Control Spontaneously Hypertensive Rats Research Articles

Effect of p-tyrosol on hemorheological parameters and cerebral capillary network in young spontaneously hypertensive rats

BackgroundMany pathological mechanisms are involved in the development of arterial hypertension; disturbance of the rheological properties of blood and microvascular rarefaction are among those mechanisms. ObjectiveThe effect of p-tyrosol (Tyr) on hemorheological parameters and microvascularization in the cerebral cortex of spontaneously hypertensive rats (SHRs) at the stage of blood pressure rising (5–11 weeks) was studied. MethodsBlood viscosity (BV), plasma viscosity (PV), hematocrit, erythrocyte aggregation and deformability, the oxygen transport capacity index (OTCI), and the capillary network in the cerebral cortex after the course of treatment of Tyr (50 mg/kg daily i.g. for 6 weeks) were studied. Control normotensive Wistar-Kyoto (WKY) rats and control SHRs received an equivalent amount of 1% starch mucilage. ResultsIn comparison with WKY rats, disturbances of rheological blood parameters and a decrease in OTCI were revealed in control SHRs at the 11 weeks of life. By the end of the experiment, brain microvascular rarefaction was observed in the control SHRs (the average density of the capillary bed was reduced due to a decrease in the number of capillaries with a diameter of 3–7 μm). In SHRs rats treated with Tyr, BV and PV, the indices of erythrocyte aggregation were lower, and OTCI was higher in comparison with control SHRs. The density of the capillary network and the number of capillaries of 3–7 μm in the cerebral cortex of SHRs rats receiving Tyr were significantly higher than the corresponding values in control SHRs. ConclusionWhen Tyr is administered to young SHRs during the development of hypertension, it limits the development of hyperviscosity syndrome, improves the oxygen transport capacity and eliminates microvascular rarefaction in the cerebral cortex.

Blood Pressure Lowering Effect of Cuban Policosanol is Accompanied by Improvement of Hepatic Inflammation, Lipoprotein Profile, and HDL Quality in Spontaneously Hypertensive Rats.

We investigated the antihypertensive effect of policosanol on spontaneously hypertensive rats (SHR). For this, we analyzed blood pressure, blood lipid, and lipoprotein properties in male SHR after consumption of Cuban policosanol (PCO). The experimental groups were as follows: normotensive Wistar Kyoto (WKY) control, SHR group fed normal diet (ND), SHR group fed 20 mg of PCO, SHR group fed 100 mg of PCO, and SHR group fed 200 mg of PCO per kg of body weight. After eight weeks, the SHR control group showed gradual increases up to 22% in systolic blood pressure (SBP) and 17.6% in the diastolic blood pressure (DBP) compared with values at week 0. However, policosanol consumption had a dose-dependent reduction effect on SBP and also reduced DBP up to 16% in a dose-dependent manner. Heart rate (HR) bpm increased by six percent in the SHR control, whereas the 20 mg, 100 mg, and 200 mg of policosanol groups showed a reduction of 36%, 28%, and 34% respectively. Although serum total cholesterol (TC) level of SHR was not affected by policosanol consumption (70–80 mg/dL), serum triglyceride (TG) level significantly decreased in the SHR + 200 mg of PCO group. Serum high-density lipoprotein cholesterol (HDL-C) level was also significantly elevated by policosanol consumption. The % HDL-C/TC ratio was elevated in the policosanol group up to 67–70%, whereas the SHR control group showed a ratio of 58%. Serum cholesteryl ester transfer protein (CETP) activity was reduced by policosanol in a dose-dependent manner. Although the serum glutamate oxaloacetate transaminase (GOT)/ glutamate pyruvate transaminase (GPT) were similar across all groups, policosanol consumption caused reduction of reactive oxygen species (ROS) levels in hepatic tissue. The SHR control group showed a 2.1-fold higher serum C-reactive protein (CRP) level than the WKY group, whereas the CRP level decreased in the SHR + 200 mg of PCO group (up to 45%) than SHR control group. Aldosterone level was reduced in the policosanol group (up to 34%) in a dose-dependent manner compared to the control. In conclusion, eight weeks of policosanol consumption in SHR resulted in remarkable reduction of blood pressure, serum aldosterone, and serum TG levels along with the elevation of HDL-C and improvement of hepatic inflammation.

