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Hypertension is one of the major causes of cardiac damage. In this study, the effects of resveratrol supplementation and regular exercise on hypertension-induced cellular stress responses of myocardium were compared.Hypertension was induced in male Wistar rats by deoxycorticosterone-acetate + salt administration for 12 weeks. Resveratrol and regular exercise were applied for the last six weeks. In addition to biochemical and molecular examinations, isoprenaline, phenylephrine and, acetylcholine-mediated contractions and sinus rate were recorded in the isolated cardiac tissues.Resveratrol and regular exercise reduced systolic blood pressure in hypertensive rats. The altered adrenergic and cholinergic responses of the right atrium and left papillary muscles in hypertension were separately improved by resveratrol and regular exercise. Resveratrol and regular exercise decreased plasma and cardiac total antioxidant capacity and, augmented the expression of antioxidant genes in hypertensive rats. While regular exercise restored the increase in p-PERK expression associated with endoplasmic reticulum stress and decrease in mitophagic marker PINK1 expression, resveratrol only ameliorated PINK1 expression in hypertensive rats. Resveratrol and exercise training suppressed hypertension-induced NLRP3 inflammasome activation by reversing the increase in NLRP3, p-NF-κB expression and the mature-IL-1β/pro-IL-1β and cleaved-caspase-1/pro-caspase-1 ratio. Resveratrol and exercise enhanced mRNA expression of caspase-3, bax, and bcl-2 involved in the apoptotic pathway, but attenuated phosphorylation of stress-related mitogenic proteins p38 and JNK induced by hypertension.Our study demonstrated the protective effect of resveratrol and exercise on hypertension-induced cardiac dysfunction by modulating cellular stress responses including oxidative stress, ER stress, mitophagy, NLRP3 inflammasome-mediated inflammation, and mitogenic activation.

Hypertension is an important risk factor for cardiovascular diseases. Besides cardiovascular system, it could cause damage to liver. It has been shown that endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of hypertension. ERS inhibitor tauroursodeoxycholic-acid (TUDCA) has favorable effects on various pathologies including cardiovascular, metabolic and hepatic diseases. In this study, the hepatoprotective effect and mechanism of TUDCA were investigated in the deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Male Wistar rats were used and divided into four groups: Control, DOCA, TUDCA and DOCA + TUDCA. Hypertension was induced by DOCA-salt administration for twelve weeks after the unilateral nephrectomy. TUDCA was given for the last 4 weeks. Systolic blood pressure was measured by using tail-cuff method. At the end of the treatment, liver was isolated and weighed. The expressions of various proteins and histopathological evaluation were examined in the liver. TUDCA markedly decreased systolic blood pressure in the hypertensive animals. Hypertension caused increase in the expressions of glucose-regulated protein-78 (GRP78), matrix metalloproteinase-2 (MMP-2) and phospho-inhibitor kappa B-alpha (p-I kappa B-alpha) and the decrease in the expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) and phospho-extracellular signal-regulated kinase (p-ERK) in the liver. Alterations in these protein expressions were not detected in the TUDCA-treated hypertensive group. Also, hepatic balloon degeneration, inflammation and fibrosis were observed in the hypertensive group. TUDCA improved inflammation and fibrosis in the hypertensive liver. Our findings indicate that the detrimental effect of DOCA-salt-induced hypertension on the liver was defended by the inhibition of ERS. Hepatic ERS and its treatment should be taken into consideration for therapeutic approaches to hypertension.

Demirel-Yilmaz, Emine/0000-0002-2476-6225; Derici, Mehmet Kursat/0000-0002-8260-7492; Guray, Tulin/0000-0003-4572-1429 WOS: 000455010800015 PubMed: 30529467 Phosphodiesterase enzymes (PDEs) are responsible for the adjustment of cyclic nucleotide levels. Alterations in PDE expressions in different tissues cause conflicts between functional and clinical effects of PDE inhibitors. Therefore, the aim of this study was to investigate the gene and protein expressions and the functional role of PDEs in atrium and ventricle of rat heart The expressions of PDEs were examined in cardiac intact tissues and enzymatically isolated cells. The effects of PDE1-5 inhibitors (vinpocetine, EHNA, milrinone, rolipram, sildenafil, and IBMX) on basal and isoprenaline-stimulated contractions and sinus rate were recorded in the isolated spontaneously beating right atrium and electrically stimulated left papillary muscles. The mRNA and protein levels of PDEs were significantly different in atrial and ventricular intact tissues and isolated myocytes. Atrial contractions were increased with vinpocetine while suppressed by EHNA, milrinone, rolipram, sildenafil and IBMX. Milrinone, sildenafil and IBMX increased the heart rate whereas vinpocetine caused negative chronotropy. Papillary muscle contractions have been increased only with the vinpocetine and IBMX. Both the expression and the action of PDE-1-5 show atrial and ventricular differences. Therefore, these differences should be taken into account in the experimental or therapeutic approaches of the heart. Ankara University Research Foundation Ankara, TurkeyAnkara University [13B3330007] This study was supported by a research grants, 13B3330007 from the Ankara University Research Foundation Ankara, Turkey.

