Aliskiren-Loaded Nanoparticles Downregulate (Pro)renin Receptor and ACE Gene Expression in the Heart of Spontaneously Hypertensive Rats: Effect on NADPH Oxidase.

We aimed to determine effects of aliskiren, a direct renin inhibitor, loaded onto polymeric nanoparticles on the (pro)renin receptor (Atp6ap2), angiotensin II type 1 receptor (Agtr1), and angiotensin-converting enzyme (ACE) gene expression in the heart of spontaneously hypertensive rats (SHR). Twelve-week-old male SHRs were divided into an untreated group and groups treated with powdered aliskiren or aliskiren-loaded nanoparticles (25 mg/kg/day). After three weeks, the accumulation of aliskiren, distribution of polymeric nanoparticles, gene expression of Atp6ap2 and Agtr1 receptors and ACE, and protein expression of NADPH oxidase along with the conjugated diene (CD) concentration were analyzed. The accumulation of aliskiren in the heart was higher in the aliskiren-loaded nanoparticle group than in the powdered group. The fluorescent signals of nanoparticles were visible in cardiomyocytes, vessel walls, and erythrocytes. Aliskiren-loaded nanoparticles decreased the gene expression of Atp6ap2 and ACE, while not affecting Agtr1. Both forms of aliskiren decreased the protein expression of NADPH oxidase, with a more pronounced effect observed in the aliskiren-loaded nanoparticle group. CD concentration was decreased only in the aliskiren-loaded nanoparticle group. We hypothesize that aliskiren-loaded nanoparticle-mediated downregulation of Atp6ap2 and ACE may contribute to a decrease in ROS generation with beneficial effects in the heart. Moreover, polymeric nanoparticles may represent a promising tool for targeted delivery of aliskiren.

The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760.

BACKGROUND: Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H2S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN). RESULTS: Zofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H2S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H2S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect. CONCLUSIONS: Zofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H2S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling.

Taxifolin Reduces Blood Pressure via Improvement of Vascular Function and Mitigating the Vascular Inflammatory Response in Spontaneously Hypertensive Rats.

The effect of a 10-day-long treatment with taxifolin (TAX, 20 mg/kg/day p.o.) was investigated on spontaneously hypertensive rats (SHRs) with a focus on the vascular functions of isolated femoral arteries and thoracic aortas. TAX reduced blood pressure in SHRs. In femoral arteries, TAX increased acetylcholine-induced relaxation, reduced the maximal NA-induced contraction, and reduced acetylcholine-induced endothelium-dependent contraction (EDC); however, TAX had no effect on the vascular reactivity of isolated thoracic aortas. In addition, TAX elevated the total nitric oxide synthase (NOS) activity and iNOS protein expression but reduced cyclooxygenase-2 (COX2) protein expression in the tissue of the abdominal aorta without changes in Nos2 and Ptgs2 gene expressions. TAX also increased the gene expression of the anti-inflammatory interleukin-10 (Il10). In addition, in vitro studies showed that TAX has both electron donor and H atom donor properties. However, TAX failed to reduce superoxide production in the tissue of the abdominal aorta after oral administration. In conclusion, our results show that a decrease in the blood pressure in TAX-treated SHRs might be attributed to improved endothelium-dependent relaxation and reduced endothelium-dependent contraction. In addition, the results suggest that the effect of TAX on blood pressure regulation also involves the attenuation of COX2-mediated pro-inflammation and elevation of anti-inflammatory pathways.

MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of Nfe2l2 Gene, Nitric Oxide and Hydrogen Sulfide.