Neprilysin Inhibition by an Antisense Oligonucleotide (ASO) Ameliorates Kidney Damage in a Salt‐induced Rat Chronic Kidney Disease Model

Neprilysin (NEP) is the key enzyme that degrades natriuretic peptides (NPs), which are the neurohormones contributing to natriuresis, diuresis and blood pressure regulation. NEP inhibition results in enhanced natriuresis and vasodilation by augmenting NP levels, which lead to the reduction of intra‐glomerular pressure and proteinuria in the damaged kidneys. We evaluated the renoprotective effects of a Generation 2.5 NEP antisense oligonucleotide (ASO) in a hypertensive and salt‐induced severe chronic kidney disease (CKD) model. Male, uninephrectomized (UNX) spontaneously hypertensive rats (SHR) were randomized to concurrently receive seven weeks of high salt intake (1% NaCl in drinking water for 5 weeks and then 1.5% for remaining two weeks) and drug treatments (vehicle control, NEP ASO at 20 mg/kg SQ weekly or the small molecule NEP inhibitor AHU377 at 50 mg/kg PO daily). AHU377 (Sacubitril) is the main ingredient of the recently approved heart failure drug Entresto®. Age‐matched SHR naïve (SHR control, normal salt intake) and SHRs with UNX (UnX control, normal salt intake + UnX) served as negative controls. NEP ASO treated rats demonstrated improvements in proteinuria compared to vehicle control or AHU377 treatments1. There were no differences between the treatment groups in blood BUN, creatinine level and creatinine clearance. In the NEP ASO group, kidney qPCR analysis demonstrated marked reductions of NEP expression (>90%) and significantly less inflammation (MCP1, KIM1, NGAL) and fibrosis (ColIa1) relative to control or AHU377 treatments2. Western blot and NEP activity assays of kidney homogenates corroborated the qPCR findings. Meanwhile, NEP ASO and AHU377 treatments restored urinary cGMP/creatinine ratio3 suppressed by salt‐induced kidney damage. Histological examination of the kidney revealed less interstitial fibrosis, eosinophilic casts and glomerulosclerosis with NEP ASO treatment. In summary, in a severe rat CKD model, NEP ASO treatment was effective in blunting disease progression (i.e. less proteinuria, inflammation and fibrosis), which was not observed with the treatment by a small molecular NEP inhibitor AHU377. SHR control UnX control UnX, salt + vehicle UnX, salt + NEP ASO UnX, salt + AHU377 1 MicroAlb/CRE (mg/ml/mg/dL) 0.22 ± 0.04 1.25 ± 0.23 16.2 ± 3.3 2.40 ± 0.80** 26.3 ± 10.1 2 MCP1 gene expression (%) 100 ± 8 121 ± 8 347 ± 48 239 ± 18* 351 ± 31 KIM1 gene expression (%) 100 ± 28 248 ± 47 10,189 ± 2,382 1,430 ± 307* 18,970 ± 12,266 NGAL gene expression (%) 100 ± 7 157 ± 7 1,870 ± 387 463 ± 36** 1,987 ± 794 ColIa1 gene expression (%) 100 ± 10 139 ± 13 753 ± 122 474 ± 28* 752 ± 95 3 Urinary cGMP/CRE (pmol/ml/mg/dL) 33.6 ± 4.6 26.6 ± 2.4 19.5 ± 1.6 26.4 ± 2.2* 34.4 ± 4.2 1(UnX, salt + vehicle) vs. (UnX, salt + NEP ASO): ** p < 0.01 2(UnX, salt + vehicle) vs. (UnX, salt + NEP ASO): * p < 0.05, ** p < 0.01 3(UnX, salt + vehicle) vs. (UnX, salt + NEP ASO): * p < 0.05 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The benefits of soluble non-bacterial fraction of kefir on blood pressure and cardiac hypertrophy in hypertensive rats are mediated by an increase in baroreflex sensitivity and decrease in angiotensin-converting enzyme activity.

