Buket Demirci

Blockade of angiotensin II provides additional benefits in hypertension- and ageing-related cardiac and vascular dysfunctions beyond its blood pressure-lowering effects.

Objectives To assess the blockade of the renin–angiotensin system (RAS) or blood pressure-lowering on cardiovascular functions in hypertensive and ageing animals. Methods Male spontaneously hypertensive rats (SHR) and their normotensive counterparts, Wistar–Kyoto rats (WKY), at the ages of 3–4 (young), 34–35 (adult) and 74–75 (old) weeks were treated with an angiotensin II type 1 receptor antagonist, losartan (25 mg/kg) or a combination of a smooth muscle relaxant and a diuretic [H/H, hydralazine (50 mg/kg) plus hydrochlorothiazide (7.5 mg/kg), respectively] for 8 weeks. Each experimental group contained 10 SHR and 10 WKY, where equal numbers of untreated animals served as controls. Results Compared to age-matched WKY groups, SHR groups possessed, on average, 48 ± 7 mmHg and 57 ± 16 mmHg (P < 0.05) higher systolic blood pressure and left ventricular developed pressures, respectively. The values of these parameters were significantly lowered in both strains by both treatment regimens. SHR had higher heart rates, which were increased by H/H treatment selectively in adult and old animal groups of both strains. Both treatment regimens enhanced KCl-mediated, that is, receptor-independent, aortic contractile responses and bradykinin-mediated coronary vasodilatation in adult and old WKY and SHR age-groups. Although both therapies augmented endothelium-dependent and endothelium-independent relaxant responses in young and adult, but not in old, SHR aortas to the levels observed in age-matched WKY, these beneficial effects were more prominent with losartan. Moreover, losartan reduced heart to body weight ratio in all SHR age groups, and selectively in the old WKY group. Conclusions Blockade of RAS provides a better protective effect on cardiovascular function compared to sole reduction of blood pressure, and the efficacy of antihypertensive treatment is dictated by age and the hypertensive stage of the animals.

S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers

This study examined the value of blood marker S100A1 in detecting cardiotoxicity induced by chemotherapy agents; trastuzumab and lapatinib, in normal rat heart. The rats were divided into three groups: control (n = 8, no treatment), T (n = 8, one time ip treatment with 10 mg/kg trastuzumab) and L (n = 8, oral treatment with 100 mg/kg/day lapatinib for 7 days). The activities of oxidative stress parameters Malondialdehyde (MDA), Superoxide dismutase (SOD), Catalase (CAT) and Glutathione (GSH) were measured from the extracted cardiac tissues. The levels of troponinI and S100A1 expressions were measured from blood samples. All biomarkers responded to the treatments as they exhibited alterations from their normative values, validating the chemically induced cardiotoxicity. S100A1 expression attenuated significantly (75%), which made the sensitive detection of cardiotoxicity feasible. Assessment of cardiotoxicity with S100A1 may be a valuable alternative in clinical oncology of cancers in some organs such as breast and prostate, as they do not overexpress it to compete against.

Protective effect of vitamin B5 (dexpanthenol) on cardiovascular damage induced by streptozocin in rats

OBJECTIVES This study investigated whether Dexpanthenol (DEX) improves diabetic cardiovascular function and cardiac performance by regulating total oxidant and antioxidant status. METHODS Diabetes was induced by a single intraperitoneal injection of Streptozocin (50 mg/kg in 1 ml of saline) and treatment groups received DEX (300 mg/kg/day) for 6 weeks. Endothelium (in)dependent relaxation responses were assessed in thoracic aortic rings and coronary vasculature together with alpha receptor and voltage dependant contractile responses of aorta. Myocardial contractility has been recorded by an intra ventricular latex balloon. Total oxidant and antioxidant status were measured from the serum samples. RESULTS Induction of diabetes resulted in an apparent body weight loss, high blood glucose, endothelial dysfunction and increased serum oxidant status. DEX supplementation restored the endothelial dysfunction, antioxidant status and body weight whereas decreasing blood glucose level. CONCLUSION Along with the standard therapy of diabetes, DEX can be used as a safe and economical way of adjuvant therapy to diminish the burden of the disease (Tab. 3, Fig. 3, Ref. 30).