Reduced angiotensin 1-7 bioavailability due to inhibition of angiotensin-converting enzyme 2 (ACE2) may contribute to increased mortality in hypertensive individuals during COVID-19. However, effects of ACE2 inhibitor MLN-4760 in brain functions remain unknown. We investigated the selected behavioural and hemodynamic parameters in spontaneously hypertensive rats (SHRs) after a 2-week s.c. infusion of MLN-4760 (dose 1 mg/kg/day). The biochemical and molecular effects of MLN-4760 were investigated in the brainstem and blood plasma. MLN-4760 had no effects on hemodynamic and behavioural parameters. However, MLN-4760 increased plasma hydrogen sulfide (H2S) level and total nitric oxide (NO) synthase activity and conjugated dienes in the brainstem. Increased NO synthase activity correlated positively with gene expression of Nos3 while plasma H2S levels correlated positively with gene expressions of H2S-producing enzymes Mpst, Cth and Cbs. MLN-4760 administration increased gene expression of Ace2, Sod1, Sod2, Gpx4 and Hmox1, which positively correlated with expression of Nfe2l2 gene encoding the redox-sensitive transcription factor NRF2. Collectively, MLN-4760 did not exacerbate pre-existing hypertension and behavioural hyperactivity/anxiety in SHRs. However, MLN-4760-induced oxidative damage in brainstem was associated with activation of NO- and H2S-mediated compensatory mechanisms and with increased gene expression of antioxidant, NO- and H2S-producing enzymes that all correlated positively with elevated Nfe2l2 expression.

Vasoactive Effects of Chronic Treatment with Fructose and Slow-Releasing H2S Donor GYY-4137 in Spontaneously Hypertensive Rats: The Role of Nitroso and Sulfide Signalization.

Increased fructose consumption induces metabolic-syndrome-like pathologies and modulates vasoactivity and the participation of nitric oxide (NO) and hydrogen sulfide (H2S). We investigated whether a slow-releasing H2S donor, GYY-4137, could exert beneficial activity in these conditions. We examined the effect of eight weeks of fructose intake on the blood pressure, biometric parameters, vasoactive responses, and NO and H2S pathways in fructose-fed spontaneously hypertensive rats with or without three weeks of GYY-4137 i.p. application. GYY-4137 reduced triacylglycerol levels and blood pressure, but not adiposity, and all were increased by fructose intake. Fructose intake generally enhanced endothelium-dependent vasorelaxation, decreased adrenergic contraction, and increased protein expression of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and concentration of conjugated dienes in the left ventricle (LV). Although GYY-4137 administration did not affect vasorelaxant responses, it restored disturbed contractility, LV oxidative damage and decreased protein expression of TNFα in fructose-fed rats. While the participation of endogenous H2S in vasoactive responses was not affected by fructose treatment, the expression of H2S-producing enzyme cystathionine ß-synthase in the LV was increased, and the stimulation of the NO signaling pathway improved endothelial function in the mesenteric artery. On the other hand, chronic treatment with GYY-4137 increased the expression of H2S-producing enzyme cystathionine γ-lyase in the LV and stimulated the beneficial pro-relaxant and anti-contractile activity of endogenous H2S in thoracic aorta. Our results suggest that sulfide and nitroso signaling pathways could trigger compensatory vasoactive responses in hypertensive rats with metabolic disorder. A slow H2S-releasing donor could partially amend metabolic-related changes and trigger beneficial activity of endogenous H2S.

Combined Therapy with Simvastatin- and Coenzyme-Q10-Loaded Nanoparticles Upregulates the Akt-eNOS Pathway in Experimental Metabolic Syndrome.

