Pharmacoinformatics studies of coenzyme Q10 and potassium polyacrylate on angiotensin-converting enzyme associated with hypertension.

Coenzyme Q10's (CoQ10) favorable impact on cardiovascular diseases risk factors like hypertension and atherosclerosis is linked to the antioxidant action of CoQ10 in these conditions. This study showed the possible effects of CoQ10, potassium polyacrylate (PCK), and valsartan, a reference drug, on the angiotensin-converting enzyme (ACE), a crucial component of the renin-angiotensin system. The Glide tool on Maestro 11.1 was used to calculate the respective binding affinity and binding energy of these compounds towards ACE. The Schrödinger suite was used to run molecular dynamic simulations for 100 ns. The pkCSM tool was used to forecast the pharmacokinetic characteristics and toxicological effects. The SwissADME server was used to estimate the drug-like properties of these compounds. Based on their corresponding scoring values and the negative values of the binding free energies, molecular docking analysis of CoQ10 and PCK revealed that both exhibited favorable binding affinities towards the ACE, with CoQ10 having the highest binding scores. The results showed that both CoQ10 and PCK and the reference drug, valsartan, have some amino acids in common (at the pocket site of ACE) as the key residues for binding to ACE. Both CoQ10 and PCK demonstrated drug-like qualities and were not harmful, according to the predicted pharmacokinetics and toxicology studies. The results of this study suggest that because of its inhibitory interactions with ACE, CoQ10 in particular could be useful in regulating and reducing hypertension.Communicated by Ramaswamy H. Sarma.

Nitric oxide-inhibited chloride transport in cortical thick ascending limbs is reversed by 8-iso-prostaglandin-F2α.

BACKGROUND: Sodium chloride (NaCl) reabsorption in the cortical thick ascending limb (cTAL) is regulated by opposing effects. Nitric oxide (NO) inhibits NaCl reabsorption while 8-iso-prostaglandin-F2α (8-iso-PGF2α) stimulates it. Their interaction has not been evaluated in the cTAL. Because 8-iso-PGF2α has considerable stability while NO is a free radical with a short half-life, we hypothesized that, in the cTAL, the inhibition of NaCl absorption will be reversed by 8-iso-PGF2α. METHODS: Chloride absorption (JCl) was measured in isolated perfused cTALs and whether the activation of protein kinase A (PKA) is required for this interaction. Since cyclic adenosine monophosphate (cAMP) is a major messenger for the 8-iso-PGF2α signaling cascade, and NO inhibits JCl by decreasing cAMP bioavailability, we measured 8-iso-PGF2α-stimulated cAMP in the presence of sodium nitroprusside (SNP). RESULTS: The NO donor, SNP (10-6 M), decreased JCl by 41%, while luminal 8-iso-PGF2α (100 µM) increased JCl to 315 ± 46 pmol/ min/mm (p < 0.003), reversing the effects of the NO donor. SNP inhibited JCl, 8-iso-PGF2α failed to increase JCl in the presence of H89. Basal cAMP was 56 ± 13 fmol/min/mm, in the presence of SNP 57 ± 6 fmol/min/mm, and 8-iso-PGF2α increased it to 92 ± 2 fmol/min/mm (p < 0.04). CONCLUSION: We concluded that 1) NO-induced inhibition of JCl in the cTAL can be reversed by 8-iso-PGF2α, 2) 8-iso-PGF2α and NO interaction requires PKA to control JCl, and 3) in the presence of NO, 8-iso-PGF2α continues to stimulate JCl because NO cannot reverse 8-iso-PGF2α-stimulated cAMP level.

An intensive follow-up in subjects with cardiometabolic high-risk.