Background Intermittent ischemia in remote tissues can be applied before ischemic injury, during ischemic injury or at the beginning of reperfusion of an index organ ischemia. The aim of this study was to investigate the effect of Remote Ischemic Conditioning (RIC) of the leg on changes in ischemia-induced the microvascular functions of the arm. Material and methods Ischemic microvascular injury was induced by arm ischemia (20 min) and reperfusion in healthy, nonsmoker, male volunteers (ischemia group-ISC, n: 9). In another group of volunteers, to investigate the effects of remote organ ischemic conditioning 5 cycles of reperfusion followed by leg ischemia (each lasting 60 seconds) were applied either before (preRIC, n:11), or during (perRIC, n:12) or immediately after (postRIC, n:9) 20 minutes of arm ischemia. The microvascular flow of arm was assessed before and after ischemia using iontophoresis of the endothelium-derived nitric oxide (NO) releaser acetylcholine (ACh) and the endothelium-independent NO donor sodium nitroprusside (SNP). Changes in microvascular blood flow were measured using Laser Doppler imaging. The plasma level of biomarkers related to endothelial function such as nitric oxide (NO), asymmetric dimethylarginine (ADMA), total antioxidant capacity (TAC) and hydrogen sulphide (H2S) were measured. Results No difference was determined between the groups in terms of age, BMI or blood biochemicals reflecting cardiovascular status. ACh caused a rise in microvascular blood flow in a charge dependent manner. The ACh-induced flow increase was not significantly depressed by ischemia and not affected by any of the types of RIC in the study subjects. The increase in SNP-induced microvascular flow was significantly decreased in the ISC, perRIC and postRIC groups, but not in the preRIC group. Plasma levels of NO, ADMA, TAC and H2S were not changed by ischemia and RIC. Conclusion These results suggested that microvascular perfusion of human forearm skin was elevated by either endothelium or drug-derived NO. The effect of ischemia and RIC on NO-induced flow increase was affected differently by different applications in the healthy young individuals. These complicated results are taken into consideration in experimental and therapeutic interventions.

Amaç: Bu çalışma, antegrad serebral perfüzyon ve distal ılımlı hipotermik sirkülatuararrest tekniğinin endotel fonksiyonuna ilişkin biyobelirteçler üzerine etkisini standart kalp cerrahisi ile karşılaştırmayı amaçlamaktadır.Materyal-Metod: Asendan aort anevrizması için 28 ° C' da selektif antegrad serebral perfüzyon ve orta derecede hipotermik alt vücut dolaşım durması uygulanan 36 hasta (standart çalışma grubu), konvansiyonel kardiyopulmoner bypass ile standart kalp ameliyatı uygulanan (kontrol grubu) 36 hasta prospektif olarak karşılaştırıldı. Vena kava inferiordan elde edilen kan örneklerinde nitrik oksit, asimetrik dimetilarginin, hidrojen sülfit ve toplam antioksidan kapasite durumu ve laktat seviyeleri incelenmiştir. Klinik sonuçlar ve biyokimyasal parametreler değerlendirildi.Bulgular: Endotel fonksiyonuyla ilgili biyobelirteçler, asimetrik dimetilarjinin dışındaki gruplar arasında benzer bulundu. Asimetrik dimetilarjinin düzeyleri düşüktü, laktat düzeyleri ise kontrol grubuna göre anlamlı derecede yüksek bulundu. Kontrol gruptaki koroner arter hastalarının baskınlığını nedeniyle çıkan sonuçlarda kafa karıştırıcı bir faktör olarak düşünülerek koroner arter hastaları analiz dışında bırakıldığında, asimetrik dimetilarjinin düzeylerinin, iki alt grup arasında benzer olduğu bulundu.Sonuç: Çalışma grubundaki düşük plazma asimetrik dimetilarjinin seviyeleri, endotelyal nitrik oksit sentezinde koruyucu bir role sahip olabilir. Koroner arter hastalığı olan hastalar her iki gruptan da dışlandığında, endotel fonksiyonuna bağlı biyobelirteçler her iki grupta da benzerdi. Bu sebeple antegrad serebral perfüzyon ve distal ılımlı hipotermik sirkülatuar arrest tekniğinin kısa dönemde endotel fonksiyonlarını etkilemediğini düşünmekteyiz. Aim: This study aims to compare biomarkers related to endothelial function during selective antegrade cerebral perfusion with moderate hypothermic lower body circulatory arrest with that of standard cardiac surgery.Material and Methods: Thirty-six consecutive patients who underwent selective antegrade cerebral perfusion with moderately hypothermic lower body circulatory arrest at 28°C (study group) for aneurysms of the ascending aorta were prospectively compared with 36 patients who underwent standard cardiac surgery (control group) with conventional cardiopulmonary bypass. Nitric oxide, asymmetric dimethylarginine, hydrogen sulfide and total antioxidant capacity status and lactate levels in blood specimens obtained from the vena cava inferior were studied. Clinical results and biochemical parameters were evaluated.Results: Biomarkers related to endothelial function were found to be similar between the groups except for asymmetric dimethylarginine. The asymmetric dimethylarginine levels were lower, while lactate levels were significantly higher compared to the control group. When the patients with coronary artery disease were excluded from the analysis to rule out the predominance of coronary artery disease patients in one group as a confounding factor, the asymmetric dimethylarginine levels were found to be similar between the two subgroups.Conclusion: Low plasma levels of asymmetric dimethylarginine in the study group may have a protective role in endothelial nitric oxide synthesis. When patients with coronary artery disease were excluded from both group, biomarkers related to endothelial function were similar in both groups. We consider that endothelial functions are not affected adversely during short periods of moderately hypothermic lower body circulatory arrest.

