Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.

AIMS: Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. METHODS AND RESULTS: Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARß/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. CONCLUSION: These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.

A mathematical model of the metabolic process of atherosclerosis.

A mathematical model of the metabolic process of atherosclerosis is constructed. The functioning of the polyenzymatic prostacyclin-thromboxane system of blood and the influence of a level of "bad cholesterol", namely low density lipoproteins (LDL), on it are studied. With the help of the numerical experiment, we analyze the influence of the concentration of molecules of fat on hemostasis of blood in blood vessels. The kinetic curves for components of the system, phase-periodic bifurcation diagrams, attractors for various modes, and Poincaré cross-section and image of a strange attractor are constructed. The complete spectra of Lyapunov's exponents, divergencies, KS-entropies, predictability horizons, and Lyapunov dimensions of the fractality of strange attractors are calculated. Conclusions about the structural-functional connections, which determine the dependence of hemostasis of a circulatory system on the level of cholesterol in blood are drawn.

Salvia Miltiorrhiza Bge.f.alba Ameliorates the Progression of Monocrotaline-Induced Pulmonary Hypertension by Protecting Endothelial Injury in Rats.

Pulmonary hypertension (PH) is a life-threatening disease that is characterized by elevated pulmonary blood pressure, abnormally thickened pulmonary arteries, and right ventricular hypertrophy. Monocrotaline (MCT) has been used to generate an experimental model of PH in rats, with PH initiated from injuries of lung vascular endothelium. Salvia Miltiorrhiza Bge.f.alba is a widely used traditional herb in China, known to exert protective effects on vascular endothelial cell injury in animal experiments. However, the role of Salvia Miltiorrhiza Bge.f.alba in PH remains unclear. Thus, we investigated the effects of the aqueous extract of Salvia Miltiorrhiza Bge.f.alba (AESM) on MCT-induced PH and explored the pertinent mechanism. PH was induced in rats by a single subcutaneous injection of MCT (60 mg/kg body weight). Low or high dose (4.6 g/kg or 14 g/kg body weight) of AESM was then administered orally for 21 days to PH rats. Hemodynamic study showed that AESM reduced mean pulmonary artery pressure and improved right ventricle function. Lung pathological analysis revealed that AESM reduced wall thickness and lumen stenosis of pulmonary vessels. Also AESM ameliorated right ventricular hypertrophy. Measurement of biochemical parameters indicated that AESM decreased endothelin-1 and thromboxane A2 in plasma and increased nitrogen monoxide and prostacyclin in the plasma and reduced the increase of transforming growth factor ß1 in lung tissue. Our results suggest that AESM may ameliorate the progression of MCT-induced PH in rats, at least in part by its protective effect on endothelial injury. Therefore, Salvia Miltiorrhiza Bge.f.alba could be useful in the treatment of PH.

Low dose aspirin and low-molecular-weight heparin in the treatment of pregnant Libyan women with recurrent miscarriage.

BACKGROUND: Recurrent miscarriage is a major women's health problem. Aspirin and heparin have been shown to have potentially beneficial effects on trophoblast implantation. However, few published data on this issue are available from developing countries. METHODS: An open clinical trial was conducted at the Department of Obstetrics and Gynecology at Misurata Teaching Hospital in Libya from January 2009 to December 2010 to investigate the effects of treatment with low dose aspirin (LDA) versus treatment with low-molecular-weight-heparin (LMWH) in combination with LDA on patients with a history of recurrent miscarriages. A total of 150 women were enrolled in the study. Women were eligible for the study if they had a history of three or more consecutive miscarriages. Participants were randomly assigned to receive either LDA (75 mg daily) alone or a combination of LDA and LMWH (75 women per treatment group). The primary outcomes were the rate of miscarriages and live births for each group. RESULTS: Compared with the group who received LDA alone, the combination group had a significantly lower number of miscarriages (22/75 [29%] vs. 43/75 [47%], P < 0.001) and had a significantly higher number of live births (53/75 [71%] vs. 32/75 [42%], P < 0.001). Two preterm infants in the LDA group and three in the combination group were admitted to the neonatal intensive care unit. There were no significant differences in the mean (SD) birth weights of neonates born in either group (2955.4 ± 560 vs. 3050 ± 540 g for the LDA and combination groups, respectively, P = 0.444). There were no congenital abnormalities detected in either group. CONCLUSION: The combination of LDA and LMWH is better than LDA alone for the maintenance of pregnancy in patients with recurrent first trimester miscarriage. TRIAL REGISTRATION: NCT01917799.