BACKGROUND AND AIM: Addressing chronic problems requires a model of care that promotes self-management of the disease and facilitates adherence to treatment. This project was designed to enhance patient's clinical and functional outcomes through a Comprehensive Model to be implemented in our health system and to evaluate the results. METHODS AND RESULTS: Different population stratification tools were tested and designed to classify subjects according to different variables. We have developed a program to detect and screen cardiometabolic risk by integrating most of the Chronic Care Model recommendations through in-house developed management software (MoviHealth®). From the results, 1317 subjects were evaluated (27% of the whole population) during the first year of follow-up which significantly improved for all variables along the follow-up period. The blood pressure of the hypertensive population in 2010 and 2015 showed the importance of enrollment of subjects and the optimization of the blood pressure control. The result of HbA1c observed in 2010 decreased progressively to 7.1 ± 1.4% in 2015, and dyslipidemia levels improved gradually. The number of cardiovascular events requiring hospitalization decreased significantly (48%), from 1.9 events per 100 subjects in 2011 to 0.98 in 2015. CONCLUSION: Our program has combined strategies for the prevention and control of non-communicable diseases, incorporating interventions to control risk factors and to reduce morbidity and mortality. It also had improvements in life quality, accessibility to health-care services, and the promotion of self-care.

Reversal of SARS-CoV2-Induced Hypoxia by Nebulized Sodium Ibuprofenate in a Compassionate Use Program.

INTRODUCTION: Sodium ibuprofenate in hypertonic saline (NaIHS) administered directly to the lungs by nebulization and inhalation has antibacterial and anti-inflammatory effects, with the potential to deliver these benefits to hypoxic patients. We describe a compassionate use program that offered this therapy to hospitalized COVID-19 patients. METHODS: NaIHS (50 mg ibuprofen, tid) was provided in addition to standard of care (SOC) to hospitalized COVID-19 patients until oxygen saturation levels of > 94% were achieved on ambient air. Patients wore a containment hood to diminish aerosolization. Outcome data from participating patients treated at multiple hospitals in Argentina between April 4 and October 31, 2020, are summarized. Results were compared with a retrospective contemporaneous control (CC) group of hospitalized COVID-19 patients with SOC alone during the same time frame from a subset of participating hospitals from Córdoba and Buenos Aires. RESULTS: The evolution of 383 patients treated with SOC + NaIHS [56 on mechanical ventilation (MV) at baseline] and 195 CC (21 on MV at baseline) are summarized. At baseline, NaIHS-treated patients had basal oxygen saturation of 90.7 ± 0.2% (74.3% were on supplemental oxygen at baseline) and a basal respiratory rate of 22.7 ± 0.3 breath/min. In the CC group, basal oxygen saturation was 92.6 ± 0.4% (52.1% were on oxygen supplementation at baseline) and respiratory rate was 19.3 ± 0.3 breath/min. Despite greater pulmonary compromise at baseline in the NaIHS-treated group, the length of treatment (LOT) was 9.1 ± 0.2 gs with an average length of stay (ALOS) of 11.5 ± 0.3 days, in comparison with an ALOS of 13.3 ± 0.9 days in the CC group. In patients on MV who received NaIHS, the ALOS was lower than in the CC group. In both NaIHS-treated groups, a rapid reversal of deterioration in oxygenation and NEWS2 scores was observed acutely after initiation of NaIHS therapy. No serious adverse events were considered related to ibuprofen therapy. Mortality was lower in both NaIHS groups compared with CC groups. CONCLUSIONS: Treatment of COVID-19 pneumonitis with inhalational nebulized NaIHS was associated with rapid improvement in hypoxia and vital signs, with no serious adverse events attributed to therapy. Nebulized NaIHS s worthy of further study in randomized, placebo-controlled trials (ClinicalTrials.gov: NCT04382768).

Obesidad central, sarcopenia y conductas sedentarias en el riesgo cardiovascular por score Framingham y área total de placa carotídea / Central Obesity, Sarcopenia, and Sedentary Behaviors Related to Cardiovascular Risk by Framingham Score and Total Carotid Plaque Area