In addition to their LDL-cholesterol-lowering effect, statins have pleiotropic beneficial effects on the cardiovascular system. However, long-term treatment with statins may be associated with serious side effects. With the aim to make statin therapy more effective, we studied the effects of simvastatin- and coenzyme-Q10-loaded polymeric nanoparticles on the lipid profile and nitric oxide (NO)/reactive oxygen species (ROS) balance in the heart and aorta of adult male obese Zucker rats. The rats were divided into an untreated group, a group treated with empty nanoparticles, and groups treated with simvastatin-, coenzyme Q10 (CoQ10)-, or a combination of simvastatin- and CoQ10-loaded nanoparticles (SIMV+CoQ10). After 6 weeks, the lipid profile in the plasma and the concentration of conjugated dienes in the liver were determined. Nitric oxide synthase (NOS) activity, Akt, endothelial NOS (eNOS), phosphorylated eNOS (p-eNOS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and nuclear factor kappaB (NF-kappaB) protein expressions were measured in the heart and aorta. All simvastatin, CoQ10, and SIMV+CoQ10 treatments decreased plasma LDL levels, but only the combined SIMV+CoQ10 treatment increased NOS activity and the expression of Akt, eNOS, and p-eNOS in both the heart and the aorta. Interestingly, NADPH oxidase in the heart and NF-kappaB protein expression in the aorta were decreased by all treatments, including nanoparticles alone. In conclusion, only combined therapy with SIMV- and CoQ10-loaded nanoparticles increased NOS activity and upregulated the Akt-eNOS pathway in obese Zucker rats, which may represent a promising tool for the treatment of cardiometabolic diseases.

Duration of Social Isolation Affects Production of Nitric Oxide in the Rat Brain.

Social isolation deprives rodents of social interactions that are critical for normal development of brain and behavior. Several studies have indicated that postweaning isolation rearing may affect nitric oxide (NO) production. The aim of this study was to compare selected behavioral and biochemical changes related to NO production in the brain of rats reared in social isolation for different duration. At the age of 21 days, male Sprague Dawley rats were randomly assigned into four groups reared in isolation or socially for 10 or 29 weeks. At the end of the rearing, open-field and prepulse inhibition (PPI) tests were carried out. Furthermore, in several brain areas we assessed NO synthase (NOS) activity, protein expression of nNOS and iNOS isoforms and the concentration of conjugated dienes (CD), a marker of oxidative damage and lipid peroxidation. Social isolation for 10 weeks resulted in a significant decrease in PPI, which was accompanied by a decrease in NOS activity in the cerebral cortex and the cerebellum, an increase in iNOS in the hippocampus and an increase in CD concentration in cortex homogenate. On the other hand, a 29 week isolation had an opposite effect on NOS activity, which increased in the cerebral cortex and the cerebellum in animals reared in social isolation, accompanied by a decrease in CD concentration. The decrease in NOS activity after 10 weeks of isolation might have been caused by chronic stress induced by social isolation, which has been documented in previous studies. The increased oxidative state might result in the depleted NO bioavailability, as NO reacts with superoxide radical creating peroxynitrite. After 29 weeks of isolation, this loss of NO might be compensated by the subsequent increase in NOS activity.

Antioxidant Effect of Lonicera caerulea L. in the Cardiovascular System of Obese Zucker Rats.

Lonicera caerulea L. (Loni) represents a promising source of beneficial polyphenols with therapeutical potential in cardiovascular diseases. We aimed to study the effects of Loni and coenzyme Q10 (CoQ10) on selected cardiometabolic parameters and NO/ROS balance in obese Zucker rats. Male Zucker rats were divided into the control group and groups treated with CoQ10 (30 mg/kg/day) or Loni (5 g/kg/day) for 6 weeks. Blood pressure, body weight, heart weight, and plasma lipid profile were determined. NOS activity and protein expressions of eNOS, SOD, NADPH oxidase, and NF-kappa B were measured in the heart and aorta. Neither body weight nor blood pressure were significantly changed after six weeks of Loni or CoQ10 treatment. Both Loni and CoQ10 decreased the plasma LDL level. Moreover, Loni decreased the total cholesterol level. The total NOS activity did not change in the heart after the treatments. However, in the aorta, Loni treatment increased NOS activity and protein expression of SOD and decreased expressions of NADPH oxidase and NF-kappa B compared to both the control and CoQ10 groups. There were no changes in the eNOS protein expression within the groups. In conclusion, it seems that the antioxidant effect of Loni was responsible for both the decrease of plasma LDL and the total cholesterol levels and the increase of vascular NOS activity.

Fructose Intake Impairs the Synergistic Vasomotor Manifestation of Nitric Oxide and Hydrogen Sulfide in Rat Aorta.