Amaç: Hipertansiyon, gelişiminde pek çok faktörün etkili olması nedeniyle araştırılması zor bir hastalıktır. Deoksikortikosteron asetat (DOCA)-tuz hipertansiyon modeli, oldukça sık kullanılan ve insanlardaki esansiyel hipertansiyonu başarılı bir şekilde taklit edebilen bir deneysel modeldir. Hipertansiyon çalışmalarında, hayvan modelinin seçimi kadar seçilen modelinin ne kadar süreyle uygulanacağı da büyük önem taşımaktadır. Bu çalışmada, DOCA-tuz hipertansiyon modelinin farklı sürelerde uygulanmasının, kan basıncı ve damar cevapları üzerine etkileri, araştırılmıştır. Yöntemler: Deneylerde 8 haftalık, erkek Wistar albino sıçanlar kullanılmıştır. DOCA-tuz hipertansiyon modelini oluşturmak için, hayvanlara tek taraflı nefrektomi uygulanmış ardından haftada iki kez DOCA enjeksiyonu (15 mg/kg, s.c.) yapılmış ve %1 NaCl ile %0,2 KCl içeren içme suyu verilmiştir. Uygulamalara farklı hayvan gruplarına 4 hafta ve 8 hafta boyunca devam edilmiş ve kan basınçları ölçülmüştür. Süre sonunda, hayvanların torasik aortları izole edilmiş ve damar cevapları izole organ banyosunda kaydedilmiştir. Bulgular: 4 veya 8 hafta DOCA-tuz uygulaması, hayvanların kan basıncını yükseltmiş ve aortanın endotele bağımlı gevşeme cevaplarını azaltmıştır. 4 haftalık DOCA-tuz grubunda aortun KCl kasılma cevapları değişmezken, alfa-1 reseptör agonisti fenilefrin (FE) ile uyarılan kasılma cevapları azalmıştır. 8 haftalık DOCA-tuz grubunda ise, hem KCl hem de FE ile oluşan damar kasılmaları azalmıştır. Sonuç: DOCA-tuz hipertansiyon modelinin erken döneminde, endotel işlevinde ve reseptör aracılı damar kasılmalarında bozukluklar ortaya çıkmaktadır. Daha uzun süreli uygulama sonucunda ise, kan basıncı daha fazla yükselmekte, hem endotel hem de damar düz kasının işlevlerinde bozukluklar görülmektedir. Elde edilen sonuçlar, deneysel hipertansiyon modelinde farklı DOCA-tuz uygulama sürelerinin, damarların işlevleri üzerine farklı etkileri olduğunu göstermektedir.

Objectives Endoplasmic reticulum stress (ERS) has been shown to play a crucial role in the pathogenesis of hypertension. However, the role and mechanisms of ERS on hypertension-induced cardiac functional and morphological changes remain unclear. In this study, the effect of ERS inhibition with tauroursodeoxycholic acid (TUDCA) on hypertension-induced cardiac remodelling was examined. Methods Hypertension was induced by deoxycorticosterone-acetate (DOCA) and salt administration in uni-nephrectomized rats for 12 weeks. TUDCA was administered for the last four weeks. Rhythmic activity and contractions of the right atrium and left papillary muscle (LPM) were recorded. In the left ventricle, the expression of various proteins was examined and histopathological evaluation was performed. Key findings Hypertension-induced increments in systolic blood pressure and ventricular contractions were reversed by TUDCA. In the hypertensive heart, while expressions of glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated protein kinase-like ER kinase (p-PERK), sarcoplasmic reticulum Ca-ATPase-2 (SERCA2), matrix metalloproteinase-2 (MMP-2) and nuclear NF-κB p65 increased; Bcl-2 (B-cell lymphoma-2) expression decreased and the altered levels of all these markers were restored by TUDCA. In the microscopic examination, TUDCA treatment attenuated hypertension-stimulated cardiac inflammation and fibrosis. Conclusions These results suggest that ERS inhibition may ameliorate cardiac contractility through improving ERS-associated calcium mishandling, apoptosis, inflammation and fibrosis, thereby offering therapeutic potential in hypertension-induced cardiac dysfunction.