Resumen Antecedentes: las enfermedades cardiovasculares son la principal causa de morbimortalidad mundial. La obesidad, sarcopenia, actividad física insuficiente y las conductas sedentarias impactan de manera sinérgica en el riesgo cardiovascular. Objetivo: evaluar el riesgo cardiovascular en relación con la actividad física, las conductas sedentarias y la composición corporal. Materiales y métodos: estudio observacional transversal de 95 personas adultas de ambos sexos. Se determinó el riesgo cardiovascular mediante el score de Framingham y el score de Framingham corregido por área total de placa aterosclerótica; la composición corporal, por antropometría, bioimpedancia y dinamometría como indicador indirecto; y la actividad física y las conductas sedentarias, por cuestionario validado. Se condujeron análisis descriptivos, de correlación y asociación con un 95 % de confianza. Resultados: el 95 % de las mujeres y el 98 % de los varones presentaron riesgo cardiovascular elevado; el 51,5 %, obesidad; el 95,5%, obesidad central; y el 47,3 %, fuerza muscular disminuida. Se observaron asociaciones positivas significativas entre riesgo cardiovascular y circunferencia de cintura (rho=0,26; p=0,024). No hubo asociación significativa entre la fuerza muscular y el riesgo cardiovascular (rho=-0,21; p=0,065). La conducta sedentaria tuvo un efecto promotor del riesgo cardiovascular (OR=3,9; p=0,033). Conclusiones: la obesidad central y permanecer más de 6/h día en posición sedente son factores asociados al riesgo cardiovascular.

Abstract Background: Cardiovascular diseases are the principal cause of morbidity and mortality worldwide. Obesity, sarco-penia, insufficient physical activity, and sedentary behaviors synergistically impact cardiovascular risk. Objective: Evaluate cardiovascular risk in relation to physical activity, sedentary behaviors, and body composition. Materials and Methods: Cross-sectional observational study in 95 total males and females. Cardiovascular risk was determined using the Framingham score, which corrects for total area of atherosclerotic plaque. Risk was also determined using body composition, anthropometry, bioimpedance and dynamometry as indirect indicators, physical activity, sedentary behaviors, and a validated questionnaire. Descriptive, correlation and association analyses were conducted with 95% confidence. Results: 95% of women and 98% of men presented with an elevated cardiovascular risk; 51.5% with obesity, 95.5% central obesity, and 47.3% with diminished muscular strength. Significant positive associations were observed between cardiovascular risk and waist circumference (rho=0.26; p=0.024). There was no significant association between muscle strength and cardiovascular risk (rho=-0.21, p=0.065). Sedentary behavior increased cardiovascular risk (OR=3.9; p=0.033). Conclusions: Central obesity and staying more than six hours per day in a sitting position are factors associated with cardiovascular risk.

Ibuprofen, a traditional drug that may impact the course of COVID-19 new effective formulation in nebulizable solution.

The traditional formulation of ibuprofen is poorly soluble in water, so the administered dose must be 10 times higher than the dose required for a therapeutic effect. The development of a hydrosoluble form of ibuprofen can be a strategy to reach a high concentration in the lungs by using modern inhalation devices. Therefore, the development of an inhalable formulation with high bioavailability in the lungs was the leitmotiv of our investigation. The hypertonic ibuprofen solution to be nebulized (NIH) presents great relevant characteristics: bactericidal, virucidal, mucolytic and has a known anti-inflammatory property. Bactericidal and virucidal effects are related to the physico-chemical properties of Na-ibuprofenate as an amphipathic molecule. It has the capability to insert into the bilayer membranes destabilizing the structure, altering its biological properties and avoiding the duplication or infection. Our preliminary results indicate that the presence of this high ionic strength solution reduces 10 times the amount of ibuprofen necessary to kill bacteria, but also the time to kill 1x106 bacteria, from 4 h (in its absence) to only three minutes (in its presence). That was observed using Pseudomona aeruginosa, methicillin-resistant Staphylococcus aureus and Burkholderia cepacia. Also, "in vitro'' ibuprofen demonstrated virucidal activity against the so-called enveloped virus, a family that includes coronavirus strain (2019-nCoV). We observed too, the markedly reduced local inflammation in the airways after administering NIH lays on its ability to inhibit the enzyme cyclooxygenase and to markedly diminish reactive oxygen species (ROS). Other investigators also showed the importance of actin in the rapid spread of virus infection. Furthermore, reorganization of the actin filaments is a key step in lung inflammation induced by systemic inflammatory responses caused by SARS-CoV-2. These findings suggest that the interaction between actin proteins and S1 is involved in the 2019-nCoV infection and pathogenesis. Consequently, the possibility of interfering in this interaction could represent a valid hypothesis for the development of promising therapeutic and prevention strategies. In conclusion, we consider that treating people with COVID-19 with NIH may be beneficial and an opportunity to contribute for the current global health emergency.

