Akkermansia muciniphila extracellular vesicles have a protective effect against hypertension.

Akkermansia muciniphila (Am) shows a beneficial role as a probiotic in the treatment of metabolic syndrome. However, the mechanism remains to be elucidated. We tested the hypothesis that Am extracellular vesicles (AmEVs) have a protective effect against hypertension. Extracellular vesicles purified from anaerobically cultured Am were characterized by nanoparticle tracking analysis, transmission electron microscopy, and silver stain after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). AmEVs (1.0 × 1010 log particles/L) or vehicles were added into organ baths to induce vasorelaxation. In addition, AmEVs (1.0 × 108 or 1.0 × 109 particles/kg) or vehicles were injected into the tail veins of Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) weekly for 4 weeks. Peripheral blood mononuclear cells (PBMCs) and splenocytes isolated from both rat strains were analyzed by flow cytometry, RT-qPCR, and western blot. AmEVs affected neither vascular contraction nor endothelial relaxation in thoracic aortas. Moreover, AmEVs protected against the development of hypertension in SHRs without a serious adverse reaction. Additionally, AmEVs increased the population of T regulatory (Treg) cells and tended to reduce proinflammatory cytokines. These results indicate that AmEVs have a protective effect against hypertension without a serious adverse reaction. Therefore, it is foreseen that AmEVs may be utilized as a novel therapeutic for the treatment of hypertension.

Astragalus (Astragalus mongholicus) Improves Ventricular Remodeling via ESR1 Downregulation RhoA/ROCK Pathway.

Astragalus (Astragalus mongholicus) alleviates myocardial remodeling caused by hypertension. However, the detailed molecular mechanism is unclear. This study aims to investigate the effect of Astragalus on ventricular remodeling in ovariectomized spontaneous hypertensive rats (OVX-SHR).Female SHR/NCrl rats were subjected to bilateral ovariectomy to establish the OVX-SHR model and treated with Astragalus extract by gavage. The hemodynamics and cardiac function parameters were measured. HE and Masson staining were used to detect the pathological structure of myocardial remodeling and observe the hyperplasia of myocardial collagen fibers. The immunohistochemistry tested the level of α-SMA. The expression levels of inflammatory cytokines, IκB, p65, Cleaved-Caspase3, RhoA, and ROCK1/2 were detected using Western blot. The method of qRT-PCR measured the expression of matrix metalloproteinase (MMP-2 and MMP-9).Hemodynamic and cardiac function parameters were significantly improved after a high dose of Astragalus extract and Valsartan treatment. The myocardial integrity of the model group was significantly reduced, arranged loosely, and disordered, while the expression of α-SMA was increased. However, Astragalus extract and Valsartan treatments significantly reduced the pathological damage and α-SMA. The levels of TNF-α, IL-1ß, IL-6, TGF-ß, MMP-2, and MMP-9 in the model group were increased but decreased after Astragalus extract treatment. Adding an ESR1 inhibitor attenuated the improvement effect of Astragalus extract on myocardial remodeling and restored the expression of RhoA and ROCK1/2.Astragalus extract attenuates the cardiac damage in OVX-SHR by downregulating the RhoA/ROCK pathway through ESR1.

Oil palm kernel globulin antihypertensive peptides: isolation and characterization, ACE inhibition mechanisms, zinc-chelating activity, security and stability.