In this study, the effect of liver X receptor (LXR) activation on hypertension-induced cardiac structural and functional alterations was investigated. Hypertension was induced by deoxycorticosterone acetate (DOCA)-salt administration in uninephrectomized rats for 6 weeks. LXR agonist GW3965 (3-{3-[(2-chloro3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid was given for the past week. Rhythmic activity and contractions of the isolated heart tissues were recorded. Biochemical parameters were assessed in ventricular tissue and plasma samples. Cardiac expressions of various proteins were examined, and histopathological evaluation was performed in the left ventricle and liver. GW3965 reduced systolic blood pressure and enhanced noradrenaline-stimulated papillary muscle contraction induced by DOCA-salt + uninephrectomy. Plasma and tissue total antioxidant capacity (TAC) increased and tissue 4-hydroxynonenal (4-HNE) levels decreased in the DOCA-salt group. GW3965 elevated plasma and tissue TAC levels in both of groups. Glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated-protein kinase-like ER kinase (p-PERK), matrix metalloproteinase-2 (MMP-2), and nuclear factor-kappa B p65 (NF-kappa B p65) expression was augmented, and inhibitor-kappa B-alpha (I kappa B-alpha) expression was reduced in hypertensive hearts. The altered levels of all these markers were reversed by GW3965. Also, GW3965 ameliorated DOCA-salt + uninephrectomy-induced cardiac and hepatic inflammation and fibrosis. However, GW3965 unchanged the plasma lipid levels and hepatic balloon degeneration score. These results demonstrated that LXR activation may improve hypertensioninduced cardiac changes without undesired effects.

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-κB) and tumor necrosis factor alpha (TNF-α) 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.

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.

Hypertension has complex vascular pathogenesis and therefore the molecular etiology remains poorly elucidated. Endoplasmic reticulum stress (ERS), which is a condition of the unfolded/misfolded protein accumulation in the endoplasmic reticulum, has been defined as a potential target for cardiovascular disease. In the present study, the effects of ERS inhibition on hypertension-induced alterations in the vessels were investigated. In male Wistar albino rats, hypertension was induced through unilateral nephrectomy, deoxycorticosterone-acetate (DOCA) injection (20 mg/kg, twice a week) and 1% NaCl with 0.2% KCI added to drinking water for 12 weeks. An ERS inhibitor, tauroursodeoxycolic acid (TUDCA) (150 mg/kg/day, i.p.), was administered for the final four weeks. ERS inhibition in DOCA-salt induced hypertension was observed to have reduced systolic blood pressure, improved endothelial dysfunction, enhanced plasma nitric oxide (NO) level, reduced protein expressions of phosphorylated-double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (pPERK), 78 kDa glucose-regulated protein (GRP78), Inositol trisphosphate receptor1 (IP3R1) and Epidermal growth factor receptor (EGFR), increased expressions of endoplasmic reticulum Ca2+-ATPase2 (SERCA2) and B cell lymphoma2 (Bcl2) in vessels. These findings suggest that the beneficial effects of ERS inhibition on hypertension may be related to protection of vessel functions through restoration of endoplasmic reticulum calcium homeostasis, and apoptotic and mitotic pathways.

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 role of cutaneous microvascular dysfunction is well known in the development of chronic venous disease. However, the effects of venous obstruction on microcirculation have not been well investigated. The aim of this study was to assess cutaneous microvascular function in patients with iliocaval venous obstruction (ICVO) before and after venous stent placement.Endothelium-dependent and endothelium-independent vasodilator responses to iontophoretic administration of incremental doses of acetylcholine (ACh) and sodium nitroprusside (SNP) were evaluated using a laser Doppler scanner in the perimalleolar region in the supine and sitting positions in patients with ICVO (n = 11) and in healthy control subjects (n = 15). Cutaneous microvascular function, the Venous Clinical Severity Score (VCSS), and the Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) clinical class were re-evaluated 3 months after stent placement in patients with ICVO.The vasodilatory responses to ACh and SNP in the cutaneous microcirculation were lower in patients with ICVO than in healthy subjects in the sitting position (P .05). Recanalization and stent placement were successful in all patients in the evaluation of VCSS and clinical class, and a significant decrease was determined in the signs and symptoms of the venous disease (P .01). Stent placement resulted in a significant increase in vasodilation response to both ACh and SNP in the supine position and no improvement in the sitting position in patients with ICVO.ICVO impairs endothelium-dependent and endothelium-independent vasodilation in the perimalleolar region. Iliocaval venous stent placement may recover microvascular dysfunction at different levels.

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 Buerger's 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 modulation of cardiac functions by nitric oxide (NO) was established. This study examined the influences of phosphodiesterase (PDE) inhibitors on the action of NO in the different regions of the rat heart. NO donor diethylamine nonoate (DEA/NO) (0.1-100 μM) decreased functions of the right atrium. DEA/NO-induced depression of the developed tension of the right atrium was inhibited by [erythro-9-(2-hydroxy-3-nonyl)adenine] (PDE2 inhibitor), augmented by milrinone (PDE3 inhibitor), and upturned by rolipram (PDE4 inhibitor). A DEA/NO-induced decrease in the resting tension was inhibited by vinpocetine (PDE1 inhibitor) and [erythro-9-(2-hydroxy-3-nonyl)adenine] but reversed by rolipram. The decreased sinus rate by DEA/NO was prevented by vinpocetine and rolipram. DEA/NO increased cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP) concentrations in the right atrium, and rolipram enhanced increased cAMP level. DEA/NO had no effect on the contraction of the papillary muscle. However, unchanged contraction under DEA/NO stimulation was decreased by vinpocetine, milrinone, and rolipram. DEA/NO increased cyclic guanosine monophosphate concentration but has no effect on cAMP in the papillary muscle. However, in the presence of vinpocetine and milrinone, DEA/NO reduced cAMP level. The PDE5 inhibitor sildenafil has no effect on DEA/NO actions. This study indicates that a variety of PDE activities in different regions of the rat heart shapes the action of NO on the myocardium.