Monosialoganglioside GM1 reduces toxicity of Ptx and increase anti-metastasic effect in a murine mammary cancer model.

Having demonstrated the ability of monosialoganglioside GM1 micelles as oncology drug transporter, this work focuses on evaluating its application in an in vivo system, studying the toxicity and antitumoral effect of GM1-Ptx micellar formulation. The maximum tolerated dose (MTD) obtained after intravenous administration of GM1-Ptx in mice was 55 mg/kg and the 50% lethal dose (LD50) was 70 mg/kg. This value is higher than those described for the commercial formulations TAXOL and ABRAXANE, with LD50 of 30 and 45 mg/kg respectively. The antitumor activity, mortality and incidence of metastasis were studied on a murine model of mammary gland cancer. The GM1-Ptx formulation was administered i.v. at different doses for 9 weeks using empty GM1 micelles and saline as treatment controls. Once the treatments were completed, biochemical markers were quantified and histological tissue tests were performed. The most promising results were obtained with the treatment at a dose of 15 mg/kg/twice a week, condition in which a longer survival and significant reduction in the incidence of animals with metastasis, since only one 25% of the mice showed presence of pulmonary micro metastases.

Eicosapentaenoic acid prevents salt sensitivity in diabetic rats and decreases oxidative stress.

OBJECTIVES: Salt sensitivity (SS) is associated with increased cardiovascular risk in patients with Type 2 diabetes mellitus (T2-DM) due to an increase in renal oxidation. ω-3 polyunsaturated fatty acids have shown antioxidant effects, but a typical Western diet contains limited content. In particular, ω-3 polyunsaturated fatty acids are able to activate nuclear factor erythroid 2-related factor 2 (Nrf-2) to prevent diabetes mellitus-related complications by mitigating oxidative stress. Therefore, we hypothesized that eicosapentaenoic acid (EPA; ω-3) modulates SS in rats with T2-DM by decreasing renal oxidative stress via Nrf-2 activation and enhancing the antiinflammatory response via interleukin (IL) 6 modulation. METHODS: Three-month-old male rats (n = 40) were fed with a Normal Na-diet (NNaD) and randomly selected into four groups: Healthy Wistar nondiabetic rats (Wi), diabetic controls (eSS), arachidonic acid-treated eSS (AA; ω-6), and EPA-treated eSS (ω-3). After 1 year, rats were placed in metabolic cages for 7 d and fed a NNaD, followed by a 7-d period with a High Na-diet (HNaD). Systolic blood pressure, body weight, serum IL-6 and reactive oxygen species (ROS) levels were determined at the end of each 7-d period. Glycated hemoglobin (HbA1c), triacylglycerol, creatinine, and cholesterol levels were determined. ROS levels and Nrf-2 expression in kidney lysates were also assayed. Histologic changes were evaluated. A t test or analysis of variance was used for the statistical analysis. RESULTS: After a HNaD, systolic blood pressure increased in both the control eSS and AA groups, but not in the EPA and Wi groups. However, HbA1c levels remained unchanged by the treatments, which suggests that the observed beneficial effect was independent of HbA1c levels. The IL-6 levels were higher in the eSS and AA groups, but remained unaltered in EPA and Wi rats after a HNaD diet. Interestingly, EPA protected against serum ROS in rats fed the HNaD, whereas AA did not. In kidney lysates, ROS decreased significantly in the EPA group compared with the eSS group, and Nrf-2 expression was consistently higher compared with the AA and eSS groups. Diabetic rats presented focal segmental sclerosis, adherence to Bowman capsule, and mild-to-moderate interstitial fibrosis. EPA and AA treatment prevented kidney damage. CONCLUSIONS: An adequate ω3-to-ω6 ratio prevents SS in diabetic rats by a mechanism that is independent of glucose metabolism but associated with the prevention of renal oxidative stress generation. These data suggest that EPA antioxidant properties may prevent the development of hypertension or kidney damage.

