Effect of Vitamin D Status on Vascular Function of the Aorta in a Rat Model of PCOS.

Polycystic ovary syndrome (PCOS) is associated with elevated cardiovascular risk. Early vascular dysfunction may lead to the development of cardiovascular disease in PCOS. Vitamin D deficiency (VDD) is a common comorbidity of PCOS that contributes to the pathogenesis of the disease and its complications. Both PCOS and VDD are accompanied by increased oxidative stress that may be involved in the arising vascular dysfunction. We aimed to investigate the role of vitamin D status on aortic function. PCOS was induced by an 8-week-long transdermal testosterone treatment of female rats, and low and adequate vitamin D status was achieved by dietary means. Contraction and relaxation abilities of isolated aortic segments were measured by myograph. Resorcin-fuchsin staining and immunohistochemical labeling of 3-nitrotyrosine were performed. No difference was shown in the norepinephrine-induced contraction of the aortas of different groups, whereas we detected reduced acetylcholine- and insulin-evoked relaxation in VDD groups. A lower level of resorcin-fuchsin staining and elevated 3-nitrotyrosine immunostaining was observed in VDD. In our study, we demonstrated early endothelial dysfunction in VDD PCOS rat model. Vitamin D supplementation could prevent vascular disturbances, while VDD itself damaged endothelium-dependent vasorelaxation and induced nitrative stress.

High-dose ACEi might be harmful in COVID-19 patients with serious respiratory distress syndrome by leading to excessive bradykinin receptor activation.

PURPOSE: We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients. METHODS: The literature related to the above topic was reviewed including papers that analysed the connections, actions, interactions, consequences and occasionally suggestions for rational interventions. RESULTS/CONCLUSION: Severe broncho-alveolar inflammation seems to be caused, at least in part, by upregulation of the KKS that increases plasma and/or local tissue concentrations of bradykinin (BK) in patients with COVID-19 infection. Besides KKS activation, suppression of ACE activity results in decreased bradykinin degradation, and these changes in concert can lead to excessive BK B1 and B2 receptor (BKB1R/BKB2R) activation. Aminopeptidase P (APP), and carboxypeptidase N also degrade bradykinin, but their protein expression and activity are unclear in COVID-19 infection. On the other hand, ACE2 expression is upregulated in patients with COVID-19 infection, so ACE2 activity is unlikely to be decreased despite blockade of part of ACE2 by the virus for entry into the cells. ACE2 cleaves lys-des-arginine9BK and arg-des-arginine9BK, the active metabolites of bradykinin, which stimulate the BKB1R receptor. Stimulation of BKB1R/BKB2R can exacerbate the pulmonary inflammatory response by causing vascular leakage and edema, vasodilation, smooth muscle spasm and stimulation of pain afferent nerves. Despite all uncertainties, it seems rational to treat comorbid COVID patients with serious respiratory distress syndrome with ARBs instead of high-dose ACE inhibitor (ACEi) that will further decrease bradykinin degradation and enhance BKB1R/BKB2R activation, but ACEi may not be contraindicated in patients with mild pulmonary symptoms.

Evaluation of oxidative/nitrative stress and uterine artery pulsatility index in early pregnancy.

INTRODUCTION: Increased oxidative/nitrative stress is characteristic not only in pathologic, but also in healthy pregnancy. High uterine artery pulsatility index (UtAPI) at the end of the first trimester is associated with altered placentation and elevated risk for adverse pregnancy outcomes. We aimed to examine the relationship of systemic oxidative/nitrative stress and uterine artery pulsatility index in the first trimester and their correlation to pregnancy outcomes. MATERIAL AND METHODS: Healthy pregnant women were recruited at 12-13th gestational week ultrasound examination; UtAPI was determined by color Doppler ultrasound. Patients were divided into high (UtAPI ≥ 2.3) (n = 30) and low (n = 31) resistance groups, and pregnancies were followed until labor. Systemic oxidative/nitrative stress was estimated by measuring total peroxide level, total antioxidant capacity and nitrotyrosine level. RESULTS: Plasma total peroxide level was significantly lower (2,510 ± 39 µM vs. 2,285 ± 59 µM), total antioxidant capacity was higher (781 ± 16 mM CRE vs. 822 ± 13 mM CRE) in the high UtAPI group, which were accompanied by lower birth weight (3,317 ± 64 vs. 3,517 ± 77 g, P < 0.05). Plasma total peroxide level showed a negative correlation (by Pearson) to UtAPI (P < 0.01) and positive correlation to birth weight (P < 0.05). CONCLUSIONS: According to our results, lower systemic oxidative stress showed correlation with high UtAPI measured between the 12-13th weeks of gestation. We also found significant differences in the birth weight of healthy newborns; therefore it is worth examining this relationship in pathological pregnancies.