The important role of nitric oxide (NO) in regulating cardiac functions has been investigated in prior research. However, NO-induced signaling mechanisms in the different regions of the heart have not been explored until now. In this study, the mechanism of NO effects on the spontaneously beating right atrium and left papillary muscle isolated from the rat heart was examined. The NO donor diethylamine NONOate (DEA/NO) (0.1-100 μM) depressed the resting and developed tensions, as well as the sinus rate, of the right atrium. The effect of DEA/NO on contractions of the right atrium was blocked by the soluble guanylate cyclase (sGC) inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one) (10 μM). The ATP-sensitive potassium channel (K(ATP)) blocker glyburide (3 μM) reversed DEA/NO-induced decreases in the resting tension. The suppressor effect of DEA/NO on the sinus rate was inhibited only by the superoxide radical scavenger superoxide dismutase (25 U/ml). Neither the cGMP-dependent protein kinase (PKG) inhibitor KT5823 (0.1 μM) nor the cAMP-dependent protein kinase (PKA) inhibitor KT5720 (1 μM) changed DEA/NO responses in the right atrium. While the resting tension of the right atrium was decreased by the NO precursor L-arginine (1-100 μM), it was increased by the nitric oxide synthase inhibitor L-NMMA (0.1-100 μM). The sinus rate was not affected by L-arginine or L-NMMA. The left papillary muscle contraction was not influenced by any of these NO-related agents. These results show that high concentration NO-induced depression of the contraction of the right atrium is due to sGC and K(ATP) channel activation, but suppression of the sinus rate depends on redox regulation. Our results may have important implications for the region-dependent functional disability of cardiac myocytes, as well as the regulation of heart performance in high NO-induced pathological conditions.

Resveratrol, a natural phytoalexin found in wine, has been suggested to have benefits in preventing cardiovascular diseases. However, the direct effects of resveratrol on the activity of cardiac tissues and its mechanism of action have not been determined. This study examined the effects of resveratrol on the right and left atrium and left papillary muscle isolated from the rat heart. The contractile responses of the right atrium and papillary muscle and the action potential from the left atrium were recorded and the effects of resveratrol on these responses were observed. The resting force of the isolated right atrium and the peak developed force of the left papillary muscle were depressed by resveratrol (0.1 nM - 0.1 mM). Exposure to the K(ATP) channel blocker glyburide (3 microM) prevented significantly the resveratrol-induced decrease. Resveratrol (0.1 mM) shortened the repolarization phase of action potential recorded from the left atrium and this effect of resveratrol was reversed by glyburide (3 microM). These results indicated that resveratrol depressed cardiac muscle contraction and shortened action potential duration probably due to the activation of K(ATP) channels in the rat heart.

Resveratrol causes endothelium dependent and independent relaxation of vascular smooth muscle. This study investigated the mechanisms behind the effect of resveratrol on vascular tone. Resveratrol (0.1 mM) inhibited KCl-stimulated contractions in endothelium-denuded rat aorta and this inhibition was not reversed by tetraethylammonium (TEA) (5 mM), glyburide (3 microM), ouabain (0.1 mM), thapsigargin (1 microM), or indomethacin (10 microM). KCl (90 mM) increased the intracellular free calcium concentration ([Ca2+]i) in the isolated smooth muscle cells from the rat aorta and resveratrol (0.1 mM) did not inhibit the KCl-stimulated [Ca2+]i increase. The CaCl2 (0.1-100 microM) stimulated contractions were inhibited by resveratrol (0.1 mM) in the Triton X-100 skinned smooth muscle of the aorta. In heart valve endothelium, resveratrol (0.1 mM) augmented the acetylcholine (10 microM) stimulated [Ca2+]i increase. Resveratrol-induced augmentation of the acetylcholine-stimulated [Ca2+]i elevation was reversed by glyburide (3 microM), but not by TEA (5 mM). The present study indicated that resveratrol affected vascular smooth muscle and endothelium in different ways. Resveratrol decreased the Ca2+ sensitivity but did not affect the KCl-stimulated [Ca2+]i increase in the vascular smooth muscle. In the endothelial cells, resveratrol enhanced the agonist-stimulated [Ca2+]i increase that might trigger nitric oxide synthesis from endothelial cells.