We aimed to evaluate whether long-term treatment with the soluble non-bacterial fraction of kefir affects mean arterial pressure (MAP) and cardiac hypertrophy through the modulation of baroreflex sensitivity, ACE activity, and the inflammatory-to-anti-inflammatory cytokine ratio in spontaneously hypertensive rats (SHRs). SHRs were treated with the soluble non-bacterial kefir fraction (SHR-kefir) or with kefir vehicle (SHR-soluble fraction of milk). Normotensive control Wistar Kyoto animals received the soluble fraction of milk. All treatments were administered by gavage (0.3 mL/100g/body weight), once daily for eight weeks. At the end, after basal MAP and Heart Rate (HT) measurement, barorreflex sensitivity was evaluated through in bolus administrations of sodium nitroprusside and phenylephrine (AP50 [arterial pressure 50%], the lower plateau, and HR range were measured). ACE activity and cytokines (TNF-α and IL-10) were evaluated by ELISA. Cardiac hypertrophy was analysed morphometrically. Compared to SHR control, SHR-kefir exhibited a significant decrease in both MAP (SHR: 184 ± 5; SHR-Kefir: 142 ± 8 mmHg), and HR (SHR: 360 ± 10; SHR-kefir: 310 ± 14 bpm). The non-bacterial fraction of kefir also reduced cardiac hypertrophy, TNF-α-to-IL10 ratio, and ACE activity in SHRs. SHR-kefir baroreflex sensitivity, resulted in a partial but significant recovery of baroreflex gain, as demonstrated by improvements in AP50, the lower plateau, and HR range. In summary, our results indicate that long-term administration of the non-bacterial fraction of kefir promotes a significant decrease in both MAP and HR, by improving baroreflex, and reduces cardiac hypertrophy in SHRs, likely via ACE inhibition, and reduction of the TNF-α-to-IL10 ratio.

Cyanidin 3-O-glucoside prevents the development of maladaptive cardiac hypertrophy and diastolic heart dysfunction in 20-week-old spontaneously hypertensive rats.

The present study investigated the effects of cyanidin 3-O-glucoside (C3G) in cardiomyocytes (CM) and fibroblasts exposed to endothelin 1 (ET1), as well as in the spontaneously hypertensive rat (SHR) model, alone or in combination with hydrochlorothiazide (HCT). Adult rat CM and cardiac fibroblasts (CF) were pretreated with C3G and co-incubated with ET1 (10-7 M) for 24 hours. Five-week-old male SHR and their normotensive controls, Wistar-Kyoto rats (WKY), received one of 4 treatments via oral gavage daily for 15 weeks: (1) water (control); (2) C3G (10 mg per kg per day); (3) HCT (10 mg per kg per day); (4) C3G + HCT (10 mg per kg per day each). Blood pressure (BP) was measured at 1, 8 and 15 weeks. Echocardiography measurements were performed at 15 weeks. C3G prevented ET1-induced CM death and hypertrophy. Stimulating CF with ET1 did not induce their phenoconversion; nevertheless, C3G inhibited un-stimulated CF differentiation. HCT slowed the rise of systolic BP (SBP) in the SHR over time (week 1: SHRs control = 161 ± 6.3 mmHg, SHRs HCT = 129 ± 6.3 mmHg; week 15: SHRs control = 201 ± 7.3 mmHg, SHRs HCT = 168 ± 7.3 mmHg), but C3G had no effect on SBP (week 1: SHRs control = 161 ± 6.3 mmHg, SHRs C3G = 126 ± 6.3 mmHg; week 15: SHRs control = 201 ± 7.3 mmHg, SHRs C3G = 186 ± 7.3 mmHg). SHRs treated with C3G, HCT, and C3G + HCT had lower left ventricular mass and shorter isovolumetric relaxation time compared to control SHRs. C3G ameliorated cardiac hypertrophy and diastolic dysfunction in SHRs.