Introduction: The oil palm kernel (OPK) expeller is the main byproduct of palm oil, but its utilization is limited. Methods: To obtain angiotensin-I-converting enzyme (ACE) inhibition peptides with Zn-chelating capacity, defatted oil palm kernel globulin hydrolysates (DOPKGH) were subjected to Sephadex G-15 gel electrophoresis, reverse-phase high liquid performance chromatography, and UPLC-ESI-MS/MS analysis. Results and discussion: Five representative oligopeptides, including Gln-Arg-Leu-Asp-Arg-Cys-Lys (QRLERCK), Leu-Leu-Leu-Gly-Val-Ala-Asn-Tyr-Arg (LLLGVANYR), Arg-Ala-Asp-Val-Phe-Asn-Pro-Arg (RADVFNPR), Arg-Val-Ile-Lys-Tyr-Asn-Gly-Gly-Gly-Ser-Gly (RVIKYNGGGSG), and Glu-Val-Pro-Gln-Ala-Tyr-Ile-Pro (EVPQAYIP), without potential toxicity and allergenicity, were identified in DOPKGH. Of these, only EVPQAYIP showed both ACE-inhibitory activity (IC50: 102.75 µmol/L) and Zn-chelating capacity (11.69 mg/g). Molecular docking and inhibition kinetics showed that EVPQAYIP was a competitive inhibitor of ACE because it could bind to Glu384, Lys511, and Gln281 (belonging to the central S1 and S2 pockets, respectively) of ACE. Moreover, EVPQAYIP affects zinc tetrahedral coordination in ACE by binding to Glu411; the amino and carboxyl groups of EVPQAYIP chelate with zinc ions. During gastrointestinal digestion, the ACE inhibitory activity of EVPQAYIP was relatively stable. Additionally, EVPQAYIP enhanced zinc stability in the intestine and exerted antihypertensive effects in spontaneous hypertensive rats. These results suggest the potential application of OPK peptides as ingredients in antihypertensive agents or zinc fortification.

5-Aminolevulinic acid hydrochloride enhances bupivacaine-induced hypotension in spontaneously hypertensive rats.

PURPOSE: Oral administration of 5-aminolevulinic acid hydrochloride (5-ALA-HCl) has been reported to enhance the hypotensive effects associated with anesthetics, especially in elderly hypertensive patients treated with antihypertensive agents. The present study aimed to clarify the effects of antihypertensive-agent- and anesthesia-induced hypotension by 5-ALA-HCl in spontaneously hypertensive rats (SHRs). METHODS: We measured blood pressure (BP) of SHRs and normotensive Wistar Kyoto (WKY) rats treated with amlodipine or candesartan before and after administration of 5-ALA-HCl. We also investigated the change in BP following intravenous infusion of propofol and intrathecal injection of bupivacaine in relation to 5-ALA-HCl administration. FINDINGS: Oral administration of 5-ALA-HCl significantly reduced BP in SHRs and WKY rats with amlodipine and candesartan. Infusion of propofol significantly reduced BP in SHRs treated with 5-ALA-HCl. Intrathecal injection of bupivacaine significantly declined SBP and DBP in both SHRs and WKY rats treated with 5-ALA-HCl. The bupivacaine-induced decline in SBP was significantly larger in SHRs compared with WKY rats. CONCLUSION: These findings suggest that 5-ALA-HCl does not affect the antihypertensive agents-induced hypotensive effect, but enhances the bupivacaine-induced hypotensive effect, especially in SHRs, indicating that 5-ALA may contribute to anesthesia-induced hypotension via suppression of sympathetic nerve activity in patients with hypertension.

Dapagliflozin attenuates myocardial remodeling in hypertension by activating the circadian rhythm signaling pathway.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a new kind of antidiabetic drug which has shown beneficial effects in reducing heart failure-related hospitalization and cardiovascular-related mortality. The mechanisms are complicated. Our study aimed to investigate the effects of dapagliflozin on the myocardium of spontaneously hypertensive rats (SHRs) without heart failure. Wistar-Kyoto rats were used as normal controls. SHRs were randomly divided into the SHR group and the -treated group. After 8 weeks of dapagliflozin treatment, the morphology of heart tissues was examined. The mRNA expression profiles were identified via RNA sequencing (RNA-Seq). Various analysis methods were used to find the differentially expressed genes (DEGs) to predict gene function and coexpression. After dapagliflozin treatment, systolic blood pressure was significantly reduced compared with that in the SHR group. Myocardial remodeling was ameliorated compared with that in the SHR group. After dapagliflozin intervention, 75 DEGs (|log2-fold change | > 0 and Q value < 0.05) were identified in the heart tissues compared to the SHR group. Quantitative real-time PCR analysis confirmed that the expression of the circadian rhythm genes Per3, Bhlhe41, and Nr1d1 was significantly upregulated, while the results were coincident with the RNA-Seq results. Dapagliflozin may effectively inhibit myocardial remodeling and regulate blood pressure. The mechanisms may be related to the activation of the circadian rhythm signaling pathway.

Gao-Zi-Yao improves learning and memory function in old spontaneous hypertensive rats.

