Influence of Vitamin D on the Vasoactive Effect of Estradiol in a Rat Model of Polycystic Ovary Syndrome.

We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D-animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.

Vitamin D Deficiency Reduces Vascular Reactivity of Coronary Arterioles in Male Rats.

BACKGROUND: Vitamin D deficiency (VDD) may be considered an independent cardiovascular (CV) risk factor, and it is well known that CV risk is higher in males. Our goal was to investigate the pharmacological reactivity and receptor expression of intramural coronary artery segments of male rats in cases of different vitamin D supply. METHODS: Four-week-old male Wistar rats were divided into a control group (n = 11) with optimal vitamin D supply (300 IU/kgbw/day) and a VDD group (n = 11, <0.5 IU/kgbw/day). After 8 weeks of treatment, intramural coronary artery segments were microprepared, their pharmacological reactivity was examined by in vitro microangiometry, and their receptor expression was investigated by immunohistochemistry. RESULTS: Thromboxane A2 (TXA2)-agonist induced reduced vasoconstriction, testosterone (T) and 17-ß-estradiol (E2) relaxations were significantly decreased, a significant decrease in thromboxane receptor (TP) expression was shown, and the reduction in estrogen receptor-α (ERα) expression was on the border of significance in the VDD group. CONCLUSIONS: VD-deficient male coronary arteries showed deteriorated pharmacological reactivity to TXA2 and sexual steroids (E2, T). Insufficient vasoconstrictor capacity was accompanied by decreased TP receptor expression, and vasodilator impairments were mainly functional. The decrease in vasoconstrictor and vasodilator responses results in narrowed adaptational range of coronaries, causing inadequate coronary perfusion that might contribute to the increased CV risk in VDD.

Effects of vitamin D3 derivative--calcitriol on pharmacological reactivity of aortic rings in a rodent PCOS model.

BACKGROUND: The aim of this study was to examine the effects of the hyperandrogenic state in dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS), the vascular responses to different vasoactive agents, and the modulatory role of vitamin D3. METHODS: APCOS model was induced by DHT application in 20 female Wistar rats. Ten of the DHT treated rats simultaneously received calcitriol treatment. After 10 weeks, myographs were used to test the reactivity of isolated thoracic aortic rings to norepinephrine and acetylcholine. Thereafter, the vascular rings were incubated with the NO-synthase blocker (nitro-L-arginine methyl ester) or the cyclooxygenase inhibitor (indomethacin) for 20 min, and the effects of norepinephrine and acetylcholine were re-evaluated. RESULTS: Norepinephrine-induced vasoconstriction was enhanced after DHT treatment, but this effect was attenuated by calcitriol administration. Vasorelaxation of DHT-treated thoracic aortic rings was impaired, but this could be partly reversed by calcitriol application. Impaired NO-dependent vasorelaxation in DHT-treated animals was mostly reversed by concomitant calcitriol administration, but this effect was diminished by prostanoid-dependent vasoconstriction. CONCLUSIONS: These studies show that the enhanced sensitivity to vasoconstrictors and impaired NO-dependent vasorelaxation in hyperandrogenic PCOS rats could be partially reversed by calcitriol treatment.

Endothelial relaxation mechanisms and nitrative stress are partly restored by Vitamin D3 therapy in a rat model of polycystic ovary syndrome.

AIMS: In polycystic ovary syndrome (PCOS), metabolic and cardiovascular dysfunction is related to hyperandrogenic status and insulin resistance, however, Vitamin D3 has a beneficial effect partly due to its anti-oxidant capacity. Nitrative stress is a major factor in the development of cardiovascular dysfunction and insulin resistance in various diseases. Our aim was to determine the effects of vitamin D3 in a rat model of PCOS, particularly the pathogenic role of nitrative stress. MAIN METHODS: Female Wistar rats weighing 100-140g were administered vehicle (C), dihydrotestosterone (DHT) or dihydrotestosterone plus vitamin D3 (DHT+D) (n=10 per group). On the 10th week, acetylcholine (Ach) induced relaxation ability of the isolated thoracic aorta rings was determined. In order to examine the possible role of endothelial nitric oxide synthase (eNOS) and cyclooxygenase-2 (COX-2) pathways in the impaired endothelial function, immunohistochemical labeling of aortas with anti-eNOS and anti-COX-2 antibodies was performed. Leukocyte smears, aorta and ovary tissue sections were also immunostained with anti-nitrotyrosine antibody to determine nitrative stress. KEY FINDINGS: Relaxation ability of aorta was reduced in group DHT, and vitamin D3 partly restored Ach induced relaxation. eNOS labeling was significantly lower in DHT rats compared to the other two groups, however COX-2 staining showed an increment. Nitrative stress showed a significant increase in response to dihydrotestosterone, while vitamin D3 treatment, in case of the ovaries, was able to reverse this effect. SIGNIFICANCE: Nitrative stress may play a role in the pathogenesis of PCOS and in the development of the therapeutic effect of vitamin D3.