Protective effect of Pycnogenol on cisplatin-induced ototoxicity in rats.

Abstract Context: Pycnogenol®, which is French maritime pine bark extract, is a potent antioxidant. It is used in medical conditions caused by oxidative stress. Cisplatin (cis-diamminedichloroplatinum II) is an antineoplastic agent. However, its serious side effects such as ototoxicity limit its usage. Objective: Antioxidants can be used to prevent ototoxicity. We investigated the effect of Pycnogenol® on cisplatin-induced ototoxicity. Materials and methods: Rats were randomly assigned to four groups of five. Distortion product-evoked otoacoustic emissions (DPOAE) test was performed for each rat. The experimental groups were as follows: Control Group, Pycnogenol® Group: 10 mg/kg Pycnogenol® intraperitoneally for 7 days, Cisplatin Group: intraperitoneally 15 mg/kg single injection of cisplatin on the fifth day, Cisplatin + Pycnogenol® Group: intraperitoneally 10 mg/kg Pycnogenol® treatment for 7 days, additionally on the fifth day, 15 mg/kg single injection of cisplatin was given. On the eighth day, DPOAE was re-performed and rats were sacrificed. Apoptosis was evaluated histopathologically. Results: Mean percentage of apoptotic cells was 1.5, 3, 30 and 11% in organ of Corti and 2, 2, 40, 15% in spiral ganglion neurons in Control Group, Pycnogenol® Group, Cisplatin Group and Cisplatin + Pycnogenol® Group, respectively. Cisplatin Group and Cisplatin + Pycnogenol® Group were significantly different when compared to Control Group histopathologically both in organ of Corti and spiral ganglion neuron (p <0.001, p = 0.019, p = 0.001, p = 0.015). DPOAE results showed that Cisplatin + Pycnogenol® Group was significantly different when compared to Cisplatin Group at 3, 6 and 8 kHz (p < 0.05). Conclusion: Pycnogenol protected against cisplatin ototoxicity. Also, pycnogenol is not ototoxic.

Biochemical and Histological Effects of Thiamine Pyrophosphate against Acetaminophen-Induced Hepatotoxicity.

The aim of this study was to investigate whether thiamine pyrophosphate (TPP) has biochemical and histological preventive effects on oxidative liver damage induced by paracetamol (APAP). Rats were divided into the following groups: healthy control (HG), APAP (AG, 1500 mg/kg, orally), thiamine pyrophosphate (TPPG, 100 mg/kg, intraperitoneally), APAP+NAC (ANAC, 100 mg/kg, intraperitoneally), APAP+TPP (ATPG) and APAP+NAC+TPP (ANTG). Oxidant, antioxidant parameters, liver function tests and histological assessment were performed between groups. Malondialdehyde levels in the AG, HG, TPPG, ANAC, ATPG and ANTG groups were 0.470 ± 0.210, 0.213 ± 0.004, 0.194 ± 0.001, 0.197 ± 0.06, 0.199 ± 0.008 and 0.173 ± 0.010 μmol/g protein, respectively. Total glutathione levels were 7.787 ± 0.395, 14.925 ± 0.932, 13.200 ± 0.984, 13.162 ± 0.486, 13.287 ± 0.787 and 13.500 ± 0.891 μm/g protein, respectively. In the AG group, marked liver damage occurred with the elevation of liver function tests and oxidative stress markers, such as malondialdehyde, myeloperoxidase and nitric oxide (p < 0.05). Biochemical results were congruent with the histological changes of oxidative damage. Compared to the AG group (p < 0.05), TPP significantly reduced oxidant parameter levels in the ATPG group and simultaneously increased the antioxidant parameter levels of catalase and glutathione. The histological changes were improved to almost normal hepatic structure. Moreover, TPP had nearly the same hepatoprotective effect as NAC, and there was statistically no additional benefit with NAC co‐treatment. There was no statistically significant difference (p > 0.05) among the ANAC, ANTG and ATPG groups in terms of oxidant/antioxidant levels. TPP proved to be as efficacious as standard therapy and may be beneficial in APAP‐induced hepatotoxicity.

