Anti-shock effects of human superoxide dismutase in splanchnic artery occlusion (SAO) shock

We studied the effects of human superoxide dismutase (h-SOD) in splanchnic artery occlusion (SAO) shock. Pentobarbital anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 min developed a severe shock state usually resulting in a fatal outcome within 20 min after the release of the occlusion. h-SOD (10 mg/kg) was infused intravenously starting at reperfusion and lasting for 10 min. SAO shock rats treated with h-SOD maintained postreperfusion MABP at significantly higher values compared to rats receiving the vehicle (final MABP 84 +/- 6 vs 46 +/- 1 mm Hg, P less than 0.01, respectively). Treatment with h-SOD attenuated the plasma accumulation of free amino-nitrogen compounds (P less than 0.01 from vehicle) as well as the activity of the lysosomal protease cathepsin D (P less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in h-SOD-treated rats than in SAO rats receiving only the vehicle (27 +/- 1 vs 64 +/- 3 U/ml, P less than 0.01). SAO shock rats treated with h-SOD also exhibited a significantly higher survival rate than the SAO shock +/- vehicle group (88% vs 11%, P less than 0.01, respectively). These results support the role of oxygen-derived radicals in the pathophysiology of SAO shock, and indicate that h-SOD effectively ameliorates the deleterious effects of oxygen radicals in this severe model of ischemia and reperfusion.     

No effect of short-term 17beta-estradiol supplementation in healthy men on systemic inflammatory responses to exercise

Sex-based differences in inflammatory responses to exercise may be mediated by estrogen through increased muscle membrane stability and/or inhibited cytokine production. In this study, in vivo effects of estrogen on systemic inflammation-related responses to exercise were assessed in healthy men. In a double-blind, placebo-controlled, crossover design, 11 men cycled for 90 min at 65% Vo2 max after 8 days of 17beta-estradiol supplementation (ES; 2 mg/day) or placebo (PL; glucose polymer). After a 2-wk washout, exercise was repeated after 8 days on the alternate treatment. Blood was collected pre- and postexercise to determine IL-6, soluble intercellular adhesion molecule-1 (sICAM-1), neutrophil counts, and cortisol. Preexercise serum was assayed for sex hormones. ES increased estradiol (133+/-71 to 840+/-633 pmol/l, P=0.005) and reduced testosterone (19.9+/-3.7 to 16.1+/-3.9 nmol/l, P=0.007). Exercise increased cortisol (P=0.02), IL-6 (P<0.001) and neutrophil counts (P<0.001) with no influence on sICAM-1 (P=0.34) and no effect of ES on these changes. Postexercise IL-6 and neutrophil counts were correlated (r=0.58, P=0.005); postexercise IL-6 and cortisol (r=0.18, P=0.43) and postexercise cortisol and neutrophil counts (r=0.06, P=0.78) were not. Postexercise sICAM-1 was not correlated with the above variables (P>or=0.79). In conclusion, 8 days of ES in healthy men did not influence systemic inflammation-related responses to acute exercise. Future studies should investigate 17beta-estradiol effects on IL-6 production and neutrophil infiltration within skeletal muscle during and after exercise.     

Use of a novel peptide leukotriene receptor antagonist, Ly-163443, in splanchnic artery occlusion shock

We studied the effects of LY-163443, a novel selective receptor antagonist of LTD4 and LTE4, in splanchic artery occlusion (SAO) shock. LY-163443 antagonized the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats. Anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 minutes developed a severe shock state usually resulting in a fatal outcome within two hours after release of the occlusion. SAO shock rats pre-treated with LY-163443 before the occlusion of the splanchnic arteries maintained post-release MABP at significantly higher values compared to rats receiving either the vehicle or LY-163443 as a post-treatment 15 min after occlusion (final MABP 96 +/- 8 vs 51 +/- 1, p less than 0.01 and 53 +/- 3, p less than 0.01, respectively). Pre-treatment with LY-163443 attenuated the release of the lysosomal hydrolase, cathepsin D (p less than 0.01 from vehicle and p less than 0.05 from post-treatment groups), and the plasma accumulation of free amino-nitrogen compounds (p less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in the pre-treatment group than in the vehicle group (27 +/- 3 vs 51 +/- 6 U/ml, p less than 0.01). SAO shock rats pretreated with LY-163443 also exhibited significantly higher survival rates (p less than 0.01 from vehicle and post-treatment groups), and prolonged survival times (p less than 0.01 from vehicle and post-treatment groups).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of 17beta-estradiol on ventricular and vascular hemodynamics in postmenopausal women