AIMS: Gao-Zi-Yao has long been a unique way for treating various diseases. The present study is to explore the effect of Gao-Zi-Yao on learning and memory function in old spontaneous hypertensive rats (SHR) and its possible mechanism. METHOD: Male old SHR were received different doses of Gao-Zi-Yao for 4 weeks. Systolic blood pressure (SBP) and heart rate were monitored. Serum levels of nitric oxide (NO), interleukin (IL)-1ß, IL-2, and tumor necrotic factor (TNF)-α were measured. Morris water maze was performed to test the learning and memory function of the rats. Number of neurons in hippocampus was counted by Nissl staining. Western blot was applied to detect the expressions of learning and memory function related proteins, N-methyl-d-aspartate receptor 2B (NMDAR 2B), glutamate receptor 1 (GluR1), phosphorylated-calmodulin-dependent protein kinase II (p-CaMK II), and phosphorylated-cAMP responsive element-binding protein (p-CREB) in rat hippocampus. RESULTS: Data showed that Gao-Zi-Yao reduced SBP in old SHR, elevated NO level, and suppressed levels of IL-1ß, IL-2, TNF-α. The results of Morris water maze experiment showed that Gao-Zi-Yao dose-dependently improved learning and memory function. Number of neurons in the hippocampal dentate gyrus (DG) region of the old SHR was increased by Gao-Zi-Yao treatment. In addition, Gao-Zi-Yao elevated the protein expressions of NMDAR 2B, GluR1, p-CaMK II, and p-CREB in hippocampus. CONCLUSION: Gao-Zi-Yao decreases SBP and improves the learning and memory function of the old SHR by regulation of oxidative stress, inflammatory factors and neuron number in hippocampal DG area and the expression of learning and memory function related proteins.

Beneficial Effects of Black Cardamom (Amomum subulatum) on Hemodynamic Parameters in Normotensive and Spontaneously Hypertensive Rats.

<b>Background and Objectives:</b> <i>Amomum subulatum</i> (AS) is used to improve cardiac health in traditional medicine practice. The present study evaluates the pharmacological effect of AS aqueous extract on blood pressure in Normotensive (NR) and Spontaneously Hypertensive Rats (SHR). <b>Materials and Methods:</b> Blood pressure, Heart Rate (HR) and Heart Rate Variability (HRV), was recorded in catheterized Sprague-Dawley rats before and after AS intravenous administration by using Mikro-Tip Pressure-Volume System (MPVS), PowerLab. The receptor activity was assessed by using the drugs Acetylcholine (ACh) and Atropine (Atr). <b>Results:</b> Preliminary phytochemistry of AS suggests that it contains tannins, flavonoids and saponins. Mean Arterial Pressure (MAP) was found to decrease significantly in NR and SHR as compared with the control. The lowest dose (1 mg kg¹) produced the least (16%) while 30 mg kg¹ caused the maximum reduction (40%) in MAP. Electrocardiograph analysis revealed a significant increase in RR interval (decreased heart rate), time-domain Standard Deviation of Interbeat Interval (SDNN) and the Root Mean Square of the Successive Differences (RMSSD) and High-frequency Domain (HF%) parameters and a decrease in the Low-Frequency (LF) range, suggesting the activation and involvement of the parasympathetic limb. It was also observed that the cardiovascular effects of AS were comparable to Acetylcholine (ACh) and both were completely blocked by Atropine (1 µg kg¹). <b>Conclusion:</b> The obtained results suggest that AS has a hypotensive effect, with an impact on the HRV of NR and SHR. <i>Amomum subulatum</i> might cause an augmented effect on the cholinergic limb of the Autonomic Nervous System (ANS) and decrease the blood pressure and heart rate significantly.

The effects of the dopamine D2/3 agonist quinpirole on incentive value and palatability-based choice in a rodent model of attention-deficit/hyperactivity disorder.

