BIFUNCTIONAL ADDITIVE TO DIESEL FUELS

В статье показано, что разработка отечественных присадок на сегодняшний день является актуальной и стратегически важной задачей. На основе побочных продуктов нефтехимических производств ООО «Газпром нефтехим Салават» была разработана оптимальная рецептура депрессорной присадки, показавшая свою эффективность на дизельных топливах различного состава и происхождения. Максимальный депрессорный эффект составил 18 ºС. Влияние разработанной присадки на противоизносные свойства дизельного топлива оказало также положительный эффект со снижением скорректированного диаметра пятна износа до 24%. Физико-химические свойства дизельных топлив при введении в их состав 0,2% мас. разработанной присадки удовлетворяют требованиям ГОСТ 32511-2013. The article shows that the development of domestic additives is currently an urgent and strategically important task. The optimal formulation of the depressant additive was developed based on the by- products of the petrochemical production of Gazprom Neftekhim Salavat LLC. It has been shown effectiveness on diesel fuels of various composition and produsers. The maximum depressor effect was 18 °C. The effect of the developed additive on the anti-wear properties of diesel fuel also had a positive effect with a reduction in corrected wear scar diameter to 24%. The physico-chemical properties of diesel fuels with the introduction of 0.2% by weight of the developed additive meet the requirements of GOST 32511-2013. The significant important task - the rational use of by-products is solved with the developed additive.

Oestrogen inhibits salt-dependent hypertension by suppressing GABAergic excitation in magnocellular AVP neurons

Aims Abundant evidence indicates that oestrogen (E2) plays a protective role against hypertension. Yet, the mechanism underlying the antihypertensive effect of E2 is poorly understood. In this study, we sought to determine the mechanism through which E2 inhibits salt-dependent hypertension. Methods and results To this end, we performed a series of in vivo and in vitro experiments employing a rat model of hypertension that is produced by deoxycorticosterone acetate (DOCA)-salt treatment after uninephrectomy. We found that E2 prevented DOCA-salt treatment from inducing hypertension, raising plasma arginine-vasopressin (AVP) level, enhancing the depressor effect of the V1a receptor antagonist (Phenylac1,D-Tyr(Et)2,Lys6,Arg8,des-Gly9)-vasopressin, and converting GABAergic inhibition to excitation in hypothalamic magnocellular AVP neurons. Moreover, we obtained results indicating that the E2 modulation of the activity and/or expression of NKCC1 (Cl− importer) and KCC2 (Cl− extruder) underpins the effect of E2 on the transition of GABAergic transmission in AVP neurons. Lastly, we discovered that, in DOCA-salt-treated hypertensive ovariectomized rats, CLP290 (prodrug of the KCC2 activator CLP257, intraperitoneal injections) lowered blood pressure, and plasma AVP level and hyperpolarized GABA equilibrium potential to prevent GABAergic excitation from emerging in the AVP neurons of these animals. Conclusion Based on these results, we conclude that E2 inhibits salt-dependent hypertension by suppressing GABAergic excitation to decrease the hormonal output of AVP neurons.

Abstract 033: Depressor Mechanisms of Nicotinamide in a Murine Model of Preeclampsia