Because premenopausal women have lower cardiovascular morbidity than postmenopausal women, it has been proposed that estrogen may have a protective role. Estrogen is involved in smooth muscle relaxation both through its specific receptor as well as through calcium channel blockade. This study examined the acute effect of estradiol on invasive cardiovascular hemodynamics in 18 postmenopausal women (age 62.6 +/- 7.6 years, means +/- SD). The effect of estradiol on left ventricular chamber performance was studied in 9 women using simultaneous left ventricular pressure-volume recordings. In a further group of 9 women, the acute effect of estradiol on arterial function was assessed using input impedance (derived from simultaneous aortic pressure and flow recordings), pressure waveform analysis, and pulse wave velocity. After 2 mg micronized 17beta-estradiol was administered, serum estradiol levels increased from 50.9 +/- 21.9 to 3,190 +/- 2,216 pmol/l, P < 0.0001. There was no effect of estradiol on either left ventricular inotropic or lusitropic function. There was no acute effect of estradiol on arterial impedance, reflection coefficient, augmentation index, or pulse wave velocity. There was a trend to decreased heart rate and cardiac output in both groups of 9 women. Because heart rate and cardiac output were common to both hemodynamic data sets, results for these parameters were pooled. Across all 18 women, there was a small but significant decrease in heart rate (69.2 +/- 10.4 vs. 67.2 +/- 9.9 beats/min, P = 0.02), as well as a significant decrease in cardiac output (4.82 +/- 1.77 vs. 4.17 +/- 1.56 l/min, P = 0.002). Despite achieving supraphysiological serum levels, this study found no significant effect of acute 17beta-estradiol on ventricular or large artery function.     

Regulation of leptin by steroid hormones in rat adipose tissue.

We investigated if steroid hormones regulate the secretion and the expression of leptin in female and male rat adipose tissue fragments in vitro. Dexamethasone time and dose-dependently increased the secretion and mRNA expression of leptin with a half-maximal stimulation of approximately 1 nM. A time-course revealed a maximal stimulatory effect of 17 beta-estradiol after 24 hours. In male adipose tissue 17 beta-estradiol increased leptin secretion (32% by 50 nM 17 beta-estradiol, P = 0.07 and 34% by 500 nM 17 beta-estradiol, P < 1780.05) after 24 hours. An additional effect of estrogen was seen in the dexamethasone (50 nM) stimulated cells (38% with 50 nM 17 beta-estradiol, P < 0.05 and 48% by 500 nM 17 beta-estradiol, P < 0.05). Basal secretion of leptin was equal in female and male adipose tissue, whereas the effects of 17 beta-estradiol (50 nM) and dexamethasone were significantly increased in female as compared with male adipose tissue. Progesterone, testosterone, dihydrotestosterone and dehydroepiandrostendione-sulfate neither affected leptin secretion in male nor female adipose tissue in vitro. Furthermore, to investigate the effect of estrogen female rats were ovariectomized (OVX) and the adipose tissue was incubated in vitro and compared with adipose tissue leptin secretion from sham operated rats (SHAM), and with ovariectomized rats treated with 17 beta-estradiol (EST). A decreased basal and dexamethasone-stimulated leptin secretion from OVX rats compared with SHAM rats was found (P < 0.005) whereas 17 beta-estradiol treatment of ovariectomized rats maintained a normal leptin secretion. However, the dexamethasone stimulation was equally increased above basal levels in SHAM, OVX and EST rats (3.7 +/- 1.2, 2.9 +/- 0.8, 4.2 +/- 1.4, NS, ANOVA) respectively.     

Chronic estradiol treatment attenuates stiffening, glycoxidation, and permeability in rat carotid arteries

Aging-related changes in vascular stiffening and permeability are associated with cardiovascular disease. We examined the interaction of estradiol on the aging process in vascular tissue from rats by assessing the changes in endothelial layer permeability, arterial compliance, and glycoxidative damage levels. We isolated carotid arteries from ovariectomized (OVX) rats that underwent 1 yr of estrogen treatment with subcutaneous pellets and a subsequent 1 mo of cessation of treatment. Endothelial layer permeability and arterial compliance were determined using quantitative fluorescence microscopy. Endothelial layer permeability was reduced with estradiol treatment (estrogen groups, 2.58 +/- 0.21 ng dextran x min(-1) x cm(-2) vs. nonestrogen groups, 4.01 +/- 0.30 ng dextran x min(-1) x cm(-2); P < 0.05). Additionally, arteries from animals treated with estradiol had an increased compliance index (estrogen groups, 82.9 +/- 3.8 mm2. Torr vs. nonestrogen groups, 69.3 +/- 3.2 mm2. Torr; P < 0.05). Estradiol treatment also reduced levels of pentosidine, which is a specific marker of glycoxidative damage (estrogen groups, 0.11 +/- 0.03 pmol pentosidine/nmol collagen vs. nonestrogen groups, 0.20 +/- 0.03 pmol pentosidine/nmol collagen; P < 0.05). These results indicate that estradiol has multiple chronic vasculoprotective effects on the artery wall to maintain normal vascular wall function.     