Silymarin improves vascular function of aged ovariectomized rats.

Both aging and estrogen depletion lead to endothelial dysfunction, which is the main reason of many cardiovascular diseases. Previous reports have shown that cell protective effect of silymarin (SM) depends on its antioxidant and phytoestrogenic properties. We investigated the effect of SM on vascular stiffness of aged menopausal rats and the involvement of estrogenic activity in this effect. Isolated rat aortas were obtained from 22‐month‐old rats, after 18 months of ovariectomy (OVX) follow‐up. Each ring was incubated in tissue bath either with SM (50 mg/L) and 17β‐estradiol (10 μM, E2) or in the presence of SM/fulvestrant (50 mg/L, 10 μM). Endothelium‐intact rings were precontracted with phenylephrine (0.001–30 μM) or high potassium (40 mM); endothelium‐dependent/independent relaxant responses were obtained using acetylcholine (0.001–30 μM) and sodium nitroprusside (0.0001–3 μM), respectively. While phenylephrine sensitivity was significantly increased in OVX rats, relaxations were significantly less in aged OVX rats compared with young rats. In spite of the presence of estrogen antagonist, immediate SM treatment restored the endothelial function and vascular tone better than estrogen replacement. Additionally, as a complementary and alternative medicine, it does not cause estrogenic side effects when taken acutely. Copyright

Treated effect of silymarin on vascular function of aged rats: Dependant on nitric oxide pathway

Abstract Context: Aging leads to endothelial dysfunction and vascular stiffness which are the main causes of many cardiovascular diseases. Previous reports have shown that the cell protective effect of silymarin (SM) is dependent on its antioxidant properties. Objectives: We investigated the effect of SM on vascular functions of aged rats and the involvement of nitric oxide or cyclooxygenase (COX) activity in this effect. Materials and methods: Isolated rat aortas were obtained from 22-month old rats. Each ring was incubated with SM (50 mg/L), SM/l-nitro-arginine methyl ester (100 μM, l-NAME) or SM/indomethacin (10 μM, INDO) in tissue bath. Three- to four-month-old rats were used as young controls. Endothelium-intact rings were precontracted with α-receptor agonist phenylephrine (0.001–30 µM) or voltage-dependent high potassium (40 mM), endothelium dependent/independent relaxant responses were obtained using acetylcholine (0.001–30 µM) and sodium nitroprusside (0.0001–3 µM), respectively. Results: Aging increased phenylephrine sensitivity (6.45 ± 0.08; 6.88 ± 0.09) and decreased KCl contraction (882 ± 118.4; 499 ± 80.4). SM treatment decreased the Emax of both agents (548 ± 109; 223 ± 48.9). Aging deteriorated acetylcholine relaxation (93.9 ± 2.09; 72.0 ± 2.56) and SM improved the response (86.3 ± 1.90). l-NAME prevented the SM effect whereas INDO was ineffective. Discussion and Conclusion: Immediate SM treatment partially restored endothelial dysfunction and vascular tone in aging. The possible mechanism might not be mediated by prostacyclin or the COX pathway in acute administration; the nitric oxide pathway and calcium antagonistic features of SM relate to its action on the vessel.

Evaluation of Lapatinib and Trastuzumab for Ototoxic Effects.