Increased carotid plaque burden in patients with family medical history of premature cardiovascular events in the absence of classical risk factors.

INTRODUCTION: The hypothesis that relates atherosclerosis to traditional risk factors (TRF) seems to be not as adequate as previously thought; other risk factors (RF) need to be considered to prevent atherosclerosis progression. Although a family medical history of premature cardiovascular events (FHx) has been considered the putative RF for decades, it has not been incorporated routinely into cardiovascular risk evaluation along with another RF. The objective of this study was to investigate whether FHx is associated with a higher atherosclerotic burden, measured as carotid total plaque area (TPA) in a population having no traditional RF. MATERIAL AND METHODS: The study included 4,351 primary care patients in Argentina. After excluding a personal history of cardiovascular disease (CVD) and TRF: hypertension, diabetes mellitus, hypercholesterolemia, smoking history, and body mass index (BMI) > 25 kg/cm2, 34 patients with FHx were identified. Compared to 56 matched controls TPA was 86% higher in FHx patients (p < 0.05). A second analysis performed in hypertensive patients but no other TRF; 32 patients with FHx were identified. RESULTS: Compared with 44 matched controls, TPA was 77% higher in FHx patients (p < 0.05). A final analysis using a generalized linear model with TPA progression as the response variable suggests that TPA progresses more rapidly in FHx patients compared to controls. CONCLUSIONS: The FHx was associated with increased TPA burden and progression in the absence of other TRF. This supports ultrasound screening in FHx patients in order to detect high-risk patients who may benefit from early intervention.

High Concentrations of Sodium Chloride Improve Microbicidal Activity of Ibuprofen against Common Cystic Fibrosis Pathogens.

Ibuprofen (IBU-H), a widely used anti-inflammatory, also shows a marked antimicrobial effect against several bacterial species, including those involved in cystic fibrosis such as Pseudomona aeruginosa, methicillin resistant Staphylococcus aureus and Burkholderia cepacia complex. Additionally, our results show significant synergy between water soluble Na-ibuprofen (IBU-Na) and ionic strength. Salt concentrations above 0.5 M modify the zeta potential promoting the action of Na-IBU; thus, with 1 M sodium chloride, IBU-Na is ten times more efficient than in the absence of ionic strength, and the minimum effective contact time is reduced from hours to minutes. In short time periods, where neither IBU-Na nor controls with 1 M NaCl show activity, the combination of both leads to a reduction in the bacterial load. We also analyzed whether the changes caused by salt on the bacterial membrane also promoted the activity of other microbicide compounds used in cystic fibrosis like gentamicin, tobramycin and phosphomycin. The results show that the presence of ionic strength only enhanced the bactericidal activity of the amphipathic molecule of IBU-Na. In this respect, the effect of saline concentration was also reflected in the surface properties of IBU-Na, where, in addition to the clear differences observed between 145 mM and 1 M, singular behaviors were also found, different in each condition. The combination of anti-inflammatory activity and this improved bactericidal effect of Na-IBU in hypertonic solution provides a new alternative for the treatment of respiratory infections of fibrotic patients based on known and widely used compounds.

Angiotensin II and Anti Diuretic Hormone Exert Synergistic Effects on Thick Ascending Limb Transport in Spontaneously Hypertensive Rats.

