diabetic and STZ-diabetic rats. Diarrhea was not observed in both BCOV treated groups. In conclusion, the present study shows that the vanadium complex BCOV has antidiabetic and hypolipedimic effects. In addition, it improves the cardiovascular complications associated with diabetes.     

Vitamin C lowers blood pressure and alters vascular responsiveness in salt-induced hypertension

The present study was undertaken to investigate the effect of vitamin C treatment on blood pressure and vascular reactivity in salt-induced hypertension. Male Sprague-Dawley rats were fed a normal rat diet, a high-sodium (8% NaCl) diet, a normal rat diet plus vitamin C treament (100 mg x kg(-1) x day(-1)), or a high-sodium diet plus vitamin C treatment for 6 weeks. Salt loading significantly increased blood pressure, which was attenuated by vitamin C treatment. Aortic rings from the different groups were suspended for isometric-tension recording. The contractile response to noradrenaline was significantly increased in the salt-loaded rats. Vitamin C reduced the sensitivity of aortic rings to noradrenaline in rats on normal and high-sodium diets. In noradrenaline-precontracted rings, the relaxation response to acetylcholine, which was attenuated in the salt-loaded rats, was restored by vitamin C treatment. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) abolished the enhanced response to acetylcholine caused by vitamin C. The results suggest that the antihypertensive effect of vitamin C is associated with a reduction in vascular sensitivity to noradrenaline and enhancement of endothelium-dependent relaxation due to increased nitric oxide bioavailability.     

Increased superoxide dismutase and Na+, K+-ATPase activities in aortic strips from potassium-adapted rats: implication for altered vascular reactivity

The contributions of superoxide dismutase (SOD) and Na(+), K(+)-ATPase to the altered vascular reactivity in potassium-adapted rats were investigated to test the hypothesis that smooth muscle hyperpolarisation may be involved. Isometric contractions to noradrenaline (NA), 5-hydroxytryptamine (5-HT), and relaxations to acetylcholine (ACh), levcromakalim (LEV) and sodium nitroprusside (SNP), were measured in aortic rings from potassium-adapted rats. Pieces of the aortae were also excised from the animals and assayed for SOD and Na(+), K(+)-ATPase. Maximum contractile responses were significantly attenuated (P<0.05) in aortic rings from the potassium-adapted rats to NA and 5-HT, while relaxations were also significantly augmented (P<0.05) in the same rings to LEV and SNP, but not to ACh. Both SOD and Na(+), K(+)-ATPase activities were significantly higher (P<0.05) in the aortae from the potassium-adapted rats compared to controls. It is concluded that the alteration in vascular smooth muscle reactivity may be due to hyperpolarisation caused by the activities of SOD and Na(+), K(+)-ATPase.     

Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats

Effect of metformin treatment on blood pressure, endothelial function and oxidative stress in streptozotocin (STZ)-induced diabetes in rats was studied. In vitro effect of metformin on vascular reactivity to various agonist in the presence of metformin in untreated nondiabetic and STZ-diabetic rats were also studied. Sprague-Dawley rats were randomized into nondiabetic and STZ-diabetic groups. Rats were further randomized to receive metformin (150 mg/kg) or vehicle for 4 weeks.Metformin treatment reduced blood pressure without having any significant effect on blood glucose level in STZ-diabetic rats. Enhanced phenylephrine (PE)-induced contraction and impaired acetylcholine (Ach)-induced relaxation in STZ-diabetic rats were restored to normal by metformin treatment. Enhanced Ach-induced relaxation in metformin-treated STZ-diabetic rats was blocked due to pretreatment with 100 μM of Nω-nitro-l-arginine-methyl ester (l-NAME) or 10 μM of methylene blue but not 10 μM of indomethacin. Metformin treatment significantly increased antioxidant enzymes and reduced lipid peroxidation in STZ-diabetic rats. In vitro studies in aortic rings of untreated nondiabetic and STZ-diabetic rats showed that the presence of higher concentration of metformin (1 mM and 10 mM) significantly reduced PE-induced contraction and increased Ach-induced relaxation. Metformin per se relaxed precontracted aortic rings of untreated nondiabetic and STZ-diabetic rats in a dose-dependent manner. Pretreatment with l-NAME or removal of endothelium blocked metformin-induced relaxation at lower concentration (up to 30 μM) but not at higher concentration (above 30 μM). Metformin-induced relaxation was blocked in the presence of 1 mM of 4-aminopyridine, or 1 mM of tetraethylammonium but not in the presence of 100 μM of barium ion or 10 μM of glybenclamide. The restored endothelial function along with direct effect of metformin on aortic rings and reduced oxidative stress contributes to reduced blood pressure in STZ-diabetic rats. From the present study, it can be concluded that metformin administration to STZ-diabetic rats lowers blood pressure, and restores endothelial function.     