[Effects of ATP-sensitive potassium channel opener iptakalim against ventricular remodeling and its mechanisms of endothelial protection].

OBJECTIVE: To study the effects of iptakalim (Ipt), an ATP-sensitive potassium channel opener, on cardiac remodeling induced by isoproterenol (ISO) in Wistar rats. METHODS: ISO was given subcutaneously (85 mg/(kg x d), sc, 7 days) to induce cardiac remodeling in rats. The rats in Ipt treated group were administrated with Ipt 3 mg/kg (po) after ISO injection. After treated with Ipt for 6 weeks, the hemodynamic parameters were tested by an eight channel physiological recorder (RM-6000). Then the heart weight was weighed and the cardiac remodeling index was calculated. HE stain and Masson's stain were employed to perform histological analysis, the hydroxyproline(Hyp) content in cardiac tissue was detected by colorimetric method, radioimmunoassay was used to measure the plasma levels of endothelin-1 (ET-1) and prostacyclin (PGI2). RESULTS: Six weeks after ISO injection, the cardiac functions of model group were damaged markedly compared with those of normal group. The characteristics of ventricular remodeling in model group included that the heart weight index, myocyte cross-sectional area, myocardial fibrosis, and the hydroxyproline content in cardiac tissue were all increased significantly. The plasma level of ET-1 was increased, while the plasma level of PGI2 was decreased significantly. These changes could be reversed by Ipt treatment (3 mg/(kg x d) for 6 weeks). CONCLUSION: Ipt can reverse cardiac remodeling induced by isoproterenol in rats. The endothelial protective effect regulating effects of Ipt on the balance between the ET-1 and PGI2 system may be involved in its mechanisms.

Significant prostacyclin/thromboxane level imbalance after lower limb arterial angioplasty: a possible platelet function alteration.

PURPOSE: The authors investigated prostacyclin (PGI2) and thromboxane (TX) productions in peripheral venous blood after lower limb revascularization by percutaneous transluminal angioplasty (PTA) versus diagnostic angiography. The purpose of this study was to investigate PGI2/TX imbalance after PTA. This imbalance is of pathophysiologic importance and it is a potential sign of platelet function alteration. MATERIALS AND METHODS: Twenty-five patients requiring PTA were compared with 20 patients undergoing angiography alone from April 2004-December 2005 from a single vascular unit. Patient age range was 42-90 years, and the majority of patients were men. Prostaglandin F2-alpha (PGF2-alpha) and thromboxane B2 (TXB2) were measured sequentially (preprocedure, at 1 hour, and 24 hours after procedure). Differences between postprocedure and preprocedure level were compared statistically between angiography and PTA. RESULTS: Baseline demographics were distributed equally between the two groups except presence of critical ischemia and ankle brachial pressure index, which were two significant confounders. TXB2 was significantly higher after PTA at 1 hour and 24 hours after PTA (P = .005 and P = .014 respectively), PGF2-alpha was significantly higher 24 hours after PTA only (P = .018) (Mann-Whitney U test). CONCLUSIONS: PGI2/TX balance homeostasis is of significant pathophysiologic importance. The authors found that PTA results in significant PGI2/TX imbalance and shifts more toward increased TX production. This finding is partly suggestive of significant platelet activation. This imbalance in PGI2/TX level may have implications for future failure of PTA. Future research in reducing this platelet activation is recommended.

Aging and prostacyclin responses in aorta and platelets from WKY and SHR rats.