17beta-estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall

Estrogens have direct effects on the vascular wall that may prevent the development of atherosclerosis. In particular, estrogens, such as 17beta-estradiol (estradiol), are known to have potent antioxidant activity. Tumor necrosis factor-alpha (TNF) is found in human atheroma and produces oxygen-derived free radicals. These oxygen-derived free radicals may modify low density lipoproteins (LDL) and increase LDL binding in the artery wall. We asked: 1) does TNF increase LDL accumulation in the artery wall and 2) can the TNF-mediated increase in LDL accumulation be prevented by the antioxidant activity of estradiol? Carotid arteries from ovariectomized 3-month-old rats were removed and perfused with fluorescently labeled LDL and arterial LDL flux was measured using quantitative fluorescence microscopy. In six arteries, addition of TNF (10 ng/ml) to the perfusate resulted in a 2.3-fold increase in the rate of LDL accumulation (1.50 +/- 0.37 ng/min per cm2 vs. 3.38 +/- 0.48 ng/min per cm2; P < 0.01). Estradiol (65 pg/ml) and alpha-tocopherol (6 mg/L) both attenuated TNF-mediated LDL accumulation (P < 0.05), indicating that TNF may exert its effects on LDL accumulation through cellular production of oxygen-derived free radicals. These results support an antioxidant role for estradiol in the protection against LDL accumulation in the artery wall and subsequent progression of atherosclerosis.     

Effects of oral contraceptives on body fluid regulation.

To test the hypothesis that estrogen reduces the operating point for osmoregulation of arginine vasopressin (AVP), thirst, and body water balance, we studied nine women (25 +/- 1 yr) during 150 min of dehydrating exercise followed by 180 min of ad libitum rehydration. Subjects were tested six different times, during the early-follicular (twice) and midluteal (twice) menstrual phases and after 4 wk of combined [estradiol-norethindrone (progestin), OC E + P] and 4 wk of norethindrone (progestin only, OC P) oral contraceptive administration, in a randomized crossover design. Basal plasma osmolality (P(osm)) was lower in the luteal phase (281 +/- 1 mosmol/kgH(2)O, combined means, P < 0.05), OC E + P (281 +/- 1 mosmol/kgH(2)O, P < 0.05), and OC P (282 +/- 1 mosmol/kgH(2)O, P < 0. 05) than in the follicular phase (286 +/- 1 mosmol/kgH(2)O, combined means). High plasma estradiol concentration lowered the P(osm) threshold for AVP release during the luteal phase and during OC E + P [x-intercepts, 282 +/- 2, 278 +/- 2, 276 +/- 2, and 280 +/- 2 mosmol/kgH(2)O, for follicular, luteal (combined means), OC E + P, and OC P, respectively; P < 0.05, luteal phase and OC E + P vs. follicular phase] during exercise dehydration, and 17beta-estradiol administration lowered the P(osm) threshold for thirst stimulation [x-intercepts, 280 +/- 2, 279 +/- 2, 276 +/- 2, and 280 +/- 2 mosmol/kgH(2)O for follicular, luteal, OC E + P, and OC P, respectively; P < 0.05, OC E + P vs. follicular phase], without affecting body fluid balance. When plasma 17beta-estradiol concentration was high, P(osm) was low throughout rest, exercise, and rehydration, but plasma arginine vasopressin concentration, thirst, and body fluid retention were unchanged, indicating a lowering of the osmotic operating point for body fluid regulation.     