Chronic Lead Exposure Decreases the Vascular Reactivity of Rat Aortas: The Role of Hydrogen Peroxide

We investigated whether exposure to small concentrations of lead alters blood pressure and vascular reactivity. Male Wistar rats were sorted randomly into the following two groups: control (Ct) and treatment with 100 ppm of lead (Pb), which was added to drinking water, for 30 days. Systolic blood pressure (BP) was measured weekly. Following treatment, aortic ring vascular reactivity was assessed. Tissue samples were properly stored for further biochemical investigation. The lead concentration in the blood reached approximately 8 μg/dL. Treatment increased blood pressure and decreased the contractile responses of the aortic rings to phenylephrine (1 nM–100 mM). Following N-nitro-L arginine methyl ester (L-NAME) administration, contractile responses increased in both groups but did not differ significantly between them. Lead effects on R_max were decreased compared to control subjects following superoxide dismutase (SOD) administration. Catalase, diethyldithiocarbamic acid (DETCA), and apocynin increased the vasoconstrictor response induced by phenylephrine in the aortas of lead-treated rats but did not increase the vasoconstrictor response in the aortas of untreated rats. Tetraethylammonium (TEA) potentiated the vasoconstrictor response induced by phenylephrine in aortic segments in both groups, but these effects were greater in lead-treated rats. The co-incubation of TEA and catalase abolished the vasodilatory effect noted in the lead group. The present study is the first to demonstrate that blood lead concentrations well below the values established by international legislation increased blood pressure and decreased phenylephrine-induced vascular reactivity. The latter effect was associated with oxidative stress, specifically oxidative stress induced via increases in hydrogen peroxide levels and the subsequent effects of hydrogen peroxide on potassium channels.     

一氧化氮改变肾性高血压大鼠主动脉功能

探讨一氧化氮（ＮＯ）对二肾一夹（２Ｋ１Ｃ）肾性高血压大鼠主动脉功能的影响。实验分为５组：假手术、２Ｋ１Ｃ、卡托普利（ｃａｐｔｏｐｒｉｌ）、ＮＡＭＥ（Ｎω－Ｎｉｔｒｏ－Ｌ－ａｒｇｉｎｉｎｅ ｍｅｔｈｙｌ ｅｓｔｅｒ）和精氨酸组。结果显示：在２Ｋ１Ｃ组,大鼠手术后４周的平均动脉压显著升高,主动脉对４Ｃｈ的舒张反应明显减弱,对苯肾上腺素收缩反应明显增强,主动脉壁环鸟苷酸（ｃＧＭＰ）含量显著减少。卡托谱利     

Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis

Previous studies suggested that increased activity of phosphodiesterase (PDE)5 in the kidneys of cirrhotic rats contributes to sodium retention. This study examined the role of PDE5 in the changes in vascular reactivity, hemodynamics, and sodium excretion in rats with liver cirrhosis. Four weeks after bile duct ligation (BDL) or sham operation (SO), in vitro reactivity of aortic rings to various agents and in vivo effects of a PDE5-selective inhibitor [1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3,4d]-pyrimidin-4-(5H)-one, DMPPO] were studied. The vasodilator responses to nitroglycerin and S-nitroso-N-acetyl-penicillamine (SNAP) in phenylephrine-precontracted rings without endothelium were attenuated in BDL compared with SO rats. Pretreatment with DMPPO (0.1 microM) enhanced these responses and eliminated the differences between the two groups. Vasodilation to DMPPO itself was also less in BDL rats. The responses to phenylephrine were attenuated in endothelium-rich aorta from BDL relative to SO rats, but they were similar in endothelium-denuded aorta and remained similar despite preincubation with SNAP (0.1 microM) alone or with SNAP and DMPPO. In vivo, BDL rats were vasodilated relative to SO rats; DMPPO (5 mg/kg i.v.) decreased arterial pressure and vascular resistance in both groups equally and caused significant increase in sodium excretion in BDL rats only. In conclusion, the results are in accordance with a possible increase in PDE5 activity in aorta and kidney of cirrhotic rats that results in reduced responses to NO donors and contributes to the increase in sodium retention. PDE5 inhibitors may ameliorate sodium retention in cirrhosis but may worsen vasodilation. Examining the effect of PDE5 inhibitors after chronic administration will be more revealing.     