Candida albicans is an opportunistic pathogen that causes life-threatening systemic infection in immunocompromised host. However, little is known about the effects of yeast on the cardiovascular functions. This study examined the effects of C. albicans septicemia on the heart and vessel functions and nitric oxide (NO) production in infected rabbits. Anaesthetized animals were challenged with intravenous C. albicans (6 x 10(8)/kg) or saline and the blood pressure of rabbits were measured over 5 h. After that response of the isolated thoracic aorta, right atrium and left papillary muscle were recorded. Blood pressure significantly decreased in the infected rabbits during the septicemia but in the control animals it was stable. The blood nitrite levels and NO-synthases (eNOS, iNOS) expression and tissue nitrite levels in the heart and aorta were similar in the both groups. In the aorta isolated from C. albicans-infected rabbits, acetylcholine-induced endothelium-dependent relaxation was decreased, but contractions induced by phenylephrine were potentiated. The NOS inhibitor, L-N(G)-nitro-arginine methyl ester (L-NAME)-induced contraction increase in the right atrium was depressed by the yeast-infection. In the heart and aorta, microscopic examination revealed no tissue invasion of C. albicans. These results indicate the ability of C. albicans-induced septicemia to destroy NO-related responses of the heart and aorta and may have important implications for functional damage to endothelium and the regulation of cardiovascular functions. In addition, NOS induction and NO over-production are not stimulated by systemic C. albicans infection, which would alter the host immune reaction and homeostasis.

As the first phase of a major curricular change in a large medical school the core curriculum had to be determined. The criteria for the inclusion of topics in the core curriculum were defined for both clinical and basic sciences. A large group of faculty members have worked in 11 sub-groups to determine the core knowledge, skills and attitudes for undergraduate medical students. During this work 608 clinical topics have been reviewed. Four-hundred and eighty five of them (79%) have been included in the core curriculum. Clinical and basic science knowledge, skills and attitudes relevant to these topics have been defined and classified. A total of 1610 cognitive, 428 psychomotor skills and 247 attitudes have been named. Thus the core curriculum defined is not just a set of diseases, conditions and symptoms but also includes the details of each and every topic. Starting from this point the medical school has participated actively in defining the national core curriculum, which has also been determined according to the same criteria.

Hypertension is a risk factor for the cardiovascular diseases. Although, several drugs are used to treat hypertension, the success of the antihypertensive therapy is limited. Resveratrol decreases blood pressure in animal models of hypertension. This study researched the mechanisms behind the effects of resveratrol on hypertension. Hypertension was induced by using the deoxycorticosterone acetate (DOCA)-induced (15 mg/kg twice per week, subcutaneously) salt-sensitive hypertension model of Wistar rats. Hypertension caused a decrease in endothelium-dependent relaxations of the isolated thoracic aorta. Resveratrol treatment (50 mg/l in drinking water) prevented DOCA salt-induced hypertension, but did not improve endothelial dysfunction. Plasma nitric oxide (NO), asymmetric dimethylarginine (ADMA), total antioxidant capacity (TAC) and hydrogen sulfide (H2S) levels were not changed by DOCA salt application. However, treatment of resveratrol significantly decreased ADMA and increased TAC and H2S levels. NO level in circulation was not significantly changed by resveratrol. DOCA salt application and resveratrol treatment also caused an alteration in the epigenetic modification of vessels. Staining pattern of histone 3 lysine 27 methylation (H3K27me3) in the aorta and renal artery sections was changed. These results show that preventive effect of resveratrol on DOCA salt-induced hypertension might due to its action on the production of some blood biomarkers and the epigenetic modification of vessels that would focus upon new aspect of hypertension prevention and treatment. © 2014, Springer Science+Business Media Dordrecht.

Recent studies have shown that NO acts as a negative inotrope and chronotrop in cardiac muscle. In the present study, we investigated the effects of the chronic administration of l -NAME and l -arginine on 14-week streptozotocin (STZ)-diabetic rat atria. To study these effects, we compared the alterations of inotropic and chronotropic responses to isoprenaline (ISO) on electrically-driven left atria and spontaneously beating right atria. In addition, we compared the blood pressures of rats in all groups. The chronic administration of L -arginine resulted in a significant reduction in blood pressure of the diabetic rats. On the other hand, the chronic nitric oxide synthase inhibition resulted in a significant increase in blood pressure of diabetic animals. To our findings, maximum positive inotropic responses of ISO diminished in STZ-diabetic, L -arginine and L -NAME treated diabetic groups relative to controls but neither the basal contractility of the left atria nor the pD 2 values were altered significantly in all groups. The basal atrial rate and maximum positive chronotropic responses to ISO were found to be significantly lower in treated and untreated diabetic groups, no significant changes were observed in pD 2 values. Our results demonstrate that the changes in inotropic and chronotropic responses in diabetic rat atria were not influenced by the chronic administration of L -arginine and L -NAME treatments.