RATIONALE: Palatability and incentive value influence animal food choice. Dopamine D2/3 receptor signaling may mediate the effects of palatability and incentive value on choice. Dopamine signaling is disrupted in attention-deficit hyperactivity disorder (ADHD). Investigating behavioral choice processes under D2/3 receptor agonists will help elucidate behavioral and pharmacological correlates of ADHD. OBJECTIVES: To determine (1) how changes in incentive value affects choice of actions for outcomes that differ in palatability; (2) the effects of the D2/3 agonist quinpirole on choice based on palatability and incentive value; (3) how choice differs in spontaneously hypertensive rats (SHR; ADHD model) compared with control strains. METHODS: Rats responded instrumentally for two food outcomes (chocolate and grain pellets) that differed in palatability. Following specific satiety of one outcome, rats underwent a choice test. Prior to the choice test, rats were given intra-peritoneal quinpirole (0.01-0.1 mg/kg) body weight. These manipulations were conducted in three strains of rats: SHR rats; the normotensive Wistar-Kyoto (WKY) controls; and Wistar outbred (WIS) controls. RESULTS: All rat strains responded more vigorously for chocolate pellets compared with grain pellets. Quinpirole reduced the effects of palatability and dose-dependently increased the effects of incentive value on choice. SHR rats were the least influenced by incentive value, whereas WKY rats were the least influenced by palatability. CONCLUSIONS: These results show that D2/3 signaling modulates choice based on palatability and incentive value. Disruption of this process in SHR rats may mirror motivational impairments observed in ADHD.

Hypertension and the Kidney: Reduced Kidney Mass Is Bad for Both Normotensive and Hypertensive Rats.

BACKGROUND: Hypertension is a leading cause of chronic kidney disease worldwide. Early studies demonstrated the short-term effects of hypertension on kidney function and morphology in ablative nephropathy. The aim of this study was to investigate the long-term consequences of hypertension in 5/6 nephrectomy (5/6NE) model. METHODS: Reduction of the kidney mass by 5/6NE was created in spontaneous hypertensive rats (SHR) and genetically similar normotensive Wistar Kyoto (WKY) rats. Blood pressure, serum creatinine (SCr), hematuria, and proteinuria were monitored weekly for 23 weeks. Kidney morphology was assessed at the end of the study. Sham-operated rats from both strains were used as controls. RESULTS: Rats with 5/6NE had increased SCr, blood pressure, hematuria, and proteinuria in both SHR and WKY. Even though the SCr levels and blood pressure were greater in 5/6NE SHR as compared with 5/6NE WKY rats, absolute changes from sham-operated rats were not statistically significant between these 2 groups. 5/6NE SHR had earlier onset and higher proteinuria than 5/6NE WKY rats. Hematuria was similar in 5/6NE SHR and 5/6NE WKY rats. However, 5/6NE SHR had enlarged glomeruli, increased interstitial fibrosis, and prominent intimal thickening in the small arteries/arterioles as compared with 5/6NE WKY rats. CONCLUSIONS: The long-term severity of kidney injury correlated with higher blood pressure. Reduction of the kidney mass increases SCr, hematuria, proteinuria, and blood pressure in both normotensive and hypertensive rats. Histological assessment provides better information about underlying chronic kidney injury than actual changes in SCr and urinalysis.

Effects of physical exercise combined with captopril or losartan on left ventricular hypertrophy of hypertensive rats.

Background: Left ventricular hypertrophy (LVH) is an endpoint of hypertensive cardiac alterations. Renin-angiotensin-aldosterone system (RAAS) blockers are among the most effective on LVH regression. Physical exercise combined to antihypertensive drug contributes to arterial pressure (AP) control and LVH prevention. We evaluated the effects of physical exercise combined to captopril or losartan during eight weeks for spontaneously hypertensive rats (SHR) on some cardiac parameters.Methods: SHR (n=5-6 per group) were sedentary or trained 5 days a week in treadmill during 8 weeks; and they were treated with daily oral captopril (12.5, 25, or 50mg/kg), losartan (2.5, 5, or 10mg/kg), or vehicle. At the end, it was obtained systolic AP (SAP), electrocardiogram (ECG), and hearts metalloproteinase 2 (MMP-2) activity and histology.Results: Captopril 25 and 50 mg/kg, and losartan 10 mg/kg lowered SAP of sedentary and trained SHR. Losartan 5 mg/kg combined with physical exercise also lowered SAP. Combined with exercise, captopril 50 mg/kg lowered 13.6% of QT interval, 14.2% of QTc interval, and 22.8% of Tpeak-Tend compared to sedentary SHR. Losartan 5 and 10mg/kg lowered QT interval of sedentary and trained SHR. Losartan 2.5, 5 and 10mg/kg combined with physical exercise lowered respectively 25.4%, 24.8%, and 31.8% of MMP-2 activity. Losartan (10mg/kg) combined with exercise reduced cardiomyocyte diameter.Conclusion: These data support the hypothesis of physical exercise combined with RAAS blockers could improve the benefits on hypertensive LVH treatment.

