Myricetin May Improve Cardiac Dysfunction Possibly Through Regulating Blood Pressure and Cellular Stress Molecules in High-Fructose-Fed Rats.

BACKGROUND: The aim of this study was to examine the effect of myricetin on cardiac dysfunction caused by high fructose intake. METHODS: Fructose was given to the rats as a 20% solution in drinking water for 15 weeks. Myricetin was administered by oral gavage for the last 6 weeks. Systolic blood pressure was measured by tail-cuff method. The effects of isoprenaline, phenylephrine, and acetylcholine on cardiac contractility and rhythmicity were recorded in the isolated right atrium and left ventricular papillary muscles. In addition to biochemical measurements, the cardiac expressions of cellular stress-related proteins were determined by western blotting. RESULTS: Myricetin improved systolic blood pressure but did not affect body weight, plasma glucose, and triglyceride levels in fructose-fed rats. The impairment of isoprenaline- and phenylephrine-mediated increases in atrial contraction and sinus rate in fructose-fed rats was restored by myricetin treatment. Isoprenaline, phenylephrine, and acetylcholine-mediated papillary muscle contractions were not changed by fructose or myricetin administration. The expression of the mitochondrial fission marker dynamin-related protein 1 and the mitophagic marker PTEN-induced kinase 1 (PINK1) was enhanced in the fructose-fed rat, and myricetin treatment markedly attenuated PINK1 expression. High-fructose intake augmented phosphorylation of the proinflammatory molecule Nuclear factor kappa B (NF-κB) and the stress-regulated kinase JNK1, but myricetin only reduced NF-κB expression. Moreover, myricetin diminished the elevation in the expression of the pro-apoptotic Bax. CONCLUSION: Our results imply that myricetin has a protective role in cardiac irregularities induced by a high-fructose diet through reducing systolic blood pressure, improving cardiac adrenergic responses, suppressing PINK1, NF-κB, and Bax expression, and thus reflecting a potential therapeutic value.

Resveratrol and regular exercise may attenuate hypertension-induced cardiac dysfunction through modulation of cellular stress responses.

AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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-1ß/pro-IL-1ß 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. SIGNIFICANCE: 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.

Reversal of deleterious effect of hypertension on the liver by inhibition of endoplasmic reticulum stress.

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 κB-α (p-IκB-α) 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.

Hypertension-induced cardiac impairment is reversed by the inhibition of endoplasmic reticulum stress.

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.

Activation of Liver X Receptors by GW3965 Attenuated Deoxycorticosterone Acetate-Salt Hypertension-Induced Cardiac Functional and Structural Changes.

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-chloro-3-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-κB p65 (NF-κB p65) expression was augmented, and inhibitor-κB-α (IκB-α) 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 hypertension-induced cardiac changes without undesired effects.

Differential expressions and functions of phosphodiesterase enzymes in different regions of the rat heart.

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.

Inhibition of endoplasmic reticulum stress protected DOCA-salt hypertension-induced vascular dysfunction.

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.

Role of microcirculatory function and plasma biomarkers in determining the development of cardiovascular adverse events in patients with peripheral arterial disease: A 5-year follow-up.

OBJECTIVE: The aim of this long-term follow-up study was to investigate the association of local and systemic cardiovascular complications with endothelium-dependent and-independent microvascular relaxations and blood biomarkers and biochemicals in patients with peripheral arterial disease (PAD) caused by atherosclerosis. METHODS: This prospective study included 67 patients with PAD who had not undergone any endovascular intervention, peripheral arterial surgery, or major amputation. Changes in the microvascular blood flow were measured using laser Doppler imaging after iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). The biochemical markers of high sensitivity C reactive protein (hs-CRP), nitric oxide (NO), total antioxidant capacity (TAC), asymmetric dimethyl arginine (ADMA), and hydrogen sulfide (H2S) levels were measured from blood samples. All the patients were followed up for 5 years to determine the development of cardiovascular adverse events (CVAEs) and major amputation. At the end of the follow-up period, the patients were classified into two groups: those who had a CVAE [CVAE (+)] and those who did not experience CVAE [CVAE (-)]. Parameters such as demographic features, atherosclerotic risk factors, chronic ischemia category, microvascular endothelial functions, and plasma biomarkers were compared between the groups. RESULTS: A total of 67 patients comprising 61 (91%) males and 6 (9%) females with a mean age of 62.3±9.7 years were included. During the follow-up period, 29 patients had CVAE (43.3%) and 38 patients did not have CVAE (56.7%). There was no difference between the groups in terms of ACh and SNP-induced vasodilation responses. Plasma high density lipoprotein (HDL) cholesterol values were lower in the CVAE (+) group [(CVAE+HDL: 38.4±9.1), (CVAE-HDL: 44.7±11.1), p=0.02]. Plasma hs-CRP values were significantly higher in the CVAE (+) group [(CVAE+ hs-CRP: 14.3±20.6), (CVAE-hs-CRP: 5.9±10.9), p=0.004]. No significant difference was observed between the groups in terms of plasma biomarkers and other biochemical levels. CONCLUSION: Based on the study findings, it was concluded that only low plasma HDL and high hs-CRP levels were risk factors for the development of CVAEs during follow-up of patients with PAD.

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

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.

The effects of different remote ischemic conditioning on ischemia-induced failure of microvascular circulation in humans.

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.

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.

Venous stent placement ameliorates cutaneous microvascular function in iliocaval venous obstruction.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: ICVO impairs endothelium-dependent and endothelium-independent vasodilation in the perimalleolar region. Iliocaval venous stent placement may recover microvascular dysfunction at different levels.

Age- and sex-dependent alteration of functions and epigenetic modifications of vessel 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.

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 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.

Resveratrol affects histone 3 lysine 27 methylation of vessels and blood biomarkers in DOCA salt-induced hypertension.

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.

The anti-inflammatory effect of diclofenac is considerably augmented by topical capsaicinoids-containing patch in carrageenan-induced paw oedema of rat.

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 µg/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.

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.

Various phosphodiesterase activities in different regions of the heart alter the cardiac effects of nitric oxide.

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.

Nitric oxide effects depend on different mechanisms in different regions of the rat heart.

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.