Effects of taurine on the reactivity of aortas from diabetic rats

The effects of the semi-essential amino acid-like nutrient, taurine, on alterations in the reactivities of aortas from male rats with chronic streptozotocin-induced diabetes were examined under in vitro conditions. In the absence of taurine, the contractile responsiveness of endothelium-denuded aortic rings from diabetic rats to norepinephrine, but not KCl, was enhanced compared to controls. This effect of norepinephrine on the diabetic rat aorta appeared to be associated with increased release of intracellular calcium, influx of extracellular calcium and protein kinase C-mediated responses. Incubation of endothelium-denuded aortic rings with 10 mM, but not 5 mM, taurine for 2 h reduced the augmented contractile responses of the tissues from diabetic rats to norepinephrine close to control levels, and this was associated with inhibition of responses linked to the release and influx of calcium, and protein kinase C activation. Endothelium-dependent relaxation of aortas from diabetic rats to acetylcholine was depressed relative to controls. This effect of diabetes was ameliorated close to control levels by incubating the tissues with 10 mM, but not 5 mM, taurine for 2 h. Incubation of nondiabetic rat aortic rings with 45 mM glucose for 3 h caused enhancement of contraction of the vascular smooth muscle to phenylephrine and impairment of endothelium-mediated vasorelaxation to acetylcholine, as compared to control responses. Co-incubation of the tissues with 5-10 mM taurine concentration-dependently reduced the alterations in both contractile and relaxant responses caused by high glucose. Overall, the data suggest that taurine ameliorates or prevents vascular reactivity alterations in diabetes. Such an observation provides preliminary evidence for taurine's potential as a therapeutic agent for the prevention or amelioration of vascular disorders in diabetes.     

Effects of angiotensin II on isolated toad (Bufo arenarum) aortic rings

1. The vascular response to Asn1-Val5 angiotensin II (A II) in aortic rings from Bufo arenarum toad was studied. 2. Tachyphylaxis in response to A II could be abolished after incubation with norepinephrine (NE). 3. Phentolamine treatment partially inhibited the pressor effects to A II. 4. Sar1-Ile8 A II and Sar1-Ala8 A II significantly attenuated the vascular effects of A II and did not affect the NE response. 5. We conclude that the pressor response to A II has a direct contractile effect and a catecholamine dependent component in aortic rings of Bufo arenarum toad.     

Emerging Role of Angiotensin Type 2 Receptor (AT2R)/Akt/NO Pathway in Vascular Smooth Muscle Cell in the Hyperthyroidism

Hyperthyroidism is characterized by increased vascular relaxation and decreased vascular contraction and is associated with augmented levels of triiodothyronine (T3) that contribute to the diminished systemic vascular resistance found in this condition. T3 leads to augmented NO production via PI3K/Akt signaling pathway, which in turn causes vascular smooth muscle cell (VSMC) relaxation; however, the underlying mechanisms involved remain largely unknown. Evidence from human and animal studies demonstrates that the renin-angiotensin system (RAS) plays a crucial role in vascular function and also mediates some of cardiovascular effects found during hyperthyroidism. Thus, in this study, we hypothesized that type 2 angiotensin II receptor (AT2R), a key component of RAS vasodilatory actions, mediates T3 induced-decreased vascular contraction. Marked induction of AT2R expression was observed in aortas from T3-induced hyperthyroid rats (Hyper). These vessels showed decreased protein levels of the contractile apparatus: α-actin, calponin and phosphorylated myosin light chain (p-MLC). Vascular reactivity studies showed that denuded aortic rings from Hyper rats exhibited decreased maximal contractile response to angiotensin II (AngII), which was attenuated in aortic rings pre-incubated with an AT2R blocker. Further study showed that cultured VSMC stimulated with T3 (0.1 µmol/L) for 24 hours had increased AT2R gene and protein expression. Augmented NO levels and decreased p-MLC levels were found in VSMC stimulated with T3, both of which were reversed by a PI3K/Akt inhibitor and AT2R blocker. These findings indicate for the first time that the AT2R/Akt/NO pathway contributes to decreased contractile responses in rat aorta, promoted by T3, and this mechanism is independent from the endothelium.     