Telmisartan Prevents Alveolar Bone Loss by Decreasing the Expression of Osteoclasts Markers in Hypertensive Rats With Periodontal Disease.

Periodontal disease (PD) is a prevalent inflammatory disease with the most severe consequence being the loss of the alveolar bone and teeth. We therefore aimed to evaluate the effects of telmisartan (TELM), an angiotensin II type 1 receptor (Agtr1) antagonist, on the PD-induced alveolar bone loss, in Wistar (W) and Spontaneous Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk, and 10 mg/kg TELM was concomitantly administered for 15 days. The hemimandibles were subjected to microtomography, ELISA was used for detecting tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), CXCL3, and CCL2, while qRT-PCR was used for analyzing expression of components of renin-angiotensin system (RAS) (Agt, Ace, Agt1r, Agt2r, Ace2, and Masr), and bone markers (Runx2, Osx, Catnb, Alp, Col1a1, Opn, Ocn, Bsp, Bmp2, Trap, Rank, Rankl, CtsK, Mmp-2, Mmp-9, and osteoclast-associated receptor (Oscar)). The SHR + PD group showed greater alveolar bone loss than the W + PD group, what was significantly inhibited by treatment with TELM, especially in the SHR group. Additionally, TELM reduced the production of TNF-α, IL-1ß, and CXCL3 in the SHR group. The expression of Agt increased in the groups with PD, while Agtr2 reduced, and TELM reduced the expression of Agtr1 and increased the expression of Agtr2, in W and SHRs. PD did not induce major changes in the expression of bone formation markers, except for the expression of Alp, which decreased in the PD groups. The bone resorption markers expression, Mmp9, Ctsk, and Vtn, was higher in the SHR + PD group, compared to the respective control and W + PD group. However, TELM attenuated these changes and increased the expression of Runx2 and Alp. Our study suggested that TELM has a protective effect on the progression of PD, especially in hypertensive animals, as evaluated by the resorption of the lower alveolar bone. This can be partly explained by the modulation in the expression of Angiotensin II receptors (AT1R and AT2R), reduced production of inflammatory mediators, the reduced expression of resorption markers, and the increased expression of the bone formation markers.

Antihypertensive properties of a traditional Chinese medicine GAO-ZI-YAO in elderly spontaneous hypertensive rats.

AIM: The present study aims to investigate the antihypertensive effect and the underlying mechanism of GAO-ZI-YAO, one of the traditional Chinese medicines, in elderly spontaneous hypertensive rats (SHR). METHODS: 12-month-old male SHRs were randomly divided into five groups on the basis of treatment with different doses of GAO-ZI-YAO or angiotensin II receptor-1 blocker (ARB, Irbesartan) for four weeks. Systolic blood pressure (SBP), and serum levels of nitric oxide (NO), endothelin-1 (ET-1), angiotensin II (Ang II), vascular endothelial growth factor (VEGF), interleukin (IL)-1ß, IL-2, IL-6, and tumor necrotic factor (TNF)-α were measured. The pathological changes of ventricular muscle and thoracic aorta were observed by hematoxylin-eosin staining (H&E). RESULTS: GAO-ZI-YAO treatment reduced SBP in a dose-dependent manner accompanied by the inhibition of the development of cardiovascular remodeling. Although GAO-ZI-YAO treatment markedly increased serum levels of NO and suppressed serum levels of Ang II, this medicine did not affect the serum levels of ET-1 and VEGF. In addition, GAO-ZI-YAO also inhibited inflammatory response parameters (inflammatory cell infiltration in cardiac tissues and serum levels of IL-1ß, IL-2, IL-6, and TNF-α) in a dose-dependent manner. CONCLUSION: GAO-ZI-YAO exerts antihypertensive and anti-cardiovascular-remodeling effects in elderly SHR, which may be through regulation of NO, Ang II production, and inflammation.

Corrigendum: Telmisartan Prevents Alveolar Bone Loss by Decreasing the Expression of Osteoclasts Markers in Hypertensive Rats With Periodontal Disease.

[This corrects the article DOI: 10.3389/fphar.2020.579926.].