It is known that the subcutaneous injection of a single dose of sodium selenite into suckling rats results in the development of large nuclear opacities. The intracellular transport of selenite in various cells, except lens cells, occurs via the Cl/HCO3 exchanger. The aim of the present study is to investigate the possible role of the anion-exchange inhibitor, disulfonic stilbene (SITS), in the selenite-induced catarogenesis in the rat pups. Wistar albino rats (8-10 d old) were separated into three groups: one control and two experimental. The first experimental group was injected subcutaneously with a single dose of 30 nmol sodium selenite/g body weight. The second experimental group was injected with a single dose of 10 nmol SITS/g body weight 15 min before the same dose selenite injection. The control group did not have any injections. The stage of cataract development was examined on d 7 postinjection with slit-lamp photographs. In SITS pretreated group, all eyes remained transparent (considered as stage 0), whereas in the selenite-injected group, the animals did have different stage of nuclear cataract; 8 animals have stage 5, 10 animals have stage 4, and 4 animals have stage 3. A pretreatment of SITS completely prevented cataract formation of the selenite-induced cataract model in rat pups.

The present study was designed to investigate and compare the effects of dietary antioxidants on the mechanical characteristics of the rat heart. Both sex weanling rats were fed for 12 to 14 weeks a standardized selenium (Se)- and vitamin E-deficient diet, a Se-excess diet, or a control diet. Deficiency or toxicity of Se was verified by direct (tissue Se analysis and histopathological investigations) methods. The hearts of both experimental groups revealed some alterations in contractile performance with increased heart rate and coronary perfusion pressure. The average peak contractile force of the electrically stimulated papillary muscle measured in both experimental groups was not significantly different from the control values. When expressed as a percentage, the maximal increase in the peak contractile force of papillary muscle (PCF) that was obtained with 100 nM isoproterenol, respectively, was less in both experimental groups (26% in PCF of deficient group; 34% in PCF of rich group) than in the control group (80% in PCF). A decreased stimulation of contractile force of papillary muscle strips by a β-adrenergic agonist seems to be in agreement with possible alterations in the response to inotropic agents due to a modification of the receptor function.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most used drugs in musculoskeletal disorders, but their systemic adverse effects limit their therapeutic benefit in local inflammation. On the other hand, topical preparations of capsaicinoids are widely used for musculoskeletal disorders as a complementary therapy. In this study, the effects of both topical capsaicinoids-containing patch and local subcutaneous capsaicin application on the anti-inflammatory action of NSAID were examined. Carrageenan-induced paw oedema of rats was used as the inflammation model. The volume and weight of the paw oedema and plasma extravasation in the paw were determined after carrageenan injection. The systemic application of diclofenac (3 mg/kg), which is an NSAID, significantly decreased the volume and weight of the paw oedema. Topical capsaicinoids-containing patch application or local capsaicin injection (2, 10, 20 mu g/paw) alone did not cause any effect on oedema volume and weight. However, the combination of diclofenac with topical capsaicinoids-containing patch significantly increased the effectiveness of diclofenac on inflammation. Evans blue content of the paws that represents plasma extravasation was decreased by capsaicinoids-containing patch with and without diclofenac and diclofenac combination with the lowest dose of capsaicin injection. The results of this study indicate that topical application of capsaicinoids-containing patch enhances the anti-inflammatory effect of diclofenac and its beneficial effect may not purely relate to its capsaicin content. In the treatment of local inflammatory disorders, the combination of NSAID with topical capsaicinoids-containing patch could increase the anti-inflammatory efficiency of drug without systemic side effects.

WOS: 000316956900010, PubMed ID: 22967272, 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., Ankara University Research Foundation [09B3330012], This study was supported by research grant 09B3330012 from the Ankara University Research Foundation. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

To determine the effects of amiloride on selenite-induced cataracts, to identify this agent's role as an anti-oxidant, and to study related effects on ion levels in the rat lens.Wistar albino rat pups were assigned to one of three groups, one control and two experimental. The first experimental group (Group 1; n = 22) received a subcutaneous injection of sodium selenite (30 nmol/g body weight) on postpartum day 10. The second experimental group (Group 2; n = 21) received a subcutaneous injection of amiloride (1 nmol/g body weight) 15 minutes before the sodium selenite injection. The control group (n = 22) received no injection. The pups in each group were observed during three weeks after the injection date. At the end of this period, the stage of cataract development was identified by comparison with slit lamp photographs and then the pups were sacrificed and their lenses were removed intracapsularly using a posterior approach. Cation analysis was carried out and glutathione and malondialdehyde levels were measured for each group.Cataract stage in Group 1 was significantly higher than Group 2. Mean cataract stages in Groups 1 and 2 were 3.8+/-0.12 and 1.6+/-0.25 respectively. None of the control animals developed cataracts. Amiloride-pretreated group contained significantly higher glutathione levels than Group 1. The level of malondialdehyde in Group 1 lenses was approximately twice that in the lenses of the Group 2 amiloride+selenite-treated animals. The Ca(2+) level was significantly higher in Group 1 lenses compared to the amiloride-pretreated rats, but there was no significant difference between Groups 1 and 2 with regard to Na(+) and K(+) levels.Amiloride was very effective in preventing cataract formation in the selenite-induced cataract model. This protective effect of amiloride was accompanied by higher glutathione levels and lower malondialdehyde levels in the rat pups' lenses compared to levels in animals that received selenite alone. These results suggest an anti-oxidant role for this agent, in addition to its effects on lens ion homeostasis.