Introduction: We have reported that upregulation of the endothelin (ET) system plays a pivotal role in a mouse model of preeclampsia. Because ETA receptor antagonists are teratogenic, we cannot use them to treat pregnant women. Nicotinamide (Nam) inhibits ADP ribosyl cyclase (ADPRC), diminishes a release of Ca 2+ from intracellular stores, and dilates vessels constricted by ET. We have recently reported that Nam ameliorates the high BP induced by excessive sFlt-1. Nam also shows beneficial effects on pregnancy maintenance and fetal growth. Objective: The aim of the present study is to clarify the depressor mechanisms of Nam. Methods: We measured tail-cuff BP before and 5 days after administering 1x10 9 pfu sFlt-1 in non-pregnant WT mice and mice lacking CD38, the major form of ADPRC. We next measured SBP using radiotelemetry to investigate effects of Nam 500 mg/kg BW by using DAB (2,2’-dihydroxyazobenzene, a specific inhibitor of ADPRC) 0.1 mmol/kg BW, CrMP (chromium mesoporphyrin, a specific inhibitor of heme oxygenase) 2 μmol/kg, or fasudil (a Rho kinase inhibitor) 40 mg/kg. Results: Lack of CD38 prevented sFlt-1 induced hypertension (WT 106.0 ± 2.1 mmHg, CD38-/- 105.0 ± 2.1 mmHg, WT sFlt-1 126.3 ± 2.0 mmHg, CD38-/- sFlt-1 110.2 ± 1.2 mmHg), and diminished the decrease in SBP by Nam. DAB transiently decreased SBP, whereas Nam has a depressor effect lasting more than an hour. Pretreatment with CrMP for 30 min reversed the hypotensive effect of Nam within 60min. Both Nam and fasudil decreased elevated BP by sFlt-1, and the combination of them additively decreased BP (sFlt-1 145.9 ± 3.6 mmHg, sFlt-1+Nam 122.9 ± 7.1 mmHg, sFlt-1+fasudil 93.6 ± 9.7 mmHg, sFlt-1+Nam+fasudil 81.9 ± 8.9 mmHg). Conclusions: Nam decreases BP in mice by inhibiting ADPRC and by increasing the production of HO-1. Fasudil explains why depressor effect of Nam is smaller than that of inhibiting ETAR. However, because fasudil is teratogenic, Nam is a promising drug to treat hypertension in preeclampsia.

Abstract P192: AT1R Blockade Increases the Depressor Effect of Alamandine in Normotensive SD Rats

The renin–angiotensin system (RAS) plays a critical role in blood pressure control and electrolyte homeostasis. It has been established that Ang II is not the only active peptide of the RAS. Recently, new active fragments formed through metabolism of the classical axis peptides have been identified and their biological effects characterized. One of these peptides, is Alamandine, which was described by our group. Here we investigate the effect of Alamandine on blood pressure in non-anesthetized SD rats. To study the in vivo effects of this peptide, we used 12 weeks old SD rats (300-400 g). Administration of drugs and the blood pressure measurement were performed with a cannula inserted through the femoral vein and artery, respectively. We administered Alamandine with bolus injections (0.02, 0.2 ,1 ,5, 20 and 80 ng). A biphasic effect of alamandine was observed. The greatest depressor effect of Alamandine was observed at a lower dose, 1 ng. (Δ MAP: - 10.33±0.85 mmHg p <0.05). On the other hand, the highest dose, 80 ng, did not change significantly the blood pressure. Interestingly, when Losartan (5mg/kg) was administered 30min before the injection of alamandine, the depressor effect of this peptide was increased, mainly at 0.2 ng (Δ MAP: - 6±1.05 mmHg Alamandine vs. Δ MAP: - 20.33 ± 2,34 mmHg Alamandine after Losartan p <0.05). In losartan treated rats only depressor response were observed with all doses. In conclusion, our data show that Alamandine has a biphasic effects on blood pressure and seems to interact whith AT1 receptor in a dose - dependent manner.

Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension

The aim of the present study was to determine whether long-term high salt intake in the drinking water induces hypertension in wild-type (WT) mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. Eight-week-old male WT mice were supplied with drinking water containing 2% salt for 12 wk (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at four different doses (25, 50, 75, or 100 mg/kg), captopril (75 mg/kg), losartan (100 mg/kg), hydrochlorothiazide (3 mg/kg), eplerenone (200 mg/kg), or amlodipine (6 mg/kg). Control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, whereas a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan- and eplerenone-treated groups but not in the captopril-, hydrochlorothiazide-, and amlodipine-treated groups. A high salt load significantly increased chymase-dependent ANG II-forming activity in the alimentary tract. In addition, the relative contribution of chymase to ANG II formation, but not actual average activity, showed a significant increase in skin and skeletal muscle, whereas angiotensin-converting enzyme-dependent ANG II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary renin-angiotensin system components were significantly increased in the high-salt group but were significantly suppressed in the chymase inhibitor-treated group. In conclusion, 2% salt water drinking for 12 wk caused moderate hypertension and activated the renin-angiotensin system in WT mice. A chymase inhibitor suppressed both the elevation of blood pressure and heart rate, indicating a definite involvement of chymase in salt-sensitive hypertension.