Metabolomics study of the prefrontal cortex in a rat model of attention deficit hyperactivity disorder reveals the association between cholesterol metabolism disorder and hyperactive behavior.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disease for which specific biomarkers and pathological mechanisms have yet to be identified. Methylphenidate (MPH) is commonly used to treat ADHD, but its therapeutic mechanisms and its impact on brain metabolites remain unclear. Metabolomics can help to discover biomarkers and identify pathophysiological mechanisms. We adopted an untargeted metabolomics approach based on gas chromatography-mass spectrometry to investigate the potential biomarkers and pathogenesis of ADHD. Ten Wistar-Kyoto (WKY) rats were chosen as healthy controls (vehicle, i.g.). Twenty young spontaneously hypertensive rats (SHR) were randomly allocated to the SHR group (vehicle, i.g.) and MPH group (2 mg/kg/day, i.g.). We identified 103 metabolites from the prefrontal cortex (PFC). Orthogonal partial least square-discriminate analysis showed the differential expression of these metabolites between the groups. Multivariate and univariate statistical analyses isolated 12 metabolites that differed significantly between the WKY and SHR groups: 3-hydroxymethylglutaric acid, 3-phosphoglyceric acid, adenosine monophosphate, cholesterol, lanosterol, and o-phosphoethanolamine; 3-hydroxymethylglutaric acid and cholesterol were reversed with MPH treatment. Pathway and enrichment analyses revealed that the altered metabolites belonged to the cholesterol metabolism pathways. ELISA and western blotting showed that the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase and the expression of sterol regulatory element-binding protein-2 and ATP-binding cassette transporter A1 were reduced in the PFC of the SHR; the latter two proteins were upregulated by MPH. In conclusion, metabolomics analysis identified potential biomarkers that influence cholesterol metabolism and may be implicated in the development of ADHD-like behavior. MPH can regulate cholesterol metabolism in the PFC of ADHD models. This study uncovered potential biomarkers and pathways involved in ADHD, providing new insight into its pathogenesis.

Effects of minocycline on epiplexus macrophage activation, choroid plexus injury and hydrocephalus development in spontaneous hypertensive rats.

Hydrocephalus has been reported to occur in spontaneous hypertensive rats (SHRs). The purposes of this study were (1) to use T2 magnetic resonance imaging to examine time of onset, (2) to elucidate potential underlying mechanisms and (3) to determine whether minocycline could prevent hydrocephalus development. Ventriculomegaly was evaluated by T2 imaging in SHRs and Wistar-Kyoto rats from weeks 4 to 7 after birth. Brain histology and transmission electron microscopy were used to assess the periventricular and choroid plexus damage. SHRs were also treated with either vehicle or minocycline. We found that hydrocephalus was observed in SHRs but not in Wistar-Kyoto rats. It occurred at seven weeks of age but was not present at four and five weeks. The hydrocephalus was associated with epiplexus cell (macrophage) activation, choroid plexus cell death and damage to the ventricle wall. Treatment with minocycline from week 5 attenuated hydrocephalus development and pathological changes in choroid plexus and ventricular wall at week 7. The current study found that spontaneous hydrocephalus arises at ∼7 weeks in male SHRs. The early development of hydrocephalus (persistent ventricular dilatation) may result from epiplexus cell activation, choroid plexus cell death and periventricular damage, which can be ameliorated by treatment with minocycline.

Caffeine and cannabinoid receptors modulate impulsive behavior in an animal model of attentional deficit and hyperactivity disorder.

Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity, and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosine systems in a tolerance to delay of reward task using the most widely used animal model of ADHD. Spontaneous Hypertensive Rats (SHR) and Wistar-Kyoto rats were treated chronically or acutely with caffeine, a non-selective adenosine receptor antagonist, or acutely with a cannabinoid agonist (WIN55212-2, WIN) or antagonist (AM251). Subsequently, animals were tested in the tolerance to delay of reward task, in which they had to choose between a small, but immediate, or a large, but delayed, reward. Treatment with WIN decreased, whereas treatment with AM251 increased the choices of the large reward, selectively in SHR rats, indicating a CB1 receptor-mediated increase in impulsive behavior. An acute pre-treatment with caffeine blocked WIN effects. Conversely, a chronic treatment with caffeine increased the impulsive phenotype and potentiated the WIN effects. The results indicate that both cannabinoid and adenosine receptors modulate impulsive behavior in SHR: the antagonism of cannabinoid receptors might be effective in reducing impulsive symptoms present in ADHD; in addition, caffeine showed the opposite effects on impulsive behavior depending on the length of treatment. These observations are of particular importance to consider when therapeutic manipulation of CB1 receptors is applied to ADHD patients who consume coffee.