BACKGROUND: Sodium reabsorption is increased in the thick ascending limb (TAL) of Henle in several hypertensive models. In this segment, while transport is increased by ADH via cAMP, sodium reabsorption results from Ang II-induced superoxide (O2(-)) production. Surprisingly, it is unknown whether these mechanisms overlap in hypertension. We hypothesized that Ang II and ADH have accumulative effects on TAL's transport during hypertension. METHODS: The effect of ADH/Ang II in TALs from spontaneously hypertensive rats (SHR) on oxygen consumption (QO2), cAMP and O2(-) was measured. RESULTS: Basal QO2 was 113.3 ± 14.2 nmol O2/min/mg protein. Addition of ADH (1 nM) increased QO2 by 198%. In the presence of ADH, Ang II (1 nM) elicited a QO2 transient response and then rose to 321.5 ± 28.3 (p = 0.003 vs. ADH). These accumulative effects could be due to nitric oxide synthase (NOS) uncoupling, lower Ang II ability to decrease cAMP or increased O2(-). We first measured QO2 using a NOS inhibitor. Pretreatment with L-NAME did not block the observed interaction (p = 0.001 Ang II vs. ADH). Also, Ang II blocked the ADH-stimulated cAMP accumulation in TAL of SHRs. In the presence of ADH, Ang II increased O2(-) production in TALs from SHR by 309% (p = 0.015 vs. basal). The O2(-) scavenger tempol blocked the Ang II effects on QO2. In the presence of the NADPH oxidase inhibitor apocynin, the accumulative effects of ADH and Ang II were abolished. We conclude that (1) in SHR, Ang II has accumulative effects on ADH-stimulated transport; (2) this effect is mediated by AT1 receptors, and increased O2(-) production.

Risk of vascular disease in premenopausal women with diabetes mellitus.

PURPOSE: The aims of this study were (1) to estimate the prevalence of cardiovascular disease risk factors among premenopausal and menopausal Argentinean women with and without type 2 diabetes mellitus and (2) to assess the contribution of total plaque area (TPA) to risk stratification when added to Framingham risk scores. METHODS: A descriptive cross-sectional study in primary prevention in 1257 women (ages 19-84 years) from Argentina. TPA was measured by ultrasonography. Framingham sex-specific risk equations were used to predict the risk of developing cardiovascular disease, coronary heart disease, and stroke during the next 10 years. Patients were divided into diabetic (n = 293) and control groups (n = 964), and then each group was divided according to age (>40, 40-49, 50-59, and ≥60 years). FINDINGS: No difference was observed between diabetic and control groups in the incidence of smoking or the presence of early family cardiovascular event. Overall, diabetic patients had higher body mass index, blood pressure, and TPA versus the control group. The Framingham risk score was higher in the diabetic group in all age groups. The mean (SD) coronary heart disease scores for the diabetic group at <40, 40 to 49, 50 to 59, and ≥60 were 6% (1.7%), 19% (2.5%), 38% (2.0%), and 60% (1.5%), respectively, whereas the scores in the control group 3% (0.8%), 7% (0.9%), 17% (0.9%), and 40% (0.9%), respectively. The stroke score was also enhanced in diabetic women, independent of their age. These data indicate that diabetic women in the premenopausal age or the early years of menopause age (40-50 years) are at intermediate or higher risk of developing a cardiovascular event. IMPLICATIONS: Premenopausal diabetic women should be considered at possibly high risk of cardiovascular events compared with nondiabetic women. Direct assessment of atherosclerotic burden, such as TPA, should be used early in this population instead of relying on traditional risk scores.

Anandamide inhibits transport-related oxygen consumption in the loop of Henle by activating CB1 receptors.