In this study, we evaluated the effect of eight weeks of administration of 10% fructose solution to adult Wistar Kyoto (WKY) rats on systolic blood pressure (SBP), plasma and biometric parameters, vasoactive properties of the thoracic aorta (TA), NO synthase (NOS) activity, and the expression of enzymes producing NO and H2S. Eight weeks of fructose administration did not affect SBP, glycaemia, or the plasma levels of total cholesterol or low-density and high-density lipoprotein; however, it significantly increased the plasma levels of γ-glutamyl transferase and alanine transaminase. Chronic fructose intake deteriorated endothelium-dependent vasorelaxation (EDVR) and increased the sensitivity of adrenergic receptors to noradrenaline. Acute NOS inhibition evoked a reduction in EDVR that was similar between groups; however, it increased adrenergic contraction more in fructose-fed rats. CSE inhibition decreased EDVR in WKY but not in fructose-fed rats. The application of a H2S scavenger evoked a reduction in the EDVR in WKY rats and normalized the sensitivity of adrenergic receptors in rats treated with fructose. Fructose intake did not change NOS activity but reduced the expression of eNOS and CBS in the TA and CSE and CBS in the left ventricle. Based on our results, we could assume that the impaired vascular function induced by increased fructose intake was probably not directly associated with a decreased production of NO, but rather with impairment of the NO-H2S interaction and its manifestation in vasoactive responses.

The Vasoactive Role of Perivascular Adipose Tissue and the Sulfide Signaling Pathway in a Nonobese Model of Metabolic Syndrome.

The aim of this study was to evaluate the mutual relationship among perivascular adipose tissue (PVAT) and endogenous and exogenous H2S in vasoactive responses of isolated arteries from adult normotensive (Wistar) rats and hypertriglyceridemic (HTG) rats, which are a nonobese model of metabolic syndrome. In HTG rats, mild hypertension was associated with glucose intolerance, dyslipidemia, increased amount of retroperitoneal fat, increased arterial contractility, and endothelial dysfunction associated with arterial wall injury, which was accompanied by decreased nitric oxide (NO)-synthase activity, increased expression of H2S producing enzyme, and an altered oxidative state. In HTG, endogenous H2S participated in the inhibition of endothelium-dependent vasorelaxation regardless of PVAT presence; on the other hand, aortas with preserved PVAT revealed a stronger anticontractile effect mediated at least partially by H2S. Although we observed a higher vasorelaxation induced by exogenous H2S donor in HTG rats than in Wistar rats, intact PVAT subtilized this effect. We demonstrate that, in HTG rats, endogenous H2S could manifest a dual effect depending on the type of triggered signaling pathway. H2S within the arterial wall contributes to endothelial dysfunction. On the other hand, PVAT of HTG is endowed with compensatory vasoactive mechanisms, which include stronger anti-contractile action of H2S. Nevertheless, the possible negative impact of PVAT during hypertriglyceridemia on the activity of exogenous H2S donors needs to be taken into consideration.

Vascular Effects of Low-Dose ACE2 Inhibitor MLN-4760-Benefit or Detriment in Essential Hypertension?

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1-7 (Ang 1-7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the role of ACE2 inhibition, especially within pre-existing cardiovascular pathologies. In our study, we imitated the action of SARS-CoV-2 in organisms using the low dose of the ACE2 inhibitor MLN-4760 with the aim of investigating to what degree ACE2 inhibition is detrimental to the cardiovascular system of spontaneously hypertensive rats (SHRs), which represent a model of human essential hypertension. Our study revealed the complex action of MLN-4760 in SHRs. On the one hand, we found that MLN-4760 had (1) (pro)obesogenic effects that negatively correlated with alternative renin-angiotensin system activity and Ang 1-7 in plasma, (2) negative effects on ACE1 inhibitor (captopril) action, (3) detrimental effects on the small arteries function and (4) anti-angiogenic effect in the model of chick chorioallantoic membrane. On the other hand, MLN-4760 induced compensatory mechanisms involving strengthened Mas receptor-, nitric oxide- and hydrogen sulfide-mediated signal transduction in the aorta, which was associated with unchanged blood pressure, suggesting beneficial action of MLN-4760 when administered at a low dose.