Dopaminergic Modulation of Goal-Directed Behavior in a Rodent Model of Attention-Deficit/Hyperactivity Disorder.

Aside from its clinical symptoms of inattention, impulsivity and hyperactivity, patients with Attention/Deficit-Hyperactivity Disorder (ADHD) display reward and motivational impairments. These impairments may reflect a deficit in action control, that is, an inability to flexibly adapt behavior to changing consequences. We previously showed that spontaneously hypertensive rats (SHR), an inbred rodent model of ADHD, show impairments in goal-directed action control, and instead are predominated by habits. In this study, we examined the effects of specific dopamine receptor sub-type (D1 and D2) agonists and antagonists on goal-directed behavior in SHR and the normotensive inbred control strain Wistar-Kyoto (WKY) rats. Rats acquired an instrumental response for different-flavored food rewards. A selective-satiety outcome devaluation procedure followed by a choice test in extinction revealed outcome-insensitive habitual behavior in SHR rats. Outcome-sensitive goal-directed behavior was restored in SHR rats following injection prior to the choice test of the dopamine D2 receptor agonist Quinpirole or dopamine D1 receptor antagonist SCH23390, whereas WKY rats showed habitual responding following exposure to these drugs. This novel finding indicates that the core behavioral deficit in ADHD might not be a consequence of dopamine hypofunction, but rather is due to a misbalance between activation of dopamine D1 and D2 receptor pathways that govern action control.

Tamarindus indica seeds improve carbohydrate and lipid metabolism: An in vivo study.

BACKGROUND: The tamarind seeds have a lot of nutrients that may be used to control cholesterol or glucose levels. OBJECTIVE(S): The effects of tamarind seeds (T) on lipid and carbohydrate metabolism in rats were studied. Rats were offered basal diet (BD) with T (2%, 4% or 8%) or without T. MATERIALS AND METHODS: Feeding and growth performance in rats were measured and samples of liver and blood were analyzed for glycogen content and levels of cholesterol and glucose respectively. RESULTS: The inclusion of T in the diet influences the feeding and growth performance in rats. The serum cholesterol level was reduced (p < 0.05) in Sprague Dawley (SD) rats fed on basal diet (BD) containing 4% and 8% T (0.24 ± 0.14 g/l and 0.31 ± 0.06 g/l respectively) compared to control (0.79 ± 0.04 g/l). The serum glucose levels in the spontaneous hypertensive rats (SHR) was lower (50.74 ± 2.50 mg/dl; p < 0.05) than control (93.52 ± 10.83 mg/dl) at 4% T. Incorporation of increasing doses of T resulted in linear increase of glycogen storage in livers of SD rats fed on BD and high sucrose diet. CONCLUSION: Tamarind seeds can lower blood glucose and serum cholesterol and enhance storage of glycogen in rats.

Reparo ósseo peri-implantar em tíbias de ratos espontaneamente hipertensos (SHR) tratados com losartan: análise biomecânica, molecular, microtomográfica, dinâmica óssea por fluorocromos, imunoistoquímica e histológica / Peri-implant bone healing in the tibia of spontaneously hypertensive rats (SHR) treated with losartan: a biomechanical, molecular, microtomography, bone dynamics by fluorochromes, immunohistochemical and histological analysis