This study examines the effects of Candida albicans on acethylcholineinduced, endothelium-dependent relaxation of thoracic aorta of rabbits, precontracted by phenylephrine (10−7M). Isolated vessel rings were incubated with C. Albicans, Saccharomyces cerevisiae, or their mannans, and endothelium-dependent relaxation was measured by the induction of acethylcholine. Endothelium-dependent relaxation remained unaffected after 3 hours by either C. albicans or S. cerevisiae, or their mannans. After 24 hours, however, incubation with C. albicans had completely abolished relaxation, whereas relaxation was decreased by mannan of C. albicans and continued unaffected by S. cerevisiae. In contrast, no change was registered with a 24 hours incubation of C. Albicans in a sodium nitroprusside-induced, endothelium-independent, vascular smooth muscle relaxation. Microscopical investigation of the morphological structure of vessel walls revealed penetration of C. albicans on the intimai surface after 3 hours incubation and infiltration of the yeast through the vessel wall after 24 hours. No changes in vessel morphology occurred after 3 or 24 hours with S. cerevisiae or the mannan of C. albicans. These results show the ability of C. albicans to inhibit endothelium-dependent, but not endothelium-independent, relaxation of vascular smooth muscle and may have important implications for functional damage to endothelial cells and the regulation of vessel tone and blood flow.

The effects of dietary sodium selenite and vitamin E on the microvascular permeability of rat organs such as heart, brain, kidney, liver and eye were investigated by using the Evans blue leakage method. Combined deficiency of selenium and vitamin E caused an increase in the permeability of the heart and eye with respect to their controls while it had no considerable effect on the permeability of other organs. On the other hand, toxic levels of selenium (4.2 mg/kg) in diet decreased the permeabilities in kidney, liver, and eye whereas this parameter of brain increased in the same animal group. These results suggested that low or high sodium selenite and vitamin E contents in diet could alter the microvascular permeability of different organs in different manners. It might be important to give reasonable explanations for the pathophysiology of some diseases that are characterized with organ damage and/or disfunction originated from selenium deficiency or toxicity.

1. The present study examined the effects of various agents on high calcium–induced relaxation of the rabbit thoracic aorta precontracted by phenylephrine (0.1 μM) or KCl (30 mM). 2. The vascular smooth muscle relaxation caused by high calcium was not changed in the presence of endothelium, glibenclamide (3 μM), TEA (5 mM), verapamil (1 μM), lidocaine (0.1 mM) and vanadate (0.1 mM). 3. In the presence of ouabain (0.1 mM) or potassium-free medium, high calcium–induced relaxation was completely abolished. 4. When rings were precontracted by high concentrations of phenylephrine (1 μM, 10 μM) and KCl (30 mM, 45 mM, 60 mM), calcium-induced relaxation was gradually decreased. 5. A low concentration of calcium ionophore A-23187 (0.1 μM) did not change calcium-induced relaxation, but A-23187 at a high concentration (1 μM) depressed this relaxation. 6. These results suggest that Na-K-ATPase activation could be responsible for high calcium–induced relaxation.

PubMedID: 10411590 We investigated the possibility of there being any photosensitive materials stores yielding nitric oxide (NO), and combined for the first time electrical field stimulation (EFS)- and UV light-induced relaxations in mouse gastric fundus. The tissue responded with relaxation to long wave UV light (366 nm). Repeated exposure to light decreased the fundic photorelaxation in that the initial photorelaxation was 31.5 + 6.9% whereas the last (10th) photorelaxation was 2.3 ± 0.8%. There were no significant differences between EFS (30 V, 0.5 ms, 1 Hz, 15 s)-induced relaxations obtained before (39.7 ± 7.7%) and after (33.4 ± 9.1%) UV irradiation, which were completely blocked by 10-4 M L-N(G)-nitroarginine methyl ester. Treatment of the tissue with NaNO2, L-N(G)nitro-arginine, S-nitrosoglutathione, or sodium nitroprusside for 30 min followed by prolonged washout restored the photorelaxation, whereas glyceryl trinitrate or L-arginine did not produce any improvement. EFS (30 V, 0.5 ms, 3 Hz) applied for 60 min significantly recovered the reduction of the photorelaxation. L-N-S-iminoethyl-L-ornithine, which does not contain NO2 moiety, abolished electrically induced relaxation; however, it did not change photorelaxations. UV irradiation caused relaxation only when the adventitial surface of the preparation was oriented to the source of UV light. These results indicate that there could be a photosensitive relaxant materials store yielding NO in the smooth muscle layer of the gastric fundus from mouse. This putative store can be refilled by NaNO2, L-N(G-nitro-arginine), sodium nitroprusside, S-nitrosoglutathione, or long-term EFS but not glyceryl trinitrate or L-arginine. Possible candidates for NO-yielding substances might not be an organic nitrate but an intracellular nitrite, nitrosylated substances, and unknown nitro-containing compounds, which could be all sensitive to UV light.