Vitamin E supplementation reverses renal altered vascular reactivity in chronic bile duct-ligated rats

An altered vascular reactivity is an important manifestation of the hemodynamic and renal dysfunction during liver cirrhosis. Oxidative stress-derived substances and nitric oxide (NO) have been shown to be involved in those alterations. In fact, both can affect vascular contractile function, directly or by influencing intracellular signaling pathways. Nevertheless, it is unknown whether oxidative stress contributes to the impaired systemic and renal vascular reactivity observed in cirrhosis. To test this, we evaluated the effect of vitamin E supplementation (5,000 IU/kg diet) on the vasoconstrictor and vasodilator responses of isolated perfused kidneys and aortic rings of rats with cirrhosis induced by bile duct ligation (BDL), and on the expression of renal and aortic phospho-extracellular regulated kinase 1/2 (p-ERK1/2). BDL induced a blunted renal vascular response to phenylephrine and ACh, while BDL aortic rings responded less to phenylephrine but normally to ACh. Cirrhotic rats had higher levels of oxidative stress-derived substances [measured as thiobarbituric acid-reactive substances (TBARS)] and NO (measured as urinary nitrite excretion) than controls. Vitamin E supplementation normalized the renal hyporesponse to phenylephrine and ACh in BDL, although failed to modify it in aortic rings. Furthermore, vitamin E decreased levels of TBARS, increased levels of NO, and normalized the increased kidney expression of p-ERK1/2 of the BDL rats. In conclusion, BDL rats showed a blunted vascular reactivity to phenylephrine and ACh, more pronounced in the kidney and reversed by vitamin E pretreatment, suggesting a role for oxidative stress in those abnormalities.     

Bay K 8644-like contractile effects of a peptide isolated from spontaneously hypertensive rats

The in vitro contractile effect of a peptide recently isolated from the blood of spontaneously hypertensive rats was assessed on rat aortic rings. Preincubation of aortic rings with the peptide had no effect on resting tension but significantly enhanced K+ or norepinephrine-induced contractile responses. Contractile effects were abolished by removal of extracellular calcium or by additions of the calcium channel antagonists, verapamil and nifedipine. The antagonism of peptide enhancement of contraction by verapamil was noncompetitive, whereas nifedipine blockade was competitive in nature. Moreover, preincubation of aortic rings with the peptide attenuated the contractile response to Bay K 8644, a newly described synthetic calcium channel agonist. We suggest that this peptide has similar effects to Bay K 8644 and may act as an endogenous modulator of voltage-dependent calcium channels.     

Taurine depletion alters vascular reactivity in rats

We recently showed that chronic taurine supplementation is associated with attenuation of contractile responses of rat aorta to norepinephrine and potassium chloride. However, the potential involvement of endogenous taurine in modulation of vascular reactivity is not known. Therefore, we examined the effect of beta-alanine-induced taurine depletion on the in vitro reactivity of rat aorta to selected vasoactive agents. The data indicate that both norepinephrine- and potassium-chloride-induced maximum contractile responses of endothelium-denuded aortae were enhanced in taurine-depleted rats compared with control animals. However, taurine depletion did not affect tissue sensitivity to either norepinephrine or potassium chloride. By contrast, sensitivity of the endothelium-denuded aortae to sodium nitroprusside was attenuated by taurine depletion. Similarly, taurine deficiency reduced the relaxant responses of endothelium-intact aortic rings elicited by submaximal concentrations of acetylcholine, and this effect was associated with decreased nitric oxide production. Taken together, the data suggest that taurine depletion augments contractility but attenuates relaxation of vascular smooth muscle in a nonspecific manner. Impairment of endothelium-dependent responses, which is at least in part associated with reduced nitric oxide generation, may contribute to the attenuation of the vasorelaxant responses. These vascular alterations could be of potential consequence in pathological conditions associated with taurine deficiency.     