The energy required for active Na chloride reabsorption in the thick ascending limb (TAL) depends on oxygen consumption and oxidative phosphorylation (OXP). In other cells, Na transport is inhibited by the endogenous cannabinoid anandamide through the activation of the cannabinoid receptors (CB) type 1 and 2. However, it is unclear whether anandamide alters TAL transport and the mechanisms that could be involved. We hypothesized that anandamide inhibits TAL transport via activation of CB1 receptors and NO. For this, we measured oxygen consumption (Q(O(2))) in TAL suspensions to monitor the anandamide effects on transport and OXP. Anandamide reduced Q(O(2)) in a concentration-dependent manner. During Na-K-2Cl cotransport and Na/H exchange inhibition, anandamide did not inhibit TAL Q(O(2)). To test the role of the cannabinoid receptors, we used specific agonists and antagonists of CB1 and CB2 receptors. The CB1-selective agonist WIN55212-2 reduced Q(O(2)) in a concentration-dependent manner. Also, the CB1 receptor antagonist rimonabant blocked the effect of anandamide on Q(O(2)). In contrast, the CB2-selective agonist JHW-133 had no effect on Q(O(2)), while the CB2 receptor antagonist AM-630 failed to block the anandamide effects on Q(O(2)). To confirm these results, we measured CB1 and CB2 receptor expression and only CB1 expression was detected. Because CB1 receptors are strong nitric oxide synthase (NOS) stimulators and NO inhibits transport in TALs, we evaluated the role of NO. Anandamide stimulated NO production and the NOS inhibitor N(G)-nitro-L-arginine methyl ester blocked the anandamide effects on Q(O(2)). We conclude that anandamide inhibits TAL Na transport-related Q(O(2)) via activation of CB1 receptor and NOS.

The antihypertensive actions of statins: modulation by salt intake.

Hydroxy methyl glutaryl CoA inhibitors (statins) are the agents most frequently used to reduce elevated serum cholesterol. In addition to their cholesterol lowering effects, statins also have nonlipid lowering pleiotropic properties. These include reducing oxidative stress, renin-angiotensin and endothelin synthesis and activity, and improving nitric oxide (NO) synthesis and availability. Thus, one would predict that statins might be able to exert an antihypertensive effect. Experimental models bear out the blood pressure lowering effects but the data from clinical trials have been inconsistent perhaps due to inappropriate experimental designs, sample size, blood pressure measurement techniques etc. Moreover, although experimental models strongly suggest a role for salt intake in the potential antihypertensive responses to statins, available clinical trials fail to report salt intake in the studied populations. The statins' antihypertensive effects remain an unsettled hypothesis and calls for a large clinical trial at a wide range of doses and a controlled salt intake. Statins meanwhile remain as a excellent option to control high cholesterol and in tissue injury prevention.

Atorvastatin improves sodium handling and decreases blood pressure in salt-loaded rats with chronic renal insufficiency.

OBJECTIVE: Oxidative stress and inflammation seem to mediate the cardiovascular risks associated with salt sensitivity. Because hydroxymethyl glutaryl coenzyme A reductase inhibitors decrease oxidation and increase nitric oxide (NO) synthesis, we examined the effects of atorvastatin (ator) on tissue injury in rats with a reduced renal mass produced by 5/6 nephrectomy. This salt-sensitive hypertension model causes kidney and cardiovascular injuries. METHODS: After undergoing 5/6 nephrectomy or sham surgery, male Sprague-Dawley rats were randomized into five groups: sham, reduced renal mass and a normal salt diet (NNaD), NNaD+ator (50 mg · kg(-1) · d(-1)), reduced renal mass and a high salt diet (HNaD), and HNaD+ator. After assessing the sodium balance for 7 d, we measured blood pressure (BP), creatinemia, proteinuria, nitrites, and 12(S)-hydroxy 5,8,10-heptadecatrienoic acid, the renal cortical expression of endothelial NO synthase, and the ratio of left ventricular weight to body weight. RESULTS: In NNaD rats, creatinine, proteinuria, and 12(S)-hydroxy 5,8,10-heptadecatrienoic acid increased, renal NO indices decreased, but the Na(+) balance, BP, and the left ventricular weight/body weight ratio remained unchanged. In the NNaD group, atorvastatin normalized the NO indices and decreased BP and proteinuria, although the remaining parameters continued unchanged. In contrast, HNaD increased creatinemia, proteinuria, and 12(S)-hydroxy 5,8,10-heptadecatrienoic acid excretion rates and decreased renal endothelial NO synthase. Salt retention was accompanied by increased BP and ventricular weight. In this HNaD group, atorvastatin prevented a BP increase, partly decreased sodium retention, but failed to improve NO indices, proteinuria, oxidant stress, and the left ventricular weight/body weight ratio. CONCLUSION: Atorvastatin exerts beneficial effects on renal function, injury, and salt sensitivity in rats with a reduced renal mass on an NNaD. The HNaD hampers these beneficial effects.