Reduced estradiol-induced vasodilation and poly-(ADP-ribose) polymerase (PARP) activity in the aortas of rats with experimental polycystic ovary syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by hyperandrogenism and insulin resistance, both of which have been connected to atherosclerosis. Indeed, an increased risk of clinical manifestations of arterial vascular diseases has been described in PCOS. On the other hand endothelial dysfunction can be detected early on, before atherosclerosis develops. Thus we assumed that vascular dysfunction is also related directly to the hormonal imbalance rather than to its metabolic consequences. To detect early functional changes, we applied a novel rodent model of PCOS: rats were either sham operated or hyperandrogenism was achieved by implanting subcutaneous pellets of dihydrotestosterone (DHT). After ten weeks, myograph measurements were performed on isolated aortic rings. Previously we described an increased contractility to norepinephrine (NE). Here we found a reduced immediate relaxation to estradiol treatment in pre-contracted aortic rings from hyperandrogenic rats. Although the administration of vitamin D3 along with DHT reduced responsiveness to NE, it did not restore relaxation to estradiol. Poly-(ADP-ribose) polymerase (PARP) activity was assessed by poly-ADP-ribose immunostaining. Increased PAR staining in ovaries and circulating leukocytes from DHT rats showed enhanced DNA damage, which was reduced by concomitant vitamin D3 treatment. Surprisingly, PAR staining was reduced in both the endothelium and vascular smooth muscle cells of the aorta rings from hyperandrogenic rats. Thus in the early phase of PCOS, vascular tone is already shifted towards vasoconstriction, characterized by reduced vasorelaxation and vascular dysfunction is concomitant with altered PARP activity. Based on our findings, PARP inhibitors might have a future perspective in restoring metabolic disorders in PCOS.

Altered insulin-induced relaxation of aortic rings in a dihydrotestosterone-induced rodent model of polycystic ovary syndrome.

OBJECTIVE: To clarify the effects of dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS) on the insulin-dependent vasodilatation of the thoracic aorta and the role of vitamin D in a rat model. DESIGN: Controlled experimental animal study. SETTING: Laboratory. ANIMAL(S): Thirty adolescent female Wistar rats. INTERVENTION(S): The PCOS model was induced by 10 weeks of DHT treatment (83 µg/d). One-half of the DHT-treated animals also received vitamin D (120 ng/kg/wk). MAIN OUTCOME MEASURE(S): The aortic rings of the control, DHT, and DHT plus vitamin D-treated animals were isolated. The insulin-dependent vasodilation of the isolated aortic rings was compared in Krebs-Ringer solution and under blockade of nitric oxide (NO) synthase or cyclooxygenase. RESULT(S): The insulin-dependent vasorelaxation decreased in both DHT-treated groups independently from the vitamin D treatment; NO-dependent and -independent relaxations were both impaired. In response to prostanoid, vasoconstriction was increased after DHT treatment. The NO-independent relaxation was partially improved by vitamin D treatment, which was neutralized by increased prostanoid-dependent vasoconstriction. CONCLUSION(S): Previously, we found that vitamin D treatment prevented systemic insulin resistance; however, in this study, we did not detect any influence on the vascular insulin resistance of the aorta that was induced by DHT treatment. Consequently, controlling insulin resistance with vitamin D alone did not resolve the aortic endothelial dysfunction caused by the hyperandrogenic state.

Pharmacological reactivity of resistance vessels in a rat PCOS model - vascular effects of parallel vitamin D3 treatment.

The aim of this study was to clarify the effects of dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS) on pharmacological reactivity of a resistance vessel in a rat model and the possible modulatory role of 1,25-(OH)2-cholecalciferol (vitamin D3). The PCOS model was induced in adolescent female Wistar rats by a 10-week DHT treatment. Norepinephrine induced contractility and acetylcholine relaxation were tested in arterioles by pressure arteriography in control as well as DHT- and DHT plus vitamin D3-treated (DHT+D3) animals. Decreased vasoconstriction and dilatation were detected after DHT treatment. Concomitant vitamin D3 treatment increased the contractile response and resulted in more relaxed vessels. Endothelial dilation tested with acetylcholine was lower after DHT treatment, this effect was not depend on vitamin D3 supplementation. In conclusion, hyperandrogenic state resulted in reduced endothelium- and smooth muscle-dependent vasorelaxation and constriction with a complete loss of nitric oxide (NO)-dependent relaxation compared with controls. These alterations caused by chronic DHT treatment were partially reversed by concomitant vitamin D3 administration.