The aqueous garlic, onion and leek extracts release nitric oxide from S-nitrosoglutathione and prolong relaxation of aortic rings

Garlic, onion and leek have beneficial effects in treatment of numerous health disorders. The aim of the present study was to investigate underlying molecular mechanisms. To test the potency of the aqueous garlic, onion and leek extracts to release NO from GSNO we have measured NO oxidation product, NO(2)-, by the Griess reagent method. Further, we studied the ability of garlic extract to relax noradrenaline-precontracted rat aortic rings in the presence of GSNO and effects of garlic extract on electrical properties of rat heart intracellular chloride channels. We have observed that: i) garlic, onion and leek extracts released NO from GSNO in the order: garlic > onion > leek; ii) the ability of garlic extract to release NO was pH-dependent (8.0 > 7.4 > 6.0) and potentiated by thiols (Cys > GSH = N-acetyl-cysteine > oxidized glutathione) at concentration 100 μmol/l; iii) the garlic extract (0.045 mg/ml) prolonged relaxation time of aortic rings induced by GSNO (50 nmol/l) and inhibited intracellular chloride channels. We suggest that NO-releasing properties of the garlic, onion and leek extracts and their interaction with Cys and GSH are involved in NO-signalling pathway which contributes to some of its numerous beneficial biological effects.     

Estrogen potentiates vasopressin-induced contraction of female rat aorta by enhancing cyclooxygenase-2 and thromboxane function

To determine the roles of estrogen and constrictor prostanoids in vasopressin (VP)-induced contraction of female rat aorta, vascular reactivity to VP was determined in thoracic aortas of intact, ovariectomized, and ovariectomized + estrogen-replaced female rats in the presence of indomethacin (Indo), NS-398, SQ-29,548, or vehicle control. The effects of estrogen on vascular reactivity to the thromboxane A(2) analog U-46619 were also examined. Maximal contractile response to VP in intact female rats (5,567 +/- 276 mg/mg of aortic ring wt) was markedly attenuated by ovariectomy (2,485 +/- 394 mg; P < 0.001) and restored by estrogen replacement with 17beta-estradiol (5,059 +/- 194 mg; P > 0.1). Indo and NS-398 significantly attenuated maximal responses to VP in intact female rats to a similar extent [3,176 +/- 179 (P < 0.0001) and 3,258 +/- 152 mg (P < 0.0001), respectively]. Ovariectomy abolished and estrogen replacement restored the inhibitory effects of Indo, NS-398, and SQ-29,548. Contractile responses of rat aorta to U-46619 were significantly greater (P < 0.0001) in females (5,040 +/- 238 mg) than in males (3,679 +/- 96 mg). Ovariectomy markedly attenuated (3,923 +/- 84 mg; P < 0.01) and estrogen replacement restored (5,024 +/- 155 mg; P > 0.1) responses to U-46619 in female aortas. These data reveal that estrogen is an important regulator of the contractile responses of female rat aorta to VP, which appears to potentiate both cyclooxygenase-2 and constrictor prostanoid function in the vascular wall.     

Effects of chronic taurine treatment on reactivity of the rat aorta

Summary. The effects of chronic taurine treatment on the reactivity of the aorta form male Wistar-Kyoto rats were investigated. Contractile responses to norepinephrine (NE) and potassium chloride (KCl) were attenuated in aortic rings from taurine-treated rats as compared to controls both in the absence and presence of endothelium. However, the degree of attenuation was greater in endothelium-intact tissues contracted with NE. Acetylcholine (Ach)-induced relaxation responses were augmented in endothelium-intact vessels from rats supplemented with taurine compared to the responses observed in control preparations. Relaxation responses of the aortae from control and taurine-treated rats to sodium nitroprusside (SNP) were not different from each other. Our results suggest that taurine treatment attenuates vascular contractility nonspecifically and this effect is partly mediated via the endothelium. Received December 20, 1999/Accepted January 9, 2000     

Modulation of temperature-induced tone by vasoconstrictor agents.