OBJECTIVE Trastuzumab and lapatinib are widely used chemotherapeutic agents. Our aim in this study was to assess the possible ototoxicity of these chemotherapeutic agents. MATERIALS AND METHODS Forty-eight rats were divided into six groups: Group 1 (control, n=8) received intraperitoneal saline for 7 days. Group 2 (n=8) and Group 3 (n=8) received 10 mg/kg and 30 mg/kg single doses of intraperitoneal trastuzumab, respectively. Lapatinib was administered by oral gavage to Group 4 (n=8) at 100 mg/kg/day and to group 5 (n=8) at 300 mg/kg/day for 7 days. Group 6 (n=8) received only one dose of 10 mg/kg intraperitoneal trastuzumab; subsequently, Group 6 received one dose of lapatinib at 100 mg/kg/day by oral gavage for 7 days. Before any medication was administered, distortion product emissions (DPOAE) were obtained. DPOAE tests were performed again on the rats on day 7, after which the mastoid bullas were harvested. The apoptosis degree was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) procedure. RESULTS The lapatinib 300 and lapatinib+trastuzumab groups (p=0.008 and p=0.001, respectively) were significantly different from the control group according to the spiral ganglion TUNEL. Apoptosis in the organ of corti was statistically different compared with the control group in the lapatinib 100, lapatinib 300, and lapatinib+trastuzumab groups (p=0.035, p=0.001, and p<0.001, respectively). Trastuzumab induced damage in only the organ of corti; however, lapatinib induced damage in both the organ of corti and spiral ganglion. The degree of the damage in the organ of corti was high when trastuzumab and lapatinib were concomitantly used. Supporting this data, a reduction in DPOAE amplitudes was observed during the combined usage of the drugs. CONCLUSION Administering trastuzumab and lapatinib causes ototoxic effects.

The effect of Hypericum perforatum on isolated rat aorta

Context: Different Hypericum species such as Hypericum perforatum (HP) L. and Hypericum triquetrifolium Turra are well known and widely used traditional medicine in Turkey. Objectives: We investigated the effect of standardized HP extract on endothelium and vascular function. Materials and methods: After suspending the aortas with endothelium in organ baths containing Krebs solution, contractile and relaxant responses were assessed in the absence and presence of HP (0.05 mg/ml). Results: Although there were significant reductions in the contractile responses to phenylephrine (1113.73 ± 164.11; 477.40 ± 39.94; p < 0.05) and potassium chloride (745.58 ± 66.73; 112.58 ± 26.58; p < 0.05), no differences in the relaxant responses to acetylcholine (94.61 ± 2.65; 87.79 ± 9.40) and sodium nitroprusside (108.82 ± 5.06; 106.43 ± 7.45) were observed. Discussion and conclusion: These data suggest that even the high dose of HP intervention does not bring any harmful effect on endothelium and smooth muscle function; meanwhile it might be beneficial on some of diseases accompanied with increased vascular contraction.

Protective effect of dexpanthenol (vitamin B5) in a rat model of LPS-induced endotoxic shock

Abstract Objectives This study investigated the protective effect of dexpanthenol (DEX) in the septic shock model of rats with biochemical parameters. Methods 12–15 weeks old male 32 Wistar rats has been used for this study. Sepsis was induced by a single intraperitoneal injection of lipopolysaccharide (LPS) (5 mg/kg) and treatment groups received single intraperitoneal injection of DEX (500 mg/kg) just 30-min before. The blood and tissue samples were obtained 16 h later of LPS intervention under the ketamine and xylasine (50 and 5 mg/kg, respectively) anesthesia. Results Giving alone DEX did not alter any physiologic levels of biochemical markers. Induction of sepsis resulted in a marked increase in ALT, AST, urea, creatinine, lactate, procalcitonin, TNF-α, IL-1β levels to show the tissue damage. In all serum parameters, liver’s GSH, CAT levels and kidney’s CAT, GSH, MDA and NO levels have ameliorated by DEX treatment in sepsis group. Conclusion Along with the standard therapy of sepsis, DEX can be used as a safe way of restoring (anti)oxidant status of kidney and liver tissues. It can be effective to control cytokine pathway, to decrease procalcitonin and regulate the metabolic process of sepsis, such as lactate.