Arteriolar insulin resistance in a rat model of polycystic ovary syndrome.

OBJECTIVE: To investigate the vascular dysfunction caused by insulin resistance in polycystic ovary syndrome (PCOS) and the effectiveness of vitamin D in an animal model. DESIGN: Controlled experimental animal study. SETTING: Animal laboratory at a university research institute. ANIMAL(S): Thirty female Wistar rats. INTERVENTION(S): Rats were divided into groups at age 21-28 weeks. Twenty of them were subjected to dihydrotestosterone (DHT) treatment (83 µg/d); ten of them also received parallel vitamin D treatment (120 ng/100 g/wk). Oral glucose tolerance tests with insulin level measurements were performed. Gracilis arterioles were tested for their contractility as well as their nitric oxide (NO)-dependent and insulin-induced dilation using pressure arteriography. MAIN OUTCOME MEASURE(S): Several physiologic parameters, glucose metabolism, and pressure arteriography. RESULT(S): DHT treatment increased the passive diameter of resistance arterioles, lowered norepinephrine-induced contraction (30.1 ± 4.7% vs. 8.7 ± 3.6%) and reduced acetylcholine-induced (122.0 ± 2.9% vs. 48.0 ± 1.4%) and insulin-induced (at 30 mU/mL: 21.7 ± 5.3 vs. 9.8 ± 5.6%) dilation. Vitamin D treatment restored insulin relaxation and norepinephrine-induced contractility; in contrast, it failed to alter NO-dependent relaxation. CONCLUSION(S): In DHT-treated rats, in addition to metabolically proven insulin resistance, decreased insulin-induced vasorelaxation was observed and was improved by vitamin D treatment without affecting NO-dependent relaxation. The reduction in insulin-induced dilation of arterioles is an important as yet undescribed pathway of vascular damage in PCOS and might explain the clinical effectiveness of vitamin D treatment.

Effects of metoprolol CR/XL on mortality and hospitalizations in patients with heart failure and history of hypertension.

BACKGROUND: We describe the effect of controlled-release/extended-release (CR/XL) metoprolol succinate once daily on mortality and hospitalizations among patients with a history of hypertension complicated by chronic systolic heart failure. METHODS AND RESULTS: We enrolled 3,991 patients with chronic heart failure of New York Heart Association functional class II-IV with an ejection fraction of < or = 0.40, stabilized with optimum standard therapy, in a double-blind randomized placebo-controlled study. A total of 1,747 patients (44%) had a history of hypertension; 871 were randomized to receive metoprolol CR/XL and 876 to receive placebo. Treatment with metoprolol CR/XL compared with placebo resulted in a significant reduction in total mortality (relative risk [RR], 0.61; 95% confidence interval [CI], 0.44-0.84; P =.0022), mainly because of reductions in sudden death (RR, 0.51; 95% CI, 0.33-0.79; P =.0022) and mortality from worsening heart failure (RR, 0.49; 95% CI, 0.25-0.99; P =.042). Total number of hospitalizations for worsening heart failure was reduced by 30% in the metoprolol CR/XL group compared with placebo (P =.015). Metoprolol CR/XL was well tolerated: 12% fewer patients withdrew from study medication (all-cause) compared with placebo (P =.048). CONCLUSIONS: A subgroup analysis of MERIT-HF shows that patients with heart failure and a history of hypertension received a similar benefit from metoprolol CR/XL treatment as all patients included in the total study.

[Hypertension and menopause]. / Hypertonia és menopausa.

Cardiovascular disease is the leading cause of death among men and women. The cardiovascular risk of the women reaches the men of same age after the menopause. Hypertension is one of the most powerful and prevalent contributor of ahterosclerotic cardiovascular disease. Hypertension affects more men than women until 55 years of age, but after 55 the percentage of women is higher. Estrogen deficiency has been linked to the rapid progression of cardiovascular risk of women after menopause. The biological background of protective effects of estrogen is not fully, but mainly understood yet. It may involve direct effects on blood vessels through modulation of endogen vasoconstrictors and vasodilators, accompanied by systematic effects of the hormone. The main effect of these influences protects the cardiovascular system. After menopause, loss of this protection may unmask a population of women prone to hypertension, who would be at higher risk for cardiovascular disease. The guidelines make no differences apart form gestational hypertension between men and women. This review would like to focus on the clinical relevance and characteristics of postmenopausal hypertension according to the literature.