One of the primary cardiovascular adjustments to hyperthermia is a sympathetically mediated increase in vascular resistance in the viscera. Nonneural factors such as a change in vascular tone or reactivity may also contribute to this response. Therefore, the aim of this study was to determine whether vascular smooth muscle tone is altered during heating to physiologically relevant temperatures >37 degrees C. Gradually increasing bath temperature from 37 degrees C (normothermia) to 43 degrees C (severe hyperthermia) produced graded contractions in vascular ring segments from rat mesenteric arteries and thoracic aortae. In untreated rings these contractions were relatively small, whereas hyperthermia elicited near-maximal increases in tension when rings were constricted with phenylephrine or KCl before heating. In phenylephrine-treated mesenteric arterial rings, the contractile responses to heating were markedly attenuated by the Ca2+ channel antagonists nifedipine and diltiazem. Diltiazem also blocked the contractile responses to heating in thoracic aortic rings. These results demonstrate that hyperthermia has a limited effect on tension generation in rat vascular smooth muscle in the absence of vascular tone. However, in the presence of agonist-induced tone, tension generation during heating is markedly enhanced and dependent on extracellular Ca2+. In conclusion, these data suggest that local regulation of vascular tone can contribute to the hemodynamic adjustments to hyperthermia.     

Crataegus special extract WS(?)1442 prevents aging-related endothelial dysfunction

Aging is associated with a markedly increased incidence of cardiovascular diseases due, in part, to the development of vascular endothelial dysfunction. The present study has evaluated whether the Crataegus special extract WS(?)1442 prevents the development of aging-related endothelial dysfunction in rats, and, if so, to determine the underlying mechanisms. Wistar rats received either a control diet or the same diet containing 100 or 300 mg/kg/day of WS(?)1442 from week 25 until week 65. Vascular reactivity was assessed in mesenteric artery rings using organ chambers, oxidative stress by dihydroethidine staining and cyclooxygenase-1 (COX-1) and -2 (COX-2) expression by immunohistochemistry. Acetylcholine-induced endothelium-dependent relaxations in mesenteric artery rings were blunted in 65-week-old rats compared to 16-week-old rats. This effect was associated with a marked reduction of the endothelium-derived hyperpolarizing factor (EDHF) component whereas the nitric oxide (NO) component was not affected. Aging was also associated with the induction of endothelium-dependent contractile responses to acetylcholine. Both aging-related impairment of endothelium-dependent relaxations and the induction of endothelium-dependent contractile responses were improved by the Crataegus treatment and by COX inhibitors. An excessive vascular oxidative stress and an upregulation of COX-1 and COX-2 were observed in the mesenteric artery of old rats compared to young rats, and these effects were improved by the Crataegus treatment. In conclusion, chronic intake of Crataegus prevented aging-related endothelial dysfunction by reducing the prostanoid-mediated contractile responses, most likely by improving the increased oxidative stress and the overexpression of COX-1 and COX-2.     

Interaction between endothelial heme oxygenase-2 and endothelin-1 in altered aortic reactivity after hypoxia in rats

The aim of this study was to determine whether increased expression of heme oxygenase (HO) contributes to impairment of aortic contractile responses after hypoxia through effects on reactivity to endothelin-1 (ET-1). Thoracic aortas from normoxic rats and rats exposed to hypoxia (10% O2) for 16 or 48 h were mounted in organ bath myographs for contractile studies, fixed in paraformaldehyde, or frozen in liquid nitrogen for protein extraction. In rings from normoxic rats, the HO inhibitor tin protoporphyrin IX (SnPP IX, 10 microM) did not alter the response to phenylephrine or ET-1. In rings from rats exposed to 16-h hypoxia, maximum tension generated in response to these agonists was higher in endothelium-intact but not -denuded rings in the presence of SnPP IX. In rings from rats exposed to 48-h hypoxia SnPP IX increased contraction in endothelium-intact but not -denuded rings. In endothelium-intact aortic rings from rats exposed to 16-h hypoxia incubated with endothelin A receptor-specific antagonist BQ-123 (10(-7) M), SnPP IX did not alter phenylephrine-induced contraction. Aortic ET-1 protein levels, measured by radioimmunoassay, were increased in rats exposed to hypoxia for 16 and 48 h. Western blotting showed that HO-1 and HO-2 protein were increased after 16 h of hypoxia and returned to near-control levels after 48 h. Increase in HO-1 protein was detected in endothelium-intact and -denuded rings. Removal of endothelium abolished the increase in HO-2 immunoreactivity. Immunohistochemistry localized expression of HO-1 protein to vascular smooth muscle, whereas HO-2 was only detected in endothelium. HO-2 is expressed by aortic endothelial cells early during hypoxic exposure and impairs ET-1-mediated potentiation of contraction to alpha-adrenoceptor stimulation.     

Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide.

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N(G)-nitro-L-arginine methyl ester (10(-5) M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.