Atorvastatin Attenuates Myocardial Hypertrophy in Spontaneously Hypertensive Rats via the C/EBPβ/PGC-1α/UCP3 Pathway

Background/Aims: Many clinical and experimental studies have shown that treatment with statins could prevent myocardial hypertrophy and remodeling induced by hypertension and myocardial infarction. But the molecular mechanism was not clear. We aimed to investigate the beneficial effects of atorvastatin on hypertension-induced myocardial hypertrophy and remodeling in spontaneously hypertensive rats (SHR) with the hope of revealing other potential mechanisms or target pathways to interpret the pleiotropic effects of atorvastatin on myocardial hypertrophy. Methods: The male and age-matched animals were randomly divided into three groups: control group (8 WKY), SHR (8 rats) and intervention group (8 SHR). The SHR in intervention group were administered by oral gavage with atorvastatin (suspension in distilled water, 10 mg/Kg once a day) for 6 weeks, and the other two groups were administered by gavage with equal quantity distilled water. Blood pressure of rats was measured every weeks using a standard tail cuff sphygmomanometer. Left ventricular (LV) dimensions were measured from short-axis views of LV under M-mode tracings using Doppler echocardiograph. Cardiomyocyte apoptosis was assessed by the TUNEL assay. The protein expression of C/EBPβ, PGC-1α and UCP3 were detected by immunohistochemistry or Western blot analysis. Results: At the age of 16 weeks, the mean arterial pressure of rats in three groups were 103.6±6.1, 151.8±12.5 and 159.1±6.2 mmHg respectively, and there wasn’t statistically significant difference between the SHR and intervention groups. Staining with Masson’s trichrome demonstrated that the increased interstitial fibrosis of LV and ventricular remodeling in the SHR group were attenuated by atorvastatin treatment. Echocardiography examination exhibited that SHR with atorvastatin treatment showed an LV wall thickness that was obviously lower than that of water-treated SHR. In hypertrophic myocardium, accompanied by increasing C/EBPβ expression and the percentage of TUNEL-positive cells, the expression of Bcl-2/Bax ratio, PGC-1α and UCP3 were reduced, all of which could be abrogated by treatment with atorvastatin for 6 weeks. Conclusion: This study further confirmed that atorvastatin could attenuate myocardial hypertrophy and remodeling in SHR by inhibiting apoptosis and reversing changes in mitochondrial metabolism. The C/EBPβ/PGC-1α/UCP3 signaling pathway might also be important for elucidating the beneficial pleiotropic effects of atorvastatin on myocardial hypertrophy.

The effects of single and combined application of ramipril and losartan on renal structure and function in hypertensive rats

ABSTRACTThe objective of the present study was to investigate the effects of single and combined administration of ramipril and losartan on renal structure and function in spontaneously hypertensive rats (SHRs). Thirty-two 9-week-old SHRs and eight Wistar-Kyoto (WKY) rats were randomly divided into five groups: the WKY control group, the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined mediation group. The rat body weight, SBP, heart rate, and urinary albumin excretion rate (UAER) were measured. (1) The SBP was reduced to the normal level in all groups of rats except for the SHR control group. Combined administration of ramipril and losartan can be reduced to the normal level earlier than single (P < 0.01). (2) The SHR-ramipril group and the SHR-losartan group still experienced a higher UAER than that in the WKY control group (P < 0.01). (3) The renal mass/BW ratio was decreased in the SHR-ramipril group, SHR-losartan group, and SHR-combined medication group compared to that in the SHR control group (P < 0.01). (4) Compared with the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined medication group had a lower percentage of the IOD of glomerular collagen relative to the glomerular area (P < 0.01). (5) The reduction in tubulointerstitial injury score was more significant in the SHR-combined medication group than in the SHR-ramipril group and the SHR-losartan group (P < 0.01). The combination of ramipril and losartan is superior to either single drug in reducing the UAER, resisting glomerular collagen deposition, and protecting renal tubular structure.