Prognostic value of pre-embolisation MRI features of uterine fibroids in uterine artery embolisation.

AIM: To evaluate the prognostic value of pretreatment pelvic magnetic resonance imaging (MRI) features in uterine artery embolisation (UAE) for symptomatic fibroids. MATERIALS AND METHODS: MRI characteristics of 109 fibroids (≥3 cm) in 70 patients were analysed retrospectively. Imaging was performed 1.8±1.3 (SD) months before and 6.6±1.8 months after UAE. On pretreatment images, signal intensity (SI) of fibroids was compared with that of the myometrium and skeletal muscle on T1- and T2-weighted sequences; the contrast enhancement pattern and localisation of fibroids were also analysed. Fibroid volume reduction (VR) was assessed by control imaging. The numerical analogue quality-of-life score was obtained before and after UAE. Statistical analysis was performed using the Mann-Whitney U-test, Kruskal-Wallis test, and Wilcoxon signed-rank test. RESULTS: The mean fibroid volume decreased by 51.1±30.8% during the 6.6±1.8 months (p<0.001). Mean quality-of-life score improved by 48.2±27.6 points (p<0.001). The mean VR of submucosal fibroids (82.1±18.5%) was greater than that of intramural (49.4±30.7%) and subserosal (43±28.3%) fibroids (p<0.001 for both). Fibroids that were isointense/hyperintense to myometrium on T2-weighted images showed a better response than hypointense fibroids (63.7±25.8% versus 48.6±31.3%, respectively; p=0.041). On contrast-enhanced images, isointense/hyperintense fibroids showed a better VR than hypointense fibroids (61.3±27.4% versus 47.6±31.6%, respectively; p=0.035). Baseline fibroid volume of <50 cm3 was also associated with favourable imaging outcome (p=0.021). T2 SI compared to skeletal muscle and T1 SI compared to myometrium or skeletal muscle did not show association with VR. CONCLUSIONS: Localisation, T2 SI, contrast enhancement, and <50 cm3 fibroid volume were associated with better VR; these may help with treatment decisions.

Successful management of intrauterine twin and concomitant cervical pregnancy: a case report.

Use of in vitro fertilization techniques increases the frequency of pathological implantation. However, simultaneous pregnancies are a rarity. Ectopic implantation of the embryo may occur in the cervical canal. This is the first case report, which describes successful management of an intrauterine twin pregnancy which occurred simultaneously with a cervical pregnancy. Diagnostic and therapeutic options are discussed along with the outcome of pregnancies. The cervical pregnancy was removed by aspiration, without dilation of cervical canal, which saved the lives of intrauterine fetuses and preserved fertility for following pregnancies. Finally we review the advanced methods in the literature.

Systematic investigation of different steroid precursors with respect to their effect on superoxide anion production by human neutrophil granulocytes.

Free radicals are involved in several pathological processes in living organisms, for example in athero- and oncogenesis. Some steroids are known to be effective antioxidants, while others do not play any such role. The aim of our study was to examine the antioxidant capability of different metabolites in the synthesis of steroid hormones. As a model, we chose human neutrophils producing superoxide anion, which is the source of many other radicals. Neutrophils were separated from healthy volunteers. Isolated cells were incubated with varying concentrations of steroid compounds and stimulated with N-formyl-Met-Leu-Phe. Superoxide anion production was determined by photometry. Neutrophils incubated with corticosterone and 18-hydroxy-deoxycorticosterone showed a significant reduction in superoxide production, whereas we found a significant enhancement in the presence of 11beta-hydroxyprogesterone. Furthermore, we observed a non-significant decreasing trend after incubation with cholesterol 3-sulphate and an increasing tendency using 11-hydroxyandrostenedione. We were also able to produce newer morphological and functional evidence of the role of myeloperoxidase enzyme in the steroidal antioxidant effect by electronic microscopy and use of sodium hypochlorite in our incubation model. Based on these results, we conclude that not only steroid end products but also their intermediate metabolites, most of which are also present in human plasma, partly influence free radical metabolism. Thus, this study provides further argument for the search for the molecular basis responsible for the antioxidant effect of steroid structures. This may lead to new opportunities for finding really efficient antioxidants, which might perhaps be used in a combined manner with other agents in the fight against certain life-threatening diseases.

