Suzan Emel Usanmaz

Neurotoxic effects of acute and subacute formaldehyde exposures in mice

In this study, the effects of acute and subacute formaldehyde (FA) exposures on spontaneous locomotor activity (SLMA), wet dog shake (WDS) behavior and pentylenetetrazole (PTZ) induced seizures were evaluated in Balb/C mice. SLMA was concentration dependently reduced after acute FA exposures at 1.8, 3.2, 4.5, 6.4, 9.7, and 14.8 ppm. The incidence of WDS behavior was increased only after acute FA exposures at 1.8, 3.2 and 6.4-ppm. PTZ-injections caused more intensive seizures in mice acutely exposed to FA only at 1.8 ppm. Meanwhile, the incidence of PTZ induced seizures was significantly lower after acute FA exposure at 14.8 ppm. SLMA was also reduced after subacute FA exposure at 2.0 ppm for 3 weeks. The inhibitory effects were significant after 1-week exposure at this concentration, but a tolerance developed at the end of the second week. As the concentration increased to 3.2 ppm, SLMA has found to be reduced after 2-week exposure. There was no change either on the incidence of WDS or on the parameters of PTZ-induced seizures, due to the subacute exposures of FA at the respective concentrations. In conclusion, based upon these data, acute and subacute exposures of FA produce a significant behavioral depression on mice. The data also suggest that acute FA exposures at low concentrations (such as 1.8 ppm) may increase the excitability of central nervous system (CNS).

Assessment of the Endothelial Functions in Monocrotaline-induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a life-threatening disease that causes endothelial dysfunction in the pulmonary vascular bed. Systemic endothelial dysfunction has also been reported in PH. This study compared the systemic and pulmonary vascular responses and some blood biomarkers of endothelial function in monocrotaline (MCT)-induced PH of rats. It also investigated the effect of sildenafil and iloprost treatment. MCT application induced elevation in the right ventricular pressures of the rat heart that had been reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated pulmonary artery were decreased in the PH group and this failure was reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated thoracic aorta were similar in all groups. Serotonin-induced contractions of the pulmonary artery were augmented by PH. In the isolated aorta, serotonin-stimulated contraction was not different in the control and MCT groups, but sildenafil and iloprost treatment decreased serotonin responses. The nitric oxide (NO) level in systemic circulation was not significantly changed by PH. However, sildenafil and iloprost treatments caused a decrease in the plasma level of NO. Asymmetric dimethylarginine levels in plasma were significantly decreased after MCT application and were not recovered by sildenafil and iloprost treatment. Total antioxidant capacity and H2S level of plasma were similar in all groups. Results of this study showed that MCT-induced PH caused specific toxic effects on pulmonary vasculature without any functional effects on the aorta. In addition, it was also demonstrated that sildenafil and iloprost treatments were effective in the MCT-induced PH.

Plasma nitric oxide level is correlated with microvascular functions in the peripheral arterial disease

At present there is no widely accepted biomarker for monitoring of vascular functions. The purpose of this prospective study was to investigate the association of some blood biomarkers with vascular reactivity in patients with peripheral arterial diseases (PAD). A prospective evaluation was made of 3 groups comprising a control group of healthy individuals, and patients with PAD caused by either atherosclerosis or Buergers disease. Microvascular perfusion was examined using laser Doppler imaging of cutaneous erythrocyte flux after iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). The correlation of microvascular reactivity with endothelium-related biomarkers was assessed. ACh-induced and SNP-induced vasodilations were significantly diminished in the PAD groups. The plasma nitric oxide (NO) levels of PAD patients were significantly higher than those of the control group, but asymmetric dimethylarginine, total antioxidant capacity and hydrogen sulphide levels were similar. Plasma NO level was negatively correlated with ACh and SNP-stimulated microvascular flow increase, whereas a positive correlation was detected with blood glucose and glycated hemoglobin (HbA1c) levels in all groups. These results indicate that a high plasma level of NO in PAD patients is associated with diminished endothelium-dependent and independent flow increase in the microvascular bed. An excessive amount of NO-induced nitrosative stress in an inflammatory condition that might be a reason for vascular dysfunction should be taken into consideration in the diagnostic and therapeutic approaches to PAD.

The effects of resveratrol and exercise on age and gender-dependent alterations of vascular functions and biomarkers

&NA; The purpose of this study was to determine the effects of resveratrol and regular aerobic exercise on vascular functions and biomarkers related to vessel responsiveness in an age and gender‐dependent manner. The study used young (3 months) and old (12 months) male and female Wistar albino rats. Resveratrol was given in the drinking water (0.05 mg/ml; approximately 7.5 mg/kg) for 6 weeks. In the exercise group, all rats performed treadmill running at 20 m/min on a 0° incline, 40 min/day, 3 times a week, for 6 weeks. Acetylcholine‐induced, endothelium‐dependent and sodium nitroprusside‐mediated, endothelium‐independent relaxations of rat thoracic aorta and blood levels of biomarkers were separately changed by resveratrol intake and exercise‐training in an age and gender‐dependent manner. Antioxidant enzymes and eNOS expressions in vessels were elevated by resveratrol and exercise. Resveratrol and exercise enhanced gene expressions of non‐selective PDE1, 2, 3 and cAMP selective PDE4 but not cGMP selective PDE5 in the aorta. In addition, the aortic mRNA expression of inflammation markers were altered by resveratrol and exercise‐training. The results of the study demonstrated that vessel responsiveness and biomarkers related to vascular functions were altered by resveratrol consumption and exercise‐training in an age and gender‐dependent manner. HighlightsResveratrol consumption and exercise‐training changed the vessel responsiveness.The aortic expression of genes was changed by resveratrol and exercise.Biomarkers related to vascular functions were altered by resveratrol and exercise.The effects of resveratrol and exercise on the vessel were age and sex‐dependent.