Health Effects of Grape Seed and Skin Extracts and Their Influence on Biochemical Markers.

This review is focused on the study of the effects of grape seed and skin extract (GSSE) on human health. GSSE contains high concentrations of important polyphenolic substances with high biological activity. This review is a summary of studies that investigate the effects of GSSE on diabetes mellitus, cardiovascular disease and cancer, its neuroprotective effect, and its effects on the gastrointestinal tract and other health complications related to these diseases. The results of the studies confirm that the anti-inflammatory, antiapoptotic, and pro-proliferative effects of "Vitis vinifera L." seed extract reduce the level of oxidative stress and improve the overall lipid metabolism.

Protective Effects of Polyphenols against Ischemia/Reperfusion Injury.

Myocardial infarction (MI) is a leading cause of morbidity and mortality across the world. It manifests as an imbalance between blood demand and blood delivery in the myocardium, which leads to cardiac ischemia and myocardial necrosis. While it is not easy to identify the first pathogenic cause of MI, the consequences are characterized by ischemia, chronic inflammation, and tissue degeneration. A poor MI prognosis is associated with extensive cardiac remodeling. A loss of viable cardiomyocytes is replaced with fibrosis, which reduces heart contractility and heart function. Recent advances have given rise to the concept of natural polyphenols. These bioactive compounds have been studied for their pharmacological properties and have proven successful in the treatment of cardiovascular diseases. Studies have focused on their various bioactivities, such as their antioxidant and anti-inflammatory effects and free radical scavenging. In this review, we summarized the effects and benefits of polyphenols on the cardiovascular injury, particularly on the treatment of myocardial infarction in animal and human studies.

Therapeutic Potential of Polyphenols-Loaded Polymeric Nanoparticles in Cardiovascular System.

Numerous studies document an increased production of reactive oxygen species (ROS) with a subsequent decrease in nitric oxide (NO) bioavailability in different cardiovascular diseases, including hypertension, atherosclerosis, and heart failure. Many natural polyphenols have been demonstrated to decrease ROS generation and/or to induce the endogenous antioxidant enzymatic defense system. Moreover, different polyphenolic compounds have the ability to increase the activity/expression of endothelial nitric oxide synthase (eNOS) with a subsequent enhancement of NO generation. However, as a result of low absorption and bioavailability of natural polyphenols, the beneficial effects of these substances are very limited. Recent progress in delivering polyphenols to the targeted tissues revealed new possibilities for the use of polymeric nanoparticles in increasing the efficiency and reducing the degradability of natural polyphenols. This review focuses on the effects of different natural polyphenolic substances, especially resveratrol, quercetin, curcumin, and cherry extracts, and their ability to bind to polymeric nanoparticles, and summarizes the effects of polyphenol-loaded nanoparticles, mainly in the cardiovascular system.

Beneficial Effects of Cornelian Cherries on Lipid Profile and NO/ROS Balance in Obese Zucker Rats: Comparison with CoQ10.

Cornelian cherries (CCs) belong to promising anti-obesity substances. We aimed to study effects of coenzyme Q10 (CoQ10) and two varieties of CCs on lipid profile, ROS, and nitric oxide (NO) production in obese rats. Male Zucker rats were divided into the control group and groups treated with CoQ10 (30mg/kg/day), or CC varieties: Koralovij Marka (KM) and Wild Type (WT) (5 g/kg/day, n = 6 in each group) for 6 weeks. Blood pressure (BP), bodyweight, relative heart weight, and plasma lipid profile were determined. NOS activity and expressions of eNOS, SOD, and NADPH oxidase were determined in the left ventricle (LV) and aorta. Among CC groups, KM decreased bodyweight and WT relative heart weight. Neither CoQ10 nor CCs affected BP. CoQ10 did not affect lipid profile and NOS activity either in the LV or aorta. On the other hand, WT decreased cholesterol and LDL levels. KM and WT increased NOS activity in the aorta, while not affecting the activity in the LV. KM increased eNOS expression and did not affect ROS production, while WT increased SOD and decreased NADPH oxidase without affecting eNOS expressions in both tissues. In conclusion, CCs showed better beneficial effects than CoQ10 in all parameters studied.