In spontaneously hypertensive rat (SHR) aorta, prostacyclin is an endothelium-derived contracting factor contributing to the endothelial dysfunction. This study was designed to determine whether the impairment of the prostacyclin response is influenced by aging and whether such a dysfunction is observed in platelets. Isometric tension was measured in aortic rings, and aggregation was studied in platelet-rich plasma taken from 3-, 6-, and 15-mo-old Wistar-Kyoto rats (WKY) and SHR. In aorta from 3- and 6-mo-old WKY, prostacyclin and beraprost [prostacyclin receptor (IP) agonists] produced relaxations that were enhanced by Triplion (thromboxane-prostanoid receptor antagonist). In 15-mo-old WKY, the relaxations to beraprost were maintained, but not those to prostacyclin. In SHR aorta, prostacyclin or beraprost produced no or minor relaxations, which, in younger SHR, were enhanced by Triplion. In both strains, the relaxations were inhibited by CAY-10441 (IP receptor antagonist). The relaxations to forskolin and isoproterenol were reduced with aging. When compared with those of WKY, the relaxations to isoproterenol were reduced in 3- but not in 6- or 15-mo-old SHR, whereas those to forskolin were consistently diminished at any given age. Whatever the age, prostacyclin and beraprost produced CAY-10441-sensitive inhibitions of ADP-induced platelet aggregation. Both agonists were more potent in SHR than in WKY. Therefore, in platelets from WKY and SHR, the IP receptor-dependent antiaggregant response is functional and maintained during aging. In aorta from WKY those responses are reduced by aging and, in SHR, are already compromised at 3 mo. This dysfunction of the IP receptor is only partially explained by a general dysfunction of the adenylate cyclase pathway.

Effect of palm oil on blood pressure, endothelial function and oxidative stress.

The pathogenesis of hypertension has been associated with endothelial dysfunction and oxidative stress. We have previously shown that palm oil (PO), with an unsaturated-to-saturated fatty acid ratio close to one and rich in antioxidants vitamins, reduces oxidative stress-induced hypertension in normal rats. Here, we investigated the cardiovascular effects of natural vitamin-rich PO using the Dahl Salt-sensitive hypertension model. Male rats were fed either a high salt (8%NaCl, HS) or low salt (0.3% NaCl, LS) diet with or without PO (Carotino, 5 g/kg daily) for four weeks. Mean arterial pressure (MAP), heart rate, blood flow and vascular resistance, vascular reactivity in vitro as well as remodelling of second-order mesenteric arteries were measured. Plasma levels of nitric oxide (NO), prostacyclin, thromboxane A(2) (TXA(2)) and isoprostane (ISO), were determined by enzyme immunoassay. Plasma, heart and kidney GSH and GSSG levels were analyzed by HPLC and aortic superoxide ((.)O(2)-) production by fluorescence spectrometry. High salt induced an elevation in MAP that was associated with decreased NO, prostacyclin and GSH: GSSG ratio. Plasma ISO and TXA(2), aortic and renal vascular resistance as well as aortic (.)O(2)- were increased. Palm oil reduced MAP, plasma TXA(2) and vascular resistance of the renal and aortic arteries, and increased the GSH: GSSG ratio and NO in the LS group. The HS-induced elevation in ISO and (.)O(2)- production and the reductions in kidney GSH: GSSG ratio, were attenuated by PO. The effect of PO was also associated with a reduced vessel wall-thickness: lumen diameter ratio and a greater relaxant effect of mesenteric arteries to acetylcholine, in the LS group. The mortality associated with HS was reduced by PO. Thus, palm oil attenuates the progression of salt-induced hypertension and mortality, via mechanisms involving modulation of endothelial function and reduction in oxidative stress.

[Effect of fosinopril on some parameters of endothelial function in patients with metabolic syndrome].

Angiotensin converting enzyme inhibitor fosinopril was given for 12 weeks to 92 patients with hypertension and metabolic syndrome. Spectra of carbohydrates and lipids, blood plasma kallikrein-kinin and prostacyclin-thromboxane systems, vascular endothelium dependent vasodilating function were studied in all patients. Hypertension was accompanied with lowering of endothelium dependent vasodilation which degree correlated with lowering of prostacyclin and elevation of thromboxane levels, dys-balance of kallikrein-kinin system as well as with severity of hypertension and metabolic syndrome. Effective blood pressure lowering caused by therapy with fosinopril was associated with stabilization of parameters of kallikrein-kinin and prostacyclin-thromboxane systems, improvement of endothelium dependent vasodilation.