Astringinin-mediated attenuation of the hepatic injury following trauma-hemorrhage

Although astringinin administration under adverse circulatory conditions is known to be protective, the mechanism by which astringinin produces the salutary effects remains unknown. We hypothesize that astringinin administration in males following trauma-hemorrhage decreases cytokine production and protects against hepatic injury. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure: 40 mmHg for 90 min, then resuscitation). Different doses of astringinin (0.01, 0.03, 0.1, 0.3 mg/kg of body weight) or vehicle were administered intravenously during resuscitation. Concentrations of plasma aspartate aminotransferase (AST) with alanine aminotransferase (ALT) and various hepatic parameters were measured (n = 8 rats/group) at 24 h after resuscitation. One-way ANOVA and Tukey testing were used for statistical analysis. Trauma-hemorrhage significantly increased plasma AST and ALT levels at 24 h postresuscitation; there was a dose-related benefit when astringinin was administered at doses of 0.01 to 0.3 mg/kg. In astringinin-treated (0.3 mg/kg) rats subjected to trauma-hemorrhage, there were significant improvements in liver myeloperoxidase (MPO) activity (237.80 +/- 45.89 vs. 495.95 +/- 70.64 U/mg protein, P < 0.05), interleukin-6 (IL-6) levels (218.54 +/- 34.52 vs. 478.60 +/- 76.21 pg/mg protein, P < 0.05), cytokine-induced neutrophil chemoattractant (CINC)-1 (88.32 +/- 20.33 vs. 200.70 +/- 32.68 pg/mg protein, P < 0.05), CINC-3 (110.83 +/- 26.63 vs. 290.14 +/- 76.82 pg/mg protein, P < 0.05) and intercellular adhesion molecule (ICAM)-1 concentrations (1,868.5 +/- 211.5 vs. 3,645.0 +/- 709.2 pg/mg protein, P < 0.05), as well as in histology. Results show that astringinin significantly attenuates proinflammatory responses and hepatic injury after trauma-hemorrhage. In conclusion, the salutary effects of astringinin administration on attenuation of hepatic injury following trauma-hemorrhage are likely due to reduction of pro-inflammatory mediator levels.     

Splenic denervation worsens lipopolysaccharide-induced hypotension, hemoconcentration, and hypovolemia

During lipopolysaccharide (LPS)-induced endotoxemia, increased intrasplenic fluid efflux contributes to a reduction in plasma volume. We hypothesized that splenic sympathetic nerve activity (SSNA), which increases during endotoxemia, limits intrasplenic fluid efflux. We reasoned that splenic denervation would exaggerate LPS-induced intrasplenic fluid efflux and worsen the hypotension, hemoconcentration, and hypovolemia. A nonlethal dose of LPS (150 microg x kg(-1) x h(-1) for 18 h) was infused into conscious male rats bearing transit time flow probes on the splenic artery and vein. Fluid efflux was estimated from the difference in splenic arterial inflow and venous outflow (A-V). LPS significantly increased the (A-V) flow differential (fluid efflux) in intact rats (saline -0.01 +/- 0.02 ml/min, n = 8 vs. LPS +0.21 +/- 0.06 ml/min, n = 8); this was exaggerated in splenic denervated rats (saline -0.03 +/- 0.01 ml/min, n = 7 vs. LPS +0.41 +/- 0.08 ml/min, n = 8). Splenic denervation also exacerbated the LPS-induced hypotension, hemoconcentration, and hypovolemia (peak fall in mean arterial pressure: denervated 19 +/- 3 mmHg, n = 10 vs. intact 12 +/- 1 mmHg, n = 8; peak rise in hematocrit: denervated 6.7 +/- 0.3%, n = 8 vs. intact 5.0 +/- 0.3%, n = 8; decrease in plasma volume at 90-min post-LPS infusion: denervated 1.08 +/- 0.15 ml/100 g body wt, n = 7 vs. intact 0.54 +/- 0.08 ml/100 g body wt, n = 8). The exaggerated LPS-induced hypovolemia associated with splenic denervation was mirrored in the rise in plasma renin activity (90 min post-LPS: denervated 11.5 +/- 0.8 ng x ml(-1) x h(-1), n = 9 vs. intact 6.6 +/- 0.7 ng x ml(-1) x h(-1), n = 8). These results are consistent with our proposal that SSNA normally limits LPS-induced intrasplenic fluid efflux.     

Idoxifene对人乳内动脉的舒张作用

为了研究idoxifene(吲哚昔酚,一种新型雌激素受体调节剂)对人乳内动脉(human internal mammarya artery,HIMA)的舒张作用及其机制,采用离体血管灌流的方法,观察idoxifene对完整内皮和去内皮HIMA的舒张作用,以及L-NAME和美蓝(metllylene blue,MB)对这一过程的影响,并且和17β雌二醇(17β-estradiol,E2)的舒血管作用进行了比较。实验中观察到保留血管内皮时idoxifenc(0．01～10μmol／L)和E2(0．1～100μmol／I,)可以剂量依赖性地舒张血管,且血管对idoxifene的灵敏度比对E2高15倍左右,而去内皮时则无此作用;NO合成酶阻断剂L-NAME和鸟苷酸环化酶(guanylate cyclasc,GC)的抑制剂MB使idoxifene舒张HIMA的作用完全消失。上述结果表明：idoxifene能够剂量依赖性地舒张HIMA,而且比E2更有效。idoxifene的这种作用是通过NO-GC-cGMP通路实现的。     

Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production

Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol (PI) 3-kinase, Akt, and endothelial NO synthase. We hypothesized that insulin resistance may cause imbalance between endothelial vasodilators and vasoconstrictors (e.g., NO and ET-1), leading to hypertension. Twelve-week-old male spontaneously hypertensive rats (SHR) were hypertensive and insulin resistant compared with control Wistar-Kyoto (WKY) rats (systolic blood pressure 202 +/- 11 vs. 132 +/- 10 mmHg; fasting plasma insulin 5 +/- 1 vs. 0.9 +/- 0.1 ng/ml; P < 0.001). In WKY rats, insulin stimulated dose-dependent relaxation of mesenteric arteries precontracted with norepinephrine (NE) ex vivo. This depended on intact endothelium and was blocked by genistein, wortmannin, or N(omega)-nitro-l-arginine methyl ester (inhibitors of tyrosine kinase, PI3-kinase, and NO synthases, respectively). Vasodilation in response to insulin (but not ACh) was impaired by 20% in SHR (vs. WKY, P < 0.005). Preincubation of arteries with insulin significantly reduced the contractile effect of NE by 20% in WKY but not SHR rats. In SHR, the effect of insulin to reduce NE-mediated vasoconstriction became evident when insulin pretreatment was accompanied by ET-1 receptor blockade (BQ-123, BQ-788). Similar results were observed during treatment with the MEK inhibitor PD-98059. In addition, insulin-stimulated secretion of ET-1 from primary endothelial cells was significantly reduced by pretreatment of cells with PD-98059 (but not wortmannin). We conclude that insulin resistance in SHR is accompanied by endothelial dysfunction in mesenteric vessels with impaired PI3-kinase-dependent NO production and enhanced MAPK-dependent ET-1 secretion. These results may reflect pathophysiology in other vascular beds that directly contribute to elevated peripheral vascular resistance and hypertension.     

Neuromedin U has a physiological role in the regulation of food intake and partially mediates the effects of leptin

Intracerebroventricular (ICV) administration of Neuromedin U (NMU), a hypothalamic neuropeptide, or leptin, an adipostat hormone released from adipose tissue, reduces food intake and increases energy expenditure. Leptin stimulates the release of NMU in vitro, and NMU expression is reduced in models of low or absent leptin. We investigated the role of NMU in mediating leptin-induced satiety. ICV administration of anti-NMU immunoglobulin G (IgG) (5 nmol) to satiated rats significantly increased food intake 4 h after injection, an effect seen for 相似文献   

Direct effect of the luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH on rat ovarian steroidogenesis

The luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH (LHRHa) inhibits rat ovarian estradiol secretion. To determine whether LHRHa decreases serum estradiol concentrations solely by inhibiting gonadotropin secretion or, in addition, by influencing directly ovarian estradiol biosynthesis, we examined the effects of LHRHa on the activities of 5 key ovarian steroidogenic enzymes. Fifty hypophysectomized, gonadotropin-treated rats were given either LHRHa (1 microgram/day) or saline sc during 7 days. The LHRHa treated animals exhibited a significant decrease in serum estradiol when compared with the control group (461 +/- 30 vs 31 +/- 5 pg/ml, mean +/- SE, P less than 0.001). The changes in estradiol concentration were associated with decreases in ovarian weight (372 +/- 19 vs 185 +/- 11 mg, P less than 0.001) and in the microsomal enzyme activities of 3 beta-hydroxysteroid dehydrogenase (156 +/- 5 vs 53 +/- 4 nmol/mg prot/min, P less than 0.001), 17 hydroxylase (4.7 +/- 0.8 vs 3.7 +/- 0.7 nmol/mg prot/min, P less than 0.002), 17,20 desmolase (279 +/- 14 vs 50 +/- 7 pmol/mg prot/min, P less than 0.001), 17 keto-steroid reductase (132 +/- 11 vs 6 +/- 1 nmol/mg prot/min, P less than 0.001), and aromatase (19 +/- 1.5 vs 0.9 +/- 0.1 nmol/mg prot/min, P less than 0.001) in LHRHa treated animals. These findings indicate that LHRHa can inhibit directly rat ovarian estradiol biosynthesis.     