8-iso-prostaglandin-F2α stimulates chloride transport in thick ascending limbs: role of cAMP and protein kinase A.

Salt reabsorption by the loop of Henle controls NaCl handling and blood pressure regulation. Increased oxidative stress stimulates NaCl transport in one specific segment of the loop of Henle called the thick ascending limb (TAL). The isoprostane 8-iso-prostaglandin-F2α (8-iso-PGF2α) is one of the most abundant nonenzymatic lipid oxidation products and has been implicated in the development of hypertension. However, it is not known whether 8-iso-PGF2α regulates transport or the mechanisms involved. Because protein kinase A (PKA) stimulates NaCl transport in several nephron segments, we hypothesized that 8-iso-PGF2α increases NaCl transport in the cortical TAL (cTAL) via a PKA-dependent mechanism. We examined the effect of luminal 8-iso-PGF2α on NaCl transport by measuring chloride absorption (J(Cl)) in isolated microperfused cTALs. Adding 8-iso-PGF2α to the lumen increased J(Cl) by 54% (from 288.7 ± 30.6 to 446.5 ± 44.3 pmol·min(-1)·mm(-1); P < 0.01), while adding it to the bath enhanced J(Cl) by 35% (from 236.3 ± 35.3 to 319.2 ± 39.8 pmol·min(-1)·mm(-1); P < 0.05). This stimulation was blocked by Na-K-2Cl cotransporter inhibition. Next, we tested the role of cAMP. Basal cAMP in the cTAL was 18.6 ± 1.6 fmol·min(-1)·mm(-1), and 8-iso-PGF2α raised it to 35.1 ± 1.4 fmol·min(-1)·mm(-1), an increase of 94% (P < 0.01). Because cAMP stimulates PKA, we measured J(Cl) using the PKA-selective inhibitor H89. In the presence of H89 (10 µM), 8-iso-PGF2α failed to increase transport regardless of whether it was added to the lumen (216.1 ± 16.7 vs. 209.7 ± 23.8 pmol·min(-1)·mm(-1); NS) or the bath (150.4 ± 32.9 vs. 127.1 ± 28.6 pmol·min(-1)·mm(-1); NS). We concluded that 8-iso-PGF2α stimulates cAMP and increases Cl transport in cTALs via a PKA-dependent mechanism.

The Association Between Inflammatory Markers and Hypertension. A Call for Anti-Inflammatory Strategies?

The most important goal of antihypertensive therapy is to prevent the complications associated with hypertension (stroke, myocardial infarction, end-stage renal disease, etc). For this, secondary targets such as left ventricular hypertrophy, proteinuria, dementia, and other signs of hypertension-induced organ damage help the physician to assess risks and monitor treatment efficacy. New treatment targets may be arising, however. One such target may be endothelial dysfunction. In effect, endothelial dysfunction not only may precede the elevation of blood pressure, but may also pave the way to conditions often associated with hypertension, such as diabetes, arteriosclerosis, microalbuminuria, congestive heart failure, and tissue hypertrophy. Because inflammation often accompanies endothelial dysfunction, approaches to counteract inflammation are now being evaluated. For this, antagonists of the renin-angiotensin-aldosterone system, statins, and beta blockers are all being tested. All of these agents seem to prevent or delay the induction of proinflammatory molecules aside from, and in addition to, their specific effects on blood pressure. The focus of this review is to update some of the animal and human research showing that hypertension sets off an inflammatory state and also to consider some of the anti-inflammatory approaches that may prevent the development of endothelial dysfunction, and the subsequent renal and cardiovascular damage.

Understanding the Role of Paracellular Transport in the Proximal Tubule.

Fluid and solute reabsorption by the proximal tubule is the result of both transcellular and paracellular flux. The role of transcellular transport has been extensively studied, but the importance of paracellular flux has not been as thoroughly investigated. The purpose of this review is to update concepts about the contribution of paracellular transport for reabsorption by the proximal tubule.