Chronic L-Name-Treatment Produces Hypertension by Different Mechanisms in Peripheral Tissues and Brain: Role of Central eNOS.

The goal of our study was to analyze the time course of the effect of NG-nitro-L-arginine methyl ester (L-NAME) on nitric oxide synthase (NOS) isoforms and nuclear factor-κB (NF-κB) protein expression, total NOS activity, and blood pressure (BP) in rats. Adult 12-week-old male Wistar rats were subjected to treatment with L-NAME (40 mg/kg/day) for four and seven weeks. BP was increased after 4- and 7-week L-NAME treatments. NOS activity decreased after 4-week-L-NAME treatment; however, the 7-week treatment increased NOS activity in the aorta, heart, and kidney, while it markedly decreased NOS activity in the brainstem, cerebellum, and brain cortex. The 4-week-L-NAME treatment increased eNOS expression in the aorta, heart, and kidney and this increase was amplified after 7 weeks of treatment. In the brain regions, eNOS expression remained unchanged after 4-week L-NAME treatment and prolonged treatment led to a significant decrease of eNOS expression in these tissues. NF-κB expression increased in both peripheral and brain tissues after 4 weeks of treatment and prolongation of treatment decreased the expression in the aorta, heart, and kidney. In conclusion, decreased expression of eNOS in the brain regions after 7-week L-NAME treatment may be responsible for a remarkable decrease of NOS activity in these regions. Since the BP increase persisted after 7 weeks of L-NAME treatment, we hypothesize that central regulation of BP may contribute significantly to L-NAME-induced hypertension.

Protective Effects of Nanoparticle-Loaded Aliskiren on Cardiovascular System in Spontaneously Hypertensive Rats.

Aliskiren, a renin inhibitor, has been shown to have cardioprotective and blood pressure (BP) lowering effects. We aimed to determine the effects of nanoparticle-loaded aliskiren on BP, nitric oxide synthase activity (NOS) and structural alterations of the heart and aorta developed due to spontaneous hypertension in rats. Twelve week-old male spontaneously hypertensive rats (SHR) were divided into the untreated group, group treated with powdered or nanoparticle-loaded aliskiren (25 mg/kg/day) and group treated with nanoparticles only for 3 weeks by gavage. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions, and collagen content were determined in both the heart and aorta. Vasoactivity of the mesenteric artery and wall thickness, inner diameter, and cross-sectional area (CSA) of the aorta were analyzed. After 3 weeks, BP was lower in both powdered and nanoparticle-loaded aliskiren groups with a more pronounced effect in the latter case. Only nanoparticle-loaded aliskiren increased the expression of nNOS along with increased NOS activity in the heart (by 30%). Moreover, nanoparticle-loaded aliskiren decreased vasoconstriction of the mesenteric artery and collagen content (by 11%), and CSA (by 25%) in the aorta compared to the powdered aliskiren group. In conclusion, nanoparticle-loaded aliskiren represents a promising drug with antihypertensive and cardioprotective effects.

Different adaptive NO-dependent Mechanisms in Normal and Hypertensive Conditions.

Myocardial infarction (MI) remains the leading cause of death worldwide. We aimed to investigate the effect of NO deficiency on selective biochemical parameters within discreet myocardial zones after experimentally induced MI. To induce MI, the left descending coronary artery was ligated in two groups of 16-week-old WKY rats. In one group, NO production was inhibited by L-NAME (20 mg/kg/day) administration four weeks prior to ligation. Sham operations were performed on both groups as a control. Seven days after MI, we evaluated levels of nitric oxide synthase (NOS) activity, eNOS, iNOS, NFÒ¡B/p65 and Nrf2 in ischemic, injured and non-ischemic zones of the heart. Levels of circulating TNF-α and IL-6 were evaluated in the plasma. MI led to increased NOS activity in all investigated zones of myocardium as well as circulating levels of TNF-α and IL-6. L-NAME treatment decreased NOS activity in the heart of sham operated animals. eNOS expression was increased in the injured zone and this could be a compensatory mechanism that improves the perfusion of the myocardium and cardiac dysfunction. Conversely, iNOS expression increased in the infarcted zone and may contribute to the inflammatory process and irreversible necrotic changes.