Plasma concentration of myeloperoxidase enzyme in pre- and post-climacterial people: related superoxide anion generation.

Neutrophil granulocytes are involved in the pathogenesis of atherosclerosis also through their free radical generation. The aim of the study was to test how extracellular levels of myeloperoxidase (MPO; a granulocyte enzyme playing role in free radical production) change by age and what effect this change has on the production of the free radical superoxide anion by neutrophils. We also wanted to examine whether the antioxidant effect of different steroid hormones is realized through the MPO. Plasma myeloperoxidase concentrations of healthy blood donors were quantified by ELISA. Superoxide anion production was measured by photometry. Myeloperoxidase concentration was significantly lower in plasmas obtained from older women and men than in those from younger subjects. Adding the MPO inhibitors 4-aminobenzoic acid hydrazide (ABAH) and indomethacin to the granulocytes, the generation of superoxide anion increased and the decreasing effect of the steroids on superoxide production was inhibited. Incubating the neutrophils with the product of the reaction catalyzed by MPO itself (hypochlorite anion), we found significant decrease in superoxide generation. According to our results MPO seems to diminish the production of superoxide anion and so probably has an antioxidant ability. Therefore, its lower plasma levels may contribute to the increasing incidence of atherosclerosis and other free radical mediated disorders in old people. Thus, after further studies MPO might become one of the indicators of cardiovascular risk and the scavenger capacity in general.

Acute, nongenomic vasodilatory action of estradiol is attenuated by chronic estradiol treatment.

Deficiency of estradiol or chronic estrogen treatment may alter the responses to this hormone in many tissues. A possible interaction between the acute nongenomic and the chronic effects of estradiol on microvessels have not been investigated yet. In the present study we have investigated whether acute in vitro vasodilatory action of estradiol on a small artery is altered by chronic estradiol pretreatment. Female rats were surgically ovariectomized and subjected to either estradiol replacement therapy (estradiol propionate, 450 micrograms/kg/week) or vehicle administration for 5 weeks. Cylindrical segments of the saphenous artery were studied using videocomputerized microarteriography in vitro. Estradiol, in concentrations of 10(-6) to 10(-4) M relaxed norepinephrine precontracted vessel segments in a dose-dependent manner. Magnitude of relaxation observed in arteries of estradiol replaced animals was significantly smaller at all concentrations than that of nonreplaced ovariectomized rats; maximal relaxation in the control ovariectomized group was 64.5% +/- 3.6%, while it was 34.3% +/- 4.2% only in the ovariectomized and estradiol replaced group (P < 0.001). Comparison of acute relaxations in response to papaverine and nifedipine failed to prove a reduced activity of the general relaxation machinery in estradiol replaced animals. We conclude that chronic estradiol replacement can downregulate the acute nongenomic vasorelaxation effect of this hormone in small arteries of ovariectomized rats.

Sex hormone replacement therapy reverses decreased venous distensibility in pharmacologically ovariectomized rats.