Divergent profile between hypothalamic and plasmatic aminopeptidase activities in WKY and SHR. Influence of beta-adrenergic blockade

AimsWistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) differ in their renin-angiotensin system function and sympathetic tone. The metabolism of angiotensins and vasopressin depends on the action of certain aminopeptidases whose activity may be influenced by the autonomic nervous system. Their regulation may differ between WKY and SHR in hypothalamus and plasma according to the sympathetic tone. We analyzed aminopeptidases responsible for the hydrolysis of certain angiotensins, vasopressin, cholecystokinin or enkephalins in hypothalamus and plasma of WKY and SHR in untreated controls rats and under beta-adrenoceptor blockade. Systolic blood pressure, food intake, water intake and diuresis were measured as parameters modulated by the autonomic nervous system and the above mentioned peptides. Main methodsGlutamyl-, aspartyl-, cystinyl- and alanyl-aminopeptidase activities were analyzed fluorimetrically in plasma and hypothalamus of control and propranolol-treated (100mg/kg/day administered in drinking water for 1month) WKY and SHR, using arylamide derivatives as substrates. Key findingsAn opposite response of aminopeptidases to propranolol treatment between plasma and hypothalamus was observed in either WKY and SHR. Furthermore, the behavior of aminopeptidases was inversed between WKY and SHR either in hypothalamus and plasma: while the activity increased in hypothalamus and decreased in plasma of WKY, it decreased in hypothalamus and increased in plasma of SHR. SignificanceThese results revealed an inverse response of aminopeptidases between hypothalamus and plasma and also an opposite behavior of these enzymes between WKY and SHR in hypothalamus and plasma. These observations support the involvement of the sympathetic system in the modulation of aminopeptidase activities.

20-Hydroxyecdysone attenuates cardiac remodeling in spontaneously hypertensive rats

BackgroundEcdysteroids, a group of steroid hormones found in insects and many plants, have been shown to prevent various changes in mammalian tissues after female sex hormone deprivation. PurposeTo examine whether an ecdysteroid, 20-hydroxyecdysone (20-HE), exhibits regulatory or protective roles in the cardiovascular system. Study design/methodBlood pressure and cardiac function were evaluated in spontaneously hypertensive rats (SHR) during and after daily treatment with 20-HE for six weeks. ResultsThe progressive increase in systolic blood pressure with age in SHR rats was significantly lower in animals treated with either 5 or 10mg/kg body weight of 20-HE. However, treatment with 20-HE did not diminish the increase in diastolic pressure. Echocardiography after six weeks of treatment demonstrated that the left ventricular chamber of SHR rats treated with 20-HE was smaller than that of SHR controls, while contractility was not affected by 20-HE. Histological images also demonstrated a decrease in cardiomyocyte cross-sectional area in 20-HE treated groups. Interestingly, treatment with 20-HE caused a shift in cardiac myosin heavy chain towards more β-isoforms. SHR rats treated with 20-HE also exhibited a decrease in seminal vesicular weight and an increase in testicular weight, especially at a dose of 10mg/kg body weight. This finding suggests a possible anti-androgenic effect of 20-HE. ConclusionOur finding reveal that 20-HE has a beneficial effect on reducing blood pressure and consequently preventing dilated cardiac hypertrophy in SHR rats.