Simvastatin Does Not Affect Nitric Oxide Generation Increased by Sesame Oil in Obese Zucker Rats.

Current treatments for cardiovascular and obesity-associated diseases, such as statin therapy, may be associated with several side effects. Products from food sources with polyphenolic compounds may represent promising agents in the treatment of cardiovascular and metabolic diseases with minimal side effects. Thus, we aimed to study the effect of sesame oil and simvastatin treatment on plasma lipid profile, nitric oxide generation, and oxidative load in obese Zucker rats. 12-week-old male Zucker rats were divided into the control and sesame oil- (1.25 ml/kg/day) treated Zucker lean groups, the control and sesame oil (1.25 ml/kg/day), or simvastatin (15 mg/kg/day) together with sesame oil-treated Zucker fa/fa groups, n = 6 in each group. The treatment lasted for 6 weeks. Sesame oil composition and plasma lipid profile were analyzed. Nitric oxide synthase (NOS) activity, endothelial NOS (eNOS), phosphorylated eNOS, and inducible NOS (iNOS) protein expressions were determined in the left ventricle and aorta. Oxidative load, measured as conjugated diene (CD) and thiobarbituric acid reactive substance (TBARS) concentrations, was detected in the liver. Neither sesame oil nor cotreatment with simvastatin affected plasma lipid profile in Zucker fa/fa rats. Sesame oil and similarly cotreatment with simvastatin markedly increased NOS activity and phosphorylated eNOS protein expressions in the left ventricle and aorta of Zucker fa/fa rats. There were no changes in eNOS and iNOS protein expressions within the groups and tissues investigated. Hepatic CD concentration was higher in Zucker fa/fa comparing Zucker lean rats, and sesame oil treatment decreased it significantly. Interestingly, this decrease was not seen after cotreatment with simvastatin. In conclusion, phosphorylation of eNOS and decreased oxidative load may significantly contribute to increase in total NOS activity with potential beneficial properties. Interestingly, simvastatin did not affect NO generation already increased by sesame oil in obese Zucker rats.

Effect of Bioactive Compound of Aronia melanocarpa on Cardiovascular System in Experimental Hypertension.

Aronia melanocarpa has attracted scientific interest due to its dense contents of different polyphenols. We aimed to analyse effects of Aronia melanocarpa (AME) extract on blood pressure (BP), lipid peroxidation, cytokine level, total NOS activity in the left ventricle (LV), and aorta of L-NAME-induced hypertensive rats. 12-week-old male WKY rats were assigned to the control group and groups treated with AME extract (57.90 mg/kg/day), L-NAME (40 mg/kg/day), or combination of L-NAME (40 mg/kg/day) and AME (57.90 mg/kg/day) in tap water for 3 weeks. NOS activity, eNOS protein expression, and conjugated diene (CD) concentration were determined in the LV and aorta. After 3 weeks of L-NAME treatment, BP was increased by 28% and concomitant treatment with AME reduced it by 21%. NOS activity of the LV and aorta in the L-NAME group was decreased by about 40%, while AME increased it almost on the control level. AME-induced eNOS upregulation may contribute to increase NOS activity. Moreover, AME decreased CD concentration in the LV and aorta and TNF-α and IL-6 production in the plasma were increased by L-NAME treatment. In conclusion, our results showed that active substances of Aronia melanocarpa may have a positive effect on blood pressure, NOS activity, and proinflammatory processes in L-NAME-induced hypertension.