OBJECTIVE: To test the effect of female sex hormone depletion and replacement on the distensibility and geometry of the saphenous vein in female rats. DESIGN: Twenty Sprague-Dawley rats were pharmacologically ovariectomized by triptorelin. Ten of these animals received combined hormone replacement with estradiol and medroxyprogesterone acetate. The rest were given vehicle. Ten animals kept parallel without pharmacological ovariectomy served as controls. After 3 months of treatment, a segment of the saphenous vein was dissected. Pressure-diameter curves were recorded in relaxed, contracted, and control states using a microangiograph. RESULTS: Pharmacological ovariectomy lowered venous wall distensibility measured in contraction (at P=8 mm Hg: 4.41+/-1.21*10(-3) m2/N vs. control: 0.79+/-0.14*10(-3) m2/N; p < 0.05). Hormone replacement partially restored this value (1.8+/-0.49*10(-3) m2/N). No alterations in distensibility were found in the relaxed state. After adjusting for body weight, we found that pharmacological ovariectomy lowered venous inner radius significantly compared with control (p < 0.05), whereas hormone replacement increased it compared with pharmacological ovariectomy (p < 0.05) and more significantly compared with control (p < 0.01). CONCLUSION: Sex hormone depletion induces significant alterations in venous distensibility, presumably by inducing initial remodeling of the venous wall. Hormone dependency of distensibility differed in relaxed and contracted states of the vein, so some alterations of contractile elements of the wall may be hypothesized. Lower distensibility of the venous wall found after pharmacological ovariectomy could be part of the mechanism of predisposition for postmenopausal hypertension. This can be reversed by female sex hormone replacement.

Hormone replacement reduces elevated in vivo venous tone in hypertensive ovariectomized rats.

OBJECTIVE: The venous system may play a role in the development and progression of postmenopausal hypertension. In the present study, we investigated the effect of chronic angiotensin II-induced hypertension on the geometric, elastic, and contractile properties of the saphenous vein in sex hormone deficient and replaced female rats. METHODS: Thirty Sprague-Dawley rats were ovariectomized (n = 10), ovariectomized and angiotensin-infused (n = 10), or ovariectomized plus angiotensin-infused and hormone replaced with estradiol and medroxyprogesterone (n= 10). After 4 weeks, the saphenous veins were removed and cylindrical segments of the vessels were placed into a microangiograph and cannulated at both ends. Intraluminal pressure versus outer diameter curves were registered in Krebs-Ringer solution, in maximal norepinephrine contraction, and in full papaverine relaxation. RESULTS: In vivo venous tone of the saphenous vein in ovariectomized plus angiotensin-infused animals was significantly higher than in ovariectomized animals without angiotensin treatment (27.2 +/- 3.7% versus 5.3 +/- 2.1%, respectively; P <.05). Hormone replacement restored venous tone (9.6 +/- 3.4%; P <.01). In vitro pressure-induced myogenic tone was markedly reduced by chronic angiotensin infusion, which was partially reversed by hormone replacement. Passive incremental distensibility was lowered after angiotensin infusion independently of the sex hormone state. CONCLUSION: Hormone replacement improved venous contractility (rapid adaptation response), which was seen as decreased in vivo venous tone, but venous distensibility (chronic adaptation) was not improved by hormone replacement in our short-term study. We demonstrate beneficial short-term effects of hormone replacement on the venous system in our model of postmenopausal hypertension. Further studies might be warranted to see whether long-term benefits can be achieved.

Induced myeloperoxidase activity and related superoxide inhibition during hormone replacement therapy.

OBJECTIVE: To test whether the menopause entails any changes in the myeloperoxidase activity of neutrophil granulocytes. The effects of hormone replacement therapy on myeloperoxidase activity and related changes in free radical production were also investigated. DESIGN: Laboratory investigation of the effect of oestrogen on intracellular myeloperoxidase activity and release from human neutrophil granulocytes. Analysis of related changes in superoxide anion generation. SETTING: 2nd Department of Medicine and 1st Department of Obstetrics and Gynaecology, Semmelweis University, Budapest. SAMPLES: Intracellular myeloperoxidase activity (mean peroxidase index) was measured automatically in blood samples obtained for general laboratory work-up from 135 randomly selected patients in our department. Blood samples from 11 postmenopausal women were analysed before and during hormone replacement therapy. Blood samples from 20 healthy volunteers were obtained and neutrophil granulocytes separated for in vitro measurement of superoxide anion production after adding myeloperoxidase to the incubation media. METHODS: The mean peroxidase index was measured using a Technicon H-3 instrument. myeloperoxidase release from neutrophils was quantified by ELISA technique. Superoxide production of isolated neutrophil granulocytes was measured by photometry. MAIN OUTCOME MEASURES: Intracellular activity of myeloperoxidase, concentration of myeloperoxidase-protein in supernatant of neutrophils, release of superoxide anion from neutrophil granulocytes. RESULTS: 1. Intracellular myeloperoxidase activity in neutrophils was lower in postmenopausal women, than in females with regular cycles (-1.84 +/- 3.06 versus 1.59 +/- 3.55, P < 0,001). 2. In postmenopausal women intracellular myeloperoxidase activity and myeloperoxidase release increased during hormone replacement therapy (-5.54 +/- 6.63 versus -0.2 +/- 6.05; P < 0.001 and 52.74 mU/ml +/- 25.73 versus 251.4 +/-234.1 mU/ml; P < 0.05). 3. Adding myeloperoxidase to neutrophil granulocyte suspensions, the production of superoxide anion fell (e.g. adding 280 ng/ml myeloperoxidase: 77.9 +/- 14.04 % of control production, P < 0.001). CONCLUSION: Hormone replacement restores the reduced myeloperoxidase activity in menopausal women. Adding myeloperoxidase to neutrophil granulocytes, the production of free radicals decreases.