A Korean herbal medicine, Panax notoginseng, prevents liver fibrosis and hepatic microvascular dysfunction in rats

We assessed the prevention of hepatic fibrogenesis by water-extract of Panax notoginseng Buck F.H. Chen. (Arialiaceae) root (PNS) in Long-Evans rats with cinnamon coat color (LEC rats). LEC rats were divided into three groups A, fed on a basal diet (BD); B, fed on BD plus 1% PNS; and C), fed on BD plus 0.005% lycopene as a control. All rats were sacrificed at 26 weeks of age. The percentage of the total area involved by fibrosis was 1.46 +/- 0.47 in group A, 0.83 +/- 0.10 in B (P=0.0030, B vs A) and 0.91 +/- 0.45 in C (P=0.0035, C vs. A). The percentage of the total area that was stained for alpha-SMA was 0.56 +/- 0.34 in group A, 0.15 +/- 0.02 in B (P=0.0016, B vs. A and 0.11 +/- 0.01 in C (P=0.0025, C vs. A. In group B, malondialdehyde (MDA) in the liver was lower than in group C (P=0.007). In group C, the concentration of iron in the liver was lower than in group A (P=0.0053). Thus, PNS suppressed fibrogenesis through reduced generation of lipid peroxides. The mechanisms of this preventive effect of fibrogenesis with PNS were suggested to inhibit the stellate cell activity. Second objective of this study was to determine whether PNS affects hepatic microvascular dysfunction elicited by gut ischemia and reperfusion (I/R), since gut I/R causes hepatic microvascular dysfunction, and to investigate the role of nitric oxide (NO). Male Wistar rats were exposed to 30 min of gut ischemia followed by 60 min of reperfusion. Intravital microscopy was used to monitor the number of non-perfused sinusoids (NPS). In another set of experiments, PNS (1 g/kg per day intragastrically) was administered to rats for 7 days. In some experiments, dexamethasone (ST) (2 mg/kg per day intravenously) was administered. In control rats, gut I/R elicited increases in the number of NPS, and plasma TNF-alpha and ALT activities, and these changes were mitigated by the pretreatment with PNS. Pretreatment with an NO synthase inhibitor diminished the protective effects of PNS on the increase in NPS and plasma TNF-alpha levels, but not its effect on the increase in plasma ALT activities. Pretreatment with PNS increased plasma nitrite/nitrate levels. The responses caused by gut I/R were attenuated by the pretreatment with ST. Pretreatment with an NO synthase inhibitor did not affect the effect of ST. These results suggest that PNS attenuates the gut I/R-induced hepatic microvascular dysfunction and inflammatory responses such as TNF-alpha production in the early phase via enhancement of NO production, and sequential hepatocellular damage via its anti-inflammatory effect.     

The effects of estradiol and progesterone on rat ovarian 17-hydroxylase and 3 beta-hydroxysteroid dehydrogenase activities

Testosterone biosynthesis by Leydig cells can be modulated by estradiol. This modulation appears to occur at the 17-hydroxylase and 17,20-desmolase stage. In this study we have examined the effects of estradiol and progesterone on the activities of the 17-hydroxylase (17-OH) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in rat ovarian tissue, to examine the hypothesis that estradiol may regulate these enzymes in the ovary as well as in the testis. Estradiol capsule implants produced a decrease in 17-OH activity (0.5 +/- 0.05 vs. 2.1 +/- 0.1 nmol/mg protein/min, mean +/- SEM, p less than 0.001), and an increase in 3 beta-HSD activity (15.5 +/- 0.9 vs 9.7 +/- 0.7 nmol/mg protein/min p less than 0.001). Progesterone injections produced a decrease in both 17-OH (0.9 +/- 0.1 vs. 2.3 +/- 0.2 p less than 0.005) and 3 beta-HSD (2.5 +/- .4 vs. 8.6 +/- 0.5; p less than 0.005) activities. We conclude that estradiol decreases 17-OH activity in the ovary as it does in the testis. This, coupled with an increase in 3 beta-HSD may explain the pre-ovulatory increase in progesterone seen in many species. Progesterone seems to decrease the steroidogenic activity of the ovarian tissue, perhaps offering an explanation for the gonadotropin resistance seen in corpus luteus bearing ovaries.     