Abstract 016: Bbs1 Gene Deletion From The Leptin Receptor Neurons Causes Obesity And Hypertension In Mice

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive disorder associated with several features including obesity and hypertension. Deletion of BBS genes globally or in the nervous system recapitulated many of the BBS phenotypes including obesity and hypertension. Here, we assessed the effect of ablating the Bbs1 gene from the neurons expressing the long signaling form of the leptin receptor (LepRb). Breeding Bbs1 flox with LepRb Cre mice created mice deficient in the Bbs1 gene only in LepRb-positive neurons (visualized by tdTomato expression) as indicated by loss of leptin activation of Stat3. Importantly, Bbs1 flox /LepR Cre mice display an obesity phenotype as indicated by the increased (P<0.05) body weight (39±2 vs. 30±1 g in controls) and fat mass measured by MRI (14±3 vs. 4±1 g in controls) associated with increased (P<0.05) food intake (3.4±0.1 vs. 2.9±0.1 g in controls) in 25 weeks old mice. However, body weight and fat pads of pair-fed LRb Cre /Bbs1 fl/fl mice remained significantly elevated compared to controls suggesting that LRb Cre /Bbs1 fl/fl mice have reduced energy expenditure. Consistent with this possibility, LRb Cre /Bbs1 fl/fl mice displayed decreased (P<0.05) O 2 consumption (2.6±0.1 vs. 3.1±0.1 mL/100g/min in controls) and heat production (8.1±0.3 vs. 9.6±0.3 kcal/kg/h in controls). These results indicate that hyperphagia and decreased energy expenditure contribute to the development of obesity in Bbs1 flox /LepR Cre mice. Next, we assessed the effect on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from the LepR-containing neurons. Interestingly, deletion of the Bbs1 gene in LepR neurons recapitulates the hypertension phenotype of BBS as indicated by elevated mean AP (125±4 vs 109±3 mmHg in controls, P=0.03). Conscious renal SNA was also elevated in LRb Cre /Bbs1 fl/fl mice relative to controls (97±8 vs 62±10 spikes/sec, P<0.05). Finally, the depressor effect of ganglionic blockade (hexamethonium) was exaggerated in Bbs1 flox /LepR Cre mice (-57±5 vs -38±5 mmHg in control, P=0.01). These findings demonstrate that the Bbs1 gene in LepR neurons is critical for energy homeostasis and arterial pressure regulation.

Abstract 266: Effects Of Carotid Body Tumor Resection On Blood Pressure

Introduction: Removal of carotid body (CB) improves rodent models of HTN and HF, presumably via withdrawal of chemoreflex-induced sympathetic activation. CB tumor (CBT) resection abolishes the chemoreflex in humans and is associated with opposing effects on sympathetic regulation by accompanying damage of the baroreflex. The net effect of CBT removal on BP in subjects with pre-existent HTN is unknown. Methods: Retrospective analysis of 134 patients with uni- or bilateral CBT resection between 1990-2012. Twenty subjects met HTN entry criteria (BP≥140/90 mmHg or use of antihypertensive drugs) but two were excluded from analyses because of inadequate data. BP changes were assessed by a) acute ΔSBP: the change from the average SBP for the 3 months preceding surgery to the first reading after 30 days from the procedure, and b) chronic: the slope of the regression of SBP on time over the entire follow up, expressed as ΔSBP/year. BP changes were adjusted with covariate analyses. Covariates for acute ΔSBP were: the interval between pre and post BP readings and the change in therapy during this interval (assessed by a score of medications based on equipotency). Covariates for chronic ΔSBP were: total duration of follow-up, number of SBP readings and change in therapy during the entire period of study. Results: Age and duration of HTN were 56±4 and 10±4 years, respectively. There was a significant relationship between acute ΔSBP and the chronic slopes (r=0.47, p<0.05) indicating that initial BP responses to CBT removal tend to be sustained. The univariate relationship showed that for every change of 0.4 mmHg in acute ΔSBP, there was a concomitant 1 mmHg/yr change in the chronic slope. Thirteen subjects (72%) had concordant reductions of ΔSBP and slope of any magnitude. In 6 subjects (33%), acute ΔSBP was ≥ -10 mmHg (corresponding to concomitant slopes ≥ 5.9 mmHg/yr). Conclusions: This is the first study to show that CBT removal is associated with a sustained reduction of BP in a subset of patients with comorbid HTN. Also, concomitant baroreceptor damage by CBT removal most likely leads to underestimation of the depressor effect of chemoreflex disruption. Development of a targeted removal of CB chemoreflex may conceivably have a role in the therapy of human hypertension.