Connexin 43 expression in rat aortic smooth muscle after ovariectomy and hormonal replacement.

The purpose of this study was to determine the effects of ovariectomy and long-term combined sexual hormone replacement on the gap junctional protein, connexin 43 (Cx43) of aortic medial smooth muscle cells in rats. Twenty non-pregnant mature Wistar female rats were divided into five groups (four animals in each group). Group A underwent ovariectomy, Group B underwent ovariectomy and received estradiol propionate, Group C underwent ovariectomy and received medroxyprogesterone acetate and Group D underwent ovariectomy and received both hormones. Group E was sham-operated and used as control. After 15 weeks of treatment, thoracic aortas were removed and immunohistochemistry was carried out using a specific fluorescent antibody against Cx43. Tissue sections were examined by confocal laser scanning microscopy and analysed by the Scion Image program. All five different groups had the same distribution and extent of Cx43 in the aorta. Neither the ovariectomy nor the hormone replacement had any effect on the Cx43 expression of aortic smooth muscle cells in rats as compared to control animals. These results indicate that sexual steroids do not influence the gap junctional protein Cx43 of the medial layer of aorta in rats. They may suggest that the beneficial effects of estrogen are not mediated via gap junctions in the human aorta either.

In vitro effects of different steroid hormones on superoxide anion production of human neutrophil granulocytes.

Neutrophil granulocytes play an important role in atherogenesis also through their free radical generation. According to recent studies, a point of action by which estrogens can provide protection against atherosclerosis is their inhibiting effect on superoxide anion production. The aim of our study was to test whether this means a common effect of steroids on superoxide production, or whether various steroid hormones have different action on superoxide generation of human granulocytes. Neutrophils were separated from the blood samples of twelve healthy volunteers. Isolated cells were incubated with different concentrations (10(-9), 10(-8), 10(-7) M) of hydrocortisone, aldosterone, cortexolone, 17-beta-estradiol, progesterone, and testosterone. Superoxide anion production was determined by photometry using the reduction of ferricytochrome-C. Compared to that of control cells neutrophils incubated with 17-beta-estradiol, progesterone, testosterone and hydrocortisone showed significantly reduced superoxide production. No significant alteration of superoxide anion production was found after the incubation of cells with aldosterone and cortexolone. It is concluded that similarly to estradiol other sex steroids and cortisol can inhibit the free radical production of human granulocytes, but mineralocorticoid aldosterone and Reichstein's substance S do not show such activity. Our results provide new evidence supporting the theory that certain types of steroid hormones have antioxidant capacity. This may give further reasons for investigating the molecular background of the existence or absence of this property and thus might lead to the development of new free radical scavengers.

Effect of ovariectomy and hormone replacement therapy on small artery biomechanics in angiotensin-induced hypertension in rats.