A hipertensão está associada a doenças cardiovasculares, mas também com alterações na qualidade óssea. A hipertensão, portanto, pode ser um fator de risco para a osseointegração. Estudos pré-clínicos sugerem que o Losartan, um bloqueador dos receptores da angiotensina II amplamente utilizado para tratara hipertensão, tem um efeito benéfico na consolidação do enxerto. No entanto, o efeito da hipertensão e do Losartan na osseointegração permanece desconhecido. Materiais e métodos: Aqui utilizamos ratas espontaneamente hipertensivos (SHR) e ratos Wistar albinus normotensos que receberam Losartan (30 mg/kg, p.o.) ou não tratados. Após uma semana, mini-implantes de titânio foram inseridos na tíbia. Sessenta dias após a implantação, a estabilidade do implante foi avaliada pela medição de torque de remoção considerada o ponto final primário. A tomografia computadorizada micro e a análise histomorfométrica foram parâmetros secundários. Resultados: o Losartan aumentou o torque de remoção no grupo SHR hipertenso para os níveis dos controles Wistar. Enquanto os parâmetros corticais da osseointegração permaneceram inalterados, Losartan aumentaram a formação do osso medular. A micro tomografia computadorizada revelou maior volume ósseo por volume de tecido e espessura trabecular nos ratos SHR tratados com Losartan. A análise histomorfométrica mostrou ainda que o Losartan aumentou significativamente a espessura do osso recém-formado na área medular em ratos SHR hipertensos. O Losartan não alterou significativamente os parâmetros de osseointegração em ratos normotensos. Conclusões: Os dados apresentados sugerem que o antagonista dos receptores da angiotensina II Losartan aumenta os parâmetros medulares da osseointegração no modelo da tíbia de ratos espontaneamente hipertensos(AU)

Background: Hypertension is associated with cardiovascular diseases but also with alterations in bone quality. Hypertension therefore might be a risk factor for osseointegration. Preclinical studies suggest that losartan, an angiotensin II receptor blocker widely used to treat hypertension, has a beneficial effect in graft consolidation. However, the effect of hypertension and losartan on osseointegration remains unknown. Methods: Here we used spontaneously hypertensive rats (SHR) and normotensive Wistar albinus rats receiving losartan (30 mg/kg, p.o.) or left untreated. After one week, titanium miniscrews were inserted into the tibia. Sixty days after implantation, implant stability was evaluated by removal torque measurement considered the primary endpoint. Micro computed tomography and histomorphometric analysis were secondary endpoints. Results: Losartan increased the removal torque in the hypertensive SHR group to levels of the Wistar controls. While the cortical parameters of osseointegration remained unchanged, losartan increased medullary bone formation. Micro computed tomography revealed a higher bone volume per tissue volume and trabecular thickness in the SHR rats treated with losartan. Histomorphometric analysis further showed that losartan significantly increased the thickness of newly formed bone in medullary area in hypertensive SHR rats. Losartan did not significantly alter the parameters of osseointegration in normotensive rats. Conclusions: The data presented suggest that the angiotensin II receptor antagonist losartan increases the medullary parameters of osseointegration in a tibia model of spontaneously hypertensive rats(AU)

Establishment and characterization of a rat model of hypertension with hyperlipidemia / 中国比较医学杂志

Objective To develop an ideal hypertension combined hyperlipidemia(HP/HL)rat model by feeding spontaneously hypertensive rats(SHRs)with high fat diet, and to evaluate the pathological changes in target organs including heart and kidney. Methods Twenty 3-week old male SHRs were randomly divided into two groups: normal fat control group(SHR-NC)and high fat group(SHR-HF). Moreover,ten 3-week old male Wistar-Kyoto rats(WKY)were taken as the model control group(WKY-NC). The rats in SHR-HF group were fed with high-fat diet to induce HP/HL, while rats of WKY-NC and SHR-NC groups were fed with normal diet. The systolic blood pressure(SBP)and body weight were measured every week. At the end of the experiment, the rats were sacrificed to take serum samples for blood lipid analysis including high density lipoprotein(HDL-C), low density lipoprotein(LDL-C), total cholesterol(TC)and triglyceride(TG). Heart and kidney tissue samples were collected to examine the pathological changes using HE and Masson staining. Results Compared with the SHR-NC group, the SHRs fed with high-fat diet for 23 weeks presented significant increase of blood pressure and TC, TG, LDL-C, and decrease of HDL-C. The HP/HL rat model showed pathological changes in the HP/HL target organs, heart and kidney. Renal tissues were severely damaged and showed a large area of fibrosis. Besides, left ventricular hypertrophy and myocardial fibrosis were also observed. Conclusions A HP/HL rat model is successfully constructed by feeding SHRs with high-fat diet for 23 weeks. Most importantly,this model exhibits progressive renal and cardiac alterations, similar to those of patients with HP/HL. This HP/HL rat model may become widely used for evaluation of HP/HL therapeutic drugs.