Weight loss reduces plasma endothelin-1 concentration in obese men

Obesity is associated with endothelial dysfunction that may contribute to the development of diabetes, hypertension, and atherosclerosis. Endothelin-1 (ET-1), which is produced mostly by vascular endothelial cells, has potent vasoconstrictor and proliferative activity in vascular smooth muscle cells and, therefore, has been implicated in regulation of vascular tonus and the progression of atherosclerosis, suggesting that ET-1 may be important in endothelial dysfunction. We studied whether diet-induced weight loss (i.e., lifestyle modification) affects plasma ET-1 concentration in obese individuals. We measured plasma ET-1 concentration in seven obese men (age: 48 +/- 4 years old, body mass index: 27.7 +/- 0.5 kg/m2) before and after a 3-month, diet-induced weight reduction program (i.e., lifestyle modification program). Caloric restriction reduced body weight from 78 +/- 3 to 68 +/- 2 kg (P < 0.001) and resulted in 12.1 +/- 1.2% reduction in body mass index (24.3 +/- 0.3 kg/m(2), P < 0.0001). After the weight reduction program, systolic and diastolic blood pressure significantly decreased (128 +/- 7 vs. 115 +/- 4 mm Hg, P < 0.05 and 88 +/- 4 vs. 77 +/- 2 mm Hg, P < 0.01, respectively). The plasma level of ET-1 significantly decreased after the program (5.1 +/- 0.4 vs. 4.0 +/- 0.3 pg/ml, P < 0.05). The percentage systolic blood pressure reduction and percentage plasma ET-1 concentration reduction was in a linear relationship (r = 0.86, P < 0.05). Furthermore, the relationship between percentage weight reduction and percentage plasma ET-1 concentration reduction was linear (r = 0.87, P < 0.05). We conclude that weight loss by low-calorie diet (i.e., lifestyle modification) reduces plasma ET-1 concentration in obese individuals. This reduction may contribute to the improvement of obesity-induced endothelial dysfunction.     

17beta-estradiol regulation of human growth hormone (hGH), insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) axis in hypoestrogenic, hypergonadotropic women

OBJECTIVE: Ovarian hormonal function may be as important contributing factor to hGH-IGF-I-IGFBP-3 axis as age. AIM: To examine plasma hGH, IGF-1 and IGFBP-3 levels in women with premature ovarian failure compared to healthy normal controls and postmenopausal ones. PATIENTS: Group A-15 women with premature ovarian failure (POF) (mean: age 38.9+/-5.2 years, FSH 101.4+/-29.0 IU/l; 17beta-estradiol 22.5+/-14.6 ng/l). Group B consisted of 15 menopausal women (mean: age 54.7+/-2.7 years; FSH 81.9+/-32.1 IU/l; 17beta-estradiol 17.1+/- 8.0 ng/l). Group C - controls - 15 normally menstruating women (mean: age 37.1+/-9.0 years; FSH 6.2+/-1.0 IU/l; 17beta-estradiol 144.8+/-117.1 ng/l). METHODS: Body mass and BMI were measured. Basic fasting plasma hGH, IGF-I, IGFBP-3, insulin, testosterone and LH as well as prolactin (PRL), FSH and estradiol were assessed by RIA kits. Statistical analysis. Shapiro-Wilk test, Mann-Whitney u-test, Spearman rang correlation coefficient, stepwise multiple regression. RESULTS: Mean serum IGF-I level was the lowest (p<0.005) in group B (172.0+/-54.6 microg/l) and the highest in group C (273.6+/-109.0 microg/l). The mean plasma IGF-I level in group A was similar (NS) (208.3+/-66.5 microg/l) to that found in group B and lower (p<0.02) compared with that in group C. The lowest (p<0.005) serum IGFBP-3 level was found in group B (3.1+/-0.7 microg/l) compared to group C (4.4+/-0.3 microg/l). The mean plasma IGFBP-3 level (3.1+/-1.0 microg/l) in group A was lower than in group C (p<0.005) but identical as in group B. No statistically significant differences between groups were observed in mean hGH levels. Women in group A and C were younger (p<0.001) than those in group B. The lowest mean estradiol level was found in groups A and B. The highest was in group C (p<0.001). Mean plasma LH and FSH levels were higher (p<0.001) in groups A and B vs group C. In group C there were links between IGF-I and age (r=-0.60; p=0.014) The IGF-I/age relation disappeared in the groups A and B (rA=-0.26; rB=0.10; NS). The same regards IGFBP-3/ age link (rA=-0.44, NS; rB=0,31;NS). Estradiol level was related to hGH levels in group C (r=-0.54; p<0.05). In none of groups hGH/IGF-1 as well as IGFBP-3/hGH relations were found. Prolactin accounted for 69% of the variance in IGF-I level in the group B (p=0.003) and for 24% in group A (NS). Testosterone accounted for 88% (p=0.004) of the variance in IGF-I level in group B and IGFBP-3 was responsible for 86% (p=0.038) of the variance in IGF-I level in group C. Again IGFBP-3 was responsible for 47% (p=0.023) in group A and for 49% (p=0.04) in group B of the hGH variance. CONCLUSIONS: 17b-estradiol may be as important contributor to insulin-like growth factor-I (IGF-I) plasma level as age in hypoestrogenic, hypogonadotropic women.     