OBJECTIVES: To test the effects of chronic angiotensin II administration on blood pressure and small artery biomechanics in the female sex hormone-depleted state (proposed to increase cardiovascular vulnerability) and with hormone replacement. DESIGN: Biomechanical properties of saphenous artery segments from ovariectomized (n = 10), ovariectomized + chronically angiotensin II infused-(n = 10), and ovariectomized + chronically angiotensin II-infused + sex hormone-replaced (n = 10) rats were studied. METHODS: Surgical ovariectomy was performed. Osmotic minipumps were used for chronic angiotensin II infusion (100 ng/min per kg). For hormone replacement therapy, oestradiol-propionate, 450 microg/kg for 7 days + medroxyprogesterone-acetate, 15 mg/kg for 14 days were given, intramuscularly. After 4 weeks, cylindrical segments of the saphenous artery were prepared and subjected to in-vitro microarteriographic measurements. Pressure-diameter curves (0-200 mmHg) were recorded in Krebs-Ringer solution, with smooth muscle contracted (norepinephrine, 16 micromol/l) and with relaxed (papaverine, 28 micromol/l). RESULTS: Chronic angiotensin II infusion significantly reduced the inner radius (at 100 mmHg: 298 +/- 17 microm versus 347 +/- 7 microm, P< 0.001), while wall-thickness did not change. Hormone replacement restored the morphological radius (333 +/- 7 microm). Angiotensin II infusion slightly increased the full contraction range of the segments (defined as the percentage difference between fully contracted and fully relaxed diameters), which was further significantly increased by hormone replacement (39 +/- 4%, 46 +/- 8%, 62 +/- 7% at 100 mmHg, in the three groups, respectively; P < 0.05). Despite unaltered stiffness in relaxed state, elastic moduli computed for the contracted segments decreased after hormone replacement. CONCLUSIONS: These observations give further experimental support to the hypothesis that sex hormone replacement might be useful in preventing the development and/or stabilization of postmenopausal hypertension, as well as in treating existing disease.

Postmenopausal hormone replacement improves proteinuria and impaired creatinine clearance in type 2 diabetes mellitus and hypertension.

OBJECTIVE: To determine whether hormone replacement therapy can reverse established renal microvascular damage in type 2 diabetes and hypertension. DESIGN: Prospective, single centre clinical trial. SETTING: Outpatient clinics. PARTICIPANTS: Sixteen diabetic and hypertensive postmenopausal women (age 47-57 years) METHODS: Administration of a cyclic combination of oestradiol and norgestrel orally for 3.5 monthly cycles. RESULTS: Comparing the baseline values, mean (SD) 24-hour urine protein excretion was reduced from 0.452 g (0039) to 0.370 g (0.047) (P < 0.01) and creatinine clearance was increased from 1.68 mL/sec (0.11) to 1.77 mL/sec (0.08) (P < 0.05). Fasting plasma glucose also improved from 6.92 mmol/L (0.47) to 6.51 mmol/L (0.28) (P < 0.05), as did serum total cholesterol from 7.26 mmol/L (0.28) to 6.65 mmol/L (0.14) (P < 0.05). Blood pressure did not change significantly. Univariate linear regression analysis showed no significant correlation between the individual changes in blood pressure, fasting plasma glucose or serum cholesterol and the individual changes in proteinuria or creatinine clearance. CONCLUSIONS: This study shows that hormone replacement therapy may reduce proteinuria, and even improve creatinine clearance, in diabetic and hypertensive postmenopausal women. These effects are additive to nephroprotective therapy, and the mechanisms appear unrelated to conventional risk factors for vascular complications, such as high blood pressure, elevated plasma glucose or serum cholesterol.

Effects of combined sex hormone replacement therapy on small artery biomechanics in pharmacologically ovariectomized rats.