Age- and sex-dependent alteration of functions and epigenetic modifications ofvessel and endothelium related biomarkers

Aging is a main risk factor for development of cardiovascular diseases associated with the impairment of endothelial function in both sexes. In the present study, age-related changes in vascular responsiveness, epigenetic modifications of vessel wall, and blood biomarkers related to endothelial functions were examined in an age- and sex-dependent manner. Acetylcholine (ACh)-induced relaxations of the aorta were decreased in 3-, 6-, and 12-month-old rats compared to those in 1-month-old female rats. In males, maximum relaxations related to ACh were higher in 1- and 6-month-old rats than in 3- and 12-month-old rats. Plasma levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA) decreased with age in female rats, and total antioxidant capacity (TAC) and hydrogen sulfide (H 2S) levels displayed biphasic alterations. In male rats, plasma levels of NO, TAC, and ADMA decreased with age, and H2S levels increased. Aging also caused a sex-dependent alteration in epigenetic modification of vessels. Expressions of H3K27me2, H3K27me3, H3K36me2, and H3K36me3 were much higher in vessels of 12-month-old female rats compared to those in younger age groups. These results indicate that vascular functions, epigenetic modifications of vessels, and plasma levels of endothelium-related biomarkers are affected by age and sex. These findings could be important for the assessment of vascular status over the course of the life span.

The effects of LXR agonist GW3965 on vascular reactivity and inflammation in hypertensive rat aorta

Aims: Liver X receptors (LXRs) play an important role in the regulation of cholesterol, fatty acid and glucose metabolisms together with inflammatory processes. In the present study, the effects of LXR agonist GW3965 on vascular reactivity and expression of functional proteins in DOCA‐Salt induced hypertension were examined. Main methods: Hypertension was induced through unilateral nephrectomy and deoxycorticosterone‐acetate (DOCA) injection (20 mg/kg, twice a week) for 6 weeks in male Wistar albino rats (8 weeks old). An LXR agonist GW3965 (10 mg/kg/day, i.p.) was administered to animals for last seven days. Key findings: GW3965 treatment reduced systolic blood pressures in hypertensive rats. Acetylcholine‐induced endothelium‐dependent and sodium nitroprusside‐induced endothelium‐independent vasorelaxations were decreased in hypertensive rats but not affected by GW3965. GW3965 treatment enhanced plasma nitrite levels in normotensive rats. KCl and phenylephrine (Phe)‐induced vasocontractions were reduced in hypertensive groups and increased with GW3965 treatment. Decreased sarco/endoplasmic reticulum Ca2+‐ATPase2 (SERCA2) expression in the hypertensive aorta was not changed by GW3965 treatment. Expression of inositoltrisphosphate receptor1 (IP3R1) was increased by GW3965 in normotensive animals. The nuclear factor kappaB (NF‐&kgr;B) and tumor necrosis factor alpha (TNF‐&agr;) expressions were increased in hypertensive rats and reduced by GW3965 treatment. Significance: The results of study indicate that the LXR agonist, GW3965, exhibited a beneficial effect on increased blood pressure and improved hypertension‐induced impairment in contractile activity of vessel and inflammatory markers in vascular tissue. Therefore, these effects of LXR agonists on vessel should be taken into account in experimental or therapeutic approaches to hypertension.

Time-Dependent Production of Endothelium-Related Biomarkers is Affected Differently in Hemorrhagic and Septic Shocks

Shock is associated with inflammation-induced endothelial dysfunction. The aim of this study was to determine time-dependent alteration of blood biomarkers related to endothelial function in hemorrhagic and septic shocks. Hemorrhagic shock was induced by bleeding the animals. A cecal ligation and incision model was used to induce septicemia. Resuscitation was carried out by infusion of lactated Ringer’s solution. Resuscitation extended survival time in both shock groups. Blood pressure increased by resuscitation in the hemorrhagic shock but not in the septic shock. While hemorrhage caused a decrease in plasma levels of nitric oxide (NO) and hydrogen sulfide (H2S), asymmetric dimethylarginine (ADMA) and total antioxidant capacity (TAC) levels were increased. Only NO and TAC levels at the late phase were reversed by resuscitation. On the other hand, plasma levels of NO, ADMA, and TAC were increased by septicemia and resuscitation did not alter the septicemia-induced increase. These results indicate that blood biomarkers related to endothelial function were differentially affected by hemorrhage and septicemia. The time scale of biomarker production should be taken into consideration for the diagnostic and therapeutic approaches to these life-threatening diseases.