Relationship of ovarian hormones to hypoxemia in women residents of 4,300 m

Prevalence of excessive erythrocytosis, the main sign of chronic mountain sickness (CMS), is greater in postmenopausal Andean women than in premenopausal women. It is uncertain whether this greater prevalence is related to the decline in female hormones and ventilatory function after the occurrence of the menopause. To study this, we compared the physiological variables involved in the physiopathology of CMS [end-tidal CO(2) (PET(CO(2)), Torr) and end-tidal O(2) (PET(O(2)), Torr), arterial oxygen saturation (Sa(O(2)), %), and Hb concentration (g/dl)] and progesterone and estradiol levels between postmenopausal and premenopausal women, both in the luteal and follicular phases. Women residing in Cerro de Pasco (n = 33; 4,300 m) aged 26--62 yr were studied. Postmenopausal women compared with premenopausal women in the luteal phase had lower PET(O(2)) (48 +/- 4 vs. 53 +/- 2 Torr, P = 0.005) and Sa(O(2)) levels (82 +/- 12 vs. 88 +/- 12%, P < 0.005) and higher PET(CO(2)) (34 +/- 2 vs. 29 +/- 3 Torr, P = 0.005) and Hb concentration (19 +/- 1 vs. 14 +/- 2 g/dl, P < 0.005). In addition, plasma progesterone was negatively correlated with PET(CO(2)) and positively correlated with PET(O(2)) and Sa(O(2)). No clear relationship was found among the cycle phases between estradiol and the variables studied. In conclusion, our results reveal that, before menopause, there is better oxygenation and lower Hb levels in women long residing at altitude, and this is associated with higher levels of progesterone in the luteal phase of the cycle.     

Dissociation between metabolic and vascular insulin resistance in aging

Physiological actions of insulin via activation of the phosphatidylinositol 3-kinase/Akt pathway in the endothelium serve to couple regulation of hemodynamic and metabolic homeostasis. Insulin resistance, endothelial dysfunction, and hypertension increase in prevalence with aging. We investigated the metabolic and endothelial actions of insulin in 24- vs. 3-mo Sprague-Dawley rats. With the use of the hyperinsulinemic euglycemic clamp, the rate of glucose infusion necessary to maintain equivalent plasma glucose (5.5 mmol/l) was similar in 24- vs. 3-mo rats, as was fasting glucose (5.2 +/- 0.33 vs. 4.4 +/- 0.37 mmol/l; mean +/- SE) and insulin (0.862 +/- 0.193 vs. 1.307 +/- 0.230 mg/l). Systolic blood pressure was higher in 24-mo rats (133 +/- 5 vs. 110 +/- 4 mmHg; P = 0.005). Endothelial nitric oxide (NO)-dependent relaxation to insulin was impaired in aortas of 24- vs. 3-mo rats (maximal response 8.9 +/- 4.3 vs. 34.9 +/- 3.9%; P = 0.002); N(G)-nitro-l-arginine methyl ester abolished insulin-mediated relaxation in 3- but not 24-mo rats. Endothelium NO-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation, as well as NADPH oxidase activity, were similar in 3- and 24-mo rats. Insulin increased aortic serine phosphorylation of Akt in 3-mo rats by 120% over 24-mo rats (P < 0.05) and serine phosphorylation of endothelial NO synthase (eNOS) in 3-mo rats by 380% over 24-mo rats (P < 0.05). Aortic expression of phosphorylated c-Jun NH(2)-terminal kinase-1 and serine phosphorylated insulin receptor substrate-1, known mediators of metabolic insulin resistance, was similar in 3- and 24-mo rats. Expression of caveolin-1, a regulator of eNOS activity and insulin signaling, was 55% lower in 24- than 3-mo rats (P = 0.002). In summary, impaired vasorelaxation to insulin in aging was independent of metabolic insulin sensitivity and associated with impaired insulin-mediated activation of the Akt/eNOS pathway, but intact activation of the acetylcholine-mediated Ca(2+)-calmodulin/eNOS pathway. Vascular insulin resistance in aging may add to the increased susceptibility of this population to vascular injury induced by traditional cardiovascular risk factors.