OBJECTIVES: The purpose of this study was to determine the effects of long-term combined sexual hormone replacement therapy on the biomechanical properties of the small artery wall in castrated female rats. METHODS: 30 non-pregnant mature female Sprague-Dawley rats were pharmacologically ovariectomized with 750 microg/kg triptorelin im. every 4th week. Ten of them received combined hormone replacement in form of 15 mg/kg medroxyprogesterone acetate (MPA) im. every 2 weeks and 450 microg/kg estradiol propionate im. once a week. Ten castrated animals received MPA only. Ten control, castrated animals were given the vehicles of these steroids. Ten other animals were kept parallelly, receiving the vehicles of all drugs (control animals). After 12 weeks of treatment cylindrical segments of the saphenous artery were isolated and cannulated at both ends and subjected to in vitro microarteriographic test. Pressure diameter curves, in the range of 0-200 mmHg, were recorded from segments in normal Krebs-Ringer (nKR) solution, in contraction with norepinephrine (1.6 x 10(-5) M), and then in relaxation with papaverine (2.8 x 10(-5) M). Biomechanical parameters were calculated based on the pressure diameter curves. RESULTS: Combined hormone replacement therapy significantly increased the passive diameter of small arteries, as compared to those from ovariectomized animals without hormone replacement. MPA monotherapy did not alter the vessel diameter, the inner radii at 100 mmHg intraluminal pressure were, 300+/-9 microm in the control castrated, 340+/-7 microm in the estradiol + MPA replaced and 306+/-8 microm in the MPA treated groups (P < 0.05 between the control castrated and the combined treatment groups). The vascular reactivity to norepinephrine or papaverine was not changed significantly either by combined hormone replacement or by MPA monotherapy when compared with ovariectomized controls. No significant alterations were found in wall thickness and distensibility. CONCLUSIONS: These results suggest that chronic medroxyprogesterone pretreatment does not influence the geometric, elastic and contractile properties of small arteries in castrated female rats. The combination of MPA + estradiol increased the morphological lumen: the morphological vasodilatation induced by estrogen, described earlier, was not affected by the addition of this progestin to the regimen.

The effect of ovariectomy and oestrogen replacement on small artery biomechanics in the rat.

OBJECTIVE: To determine the effects of oestrogen deficiency and hormone replacement therapy on the biomechanical properties of a small artery. SAMPLE: Thirty non-pregnant female Sprague-Dawley rats. METHODS: Twenty animals were pharmacologically ovariectomised by triptorelin and received either oestradiol propionate or its vehicle. Ten other animals received only the vehicle for the same period of time (control group). After 12 weeks of treatment, cylindrical segments of the saphenous artery were isolated and cannulated at both ends. Pressure-diameter curves were recorded from segments in normal Krebs-Ringer, using norepinephrine, and then with papaverine. The vessel segment close to the examined one was histologically evaluated. Serum levels of oestradiol and cortisol were determined. MAIN OUTCOME MEASURES: Biomechanical parameters based on the pressure-diameter curves. RESULTS: Pharmacological ovariectomy decreased the passive diameter of the arteries and oestrogen replacement therapy prevented this. Decreased reactivity to norepinephrine was also restored by oestrogen treatment. Pressure induced myogenic tone was decreased significantly by oophorectomy and increased after oestradiol treatment. No significant changes were found in wall thickness, distensibility, elastic modulus or tangential stress. No significant histological alterations were seen in the vessel wall. Oestradiol levels were significantly decreased in the castrated animals compared with the other two groups. CONCLUSIONS: These results suggest that oestrogen deficiency decreases and oestrogen replacement increases the passive diameter of small peripheral arteries, and that oestrogen enhances the reactivity of vascular smooth muscle. These responses may provide the background mechanisms for the increased incidence of arterial hypertension and hot flushes during the menopause and the ability of oestrogen substitution to prevent them.

Direct relaxing effect of estradiol-17beta and progesterone on rat saphenous artery.

Although estrogen has been reported to relax large coronary arteries immediately, its direct acute effect on small vessel tone has not been fully defined. In this study, we investigated the effect of estradiol-17beta and progesterone on isolated rat saphenous artery segments-with an internal radius of 250 microm-by measuring the outer diameter of the vessels using in vitro angiometry. Estradiol and progesterone at concentrations of 1-100 and 8.6-86 microM induced a rapid, dose-dependent relaxation of the arterial segments precontracted with norepinephrine. Maximal changes of diameters were 85.8 +/- 10 and 90.9 +/- 8%. Clomiphene citrate, a cytoplasmic receptor antagonist, did not diminish this action of estradiol, with the exception of the highest concentrations of the hormone. Thus a nongenomic pathway for this effect can be suspected. Dexamethasone did not induce similar vasodilation. It is concluded that estradiol and progesterone have similar rapid vasorelaxing effects on small muscular arteries as found previously on coronary arteries.