Effects of pentoxifylline on hemodynamic, hemorheological, and microcirculatory parameters in young SHRs during arterial hypertension development

ABSTRACTThe most common form of hypertension in young adults is isolated diastolic hypertension. Diastolic arterial pressure is determined by the total peripheral resistance and depends on both vascular hindrance and blood viscosity. The aim of our work was to study the efficiency of pentoxifylline (PTX) in young spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. The effects of a treatment course with PTX (100 mg/kg/day p.o. for 6 weeks, from 5 to 11 weeks old) on the mean, systolic, and diastolic blood pressure (BP); stroke volume; cardiac output; total peripheral resistance (TPR); whole blood viscosity (BV); plasma viscosity; hematocrit; RBC aggregation and deformability; local cerebral blood flow (lCBF); and microvascularization of the visual cortex were studied in SHRs in comparison with control SHRs and Wistar Kyoto rats. PTX-treated SHRs had significantly lower systolic, diastolic, and mean BP (by 24%, 26%, and 15%, respectively) and BV (by 5–9%) and a higher erythrocyte deformability index (by 1.5–2%), lCBF (by 42%), average diameter of capillaries (by 11%), density of the capillary network (by 23%), and percentage of capillaries with a diameter of 3–7 µm in comparison with control SHRs. In conclusion, PTX exerted positive effects on the hemodynamic, hemorheological, and microcirculatory parameters in SHRs during the development of arterial hypertension.

Effects of taurine on resting-state fMRI activity in spontaneously hypertensive rats.

Attention deficit hyperactivity disorder (ADHD) is a global behavior illness among children and adults. To investigate the effects of taurine on resting-state fMRI activity in ADHD, a spontaneously hypertensive rat (SHR) animal model was adopted. Significantly decreased serum C-reactive protein (CRP) was detected in rats of Wistar Kyoto (WKY) high-taurine group and significantly decreased interleukin (IL)-1β and CRP were detected in rats of SHR low-taurine and high-taurine groups. Moreover, significantly higher horizontal locomotion was detected in rats of WKY low-taurine and SHR low-taurine groups than in those of controls. In contrast, significantly lower horizontal locomotion was detected in rats of the SHR high-taurine group than in those of the SHR control group. Additionally, significantly lower functional connectivity (FC) and mean amplitude of low-frequency fluctuation (mALFF) in the bilateral hippocampus in rats of WKY high-taurine and SHR high-taurine groups was detected. Notably, the mALFF in rats of the SHR low-taurine and high-taurine groups was significantly lower than in those of the SHR control group. These findings suggest that the administration of a high-dose taurine probably improves hyperactive behavior in SHR rats by ameliorating the inflammatory cytokines and modulating brain functional signals in SHR rats.

Salsalate ameliorates metabolic disturbances by reducing inflammation in spontaneously hypertensive rats expressing human C-reactive protein and by activating brown adipose tissue in nontransgenic controls.

Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.

Hyperlipidic diet induced glomerular morphometric alterations and renal damage in hypertensive rats

The aim of this study was to evaluate the renal function in hypertensive hyperlipidic‐fed animals submitted to an acute NaCl overload. Weaned male spontaneously hypertensive rats (SHR) with 21 days old (40–50g) followed by 8 weeks, were divided into 4 groups (n=6/group): SHR Control (SC); SHR Salt (SS, NaCl 1% in drinking water for the 10 last days); SHR Hyperlipidic (SHL, hyperlipidic diet, 30% lipids) and SHR Hyperlipidic Salt (SHLS, hyperlipidic diet and NaCl). All the procedures followed the rules of the Committee of Research and Ethics of the Mackenzie University (CEUA Nº 127/08/2015). Metabolic evaluations consisted of glucose tolerance test, triglycerides, and total cholesterol measurements. Urine samples were collected during 24h using metabolic cages. At the end of the protocol, the animals were euthanized by anesthesia overload, serum was collected and the left kidney and the visceral fat pad were removed and weighted. Kidney slices were stained with picrosirius red to evaluate the area of the Bowman's capsule (AB) and space (BS), and glomerular tuft diameter (TD). Creatinine concentration (serum and urine) was determined by colorimetric methods and sodium concentration of the urine was measured using electrolyte analyzer. Hyperlipidic diet promoted glucose intolerance, increased triglycerides and visceral fat pad in SHL and SHLS groups. NaCl consumption determined an increase in urinary volume and sodium concentration in SS and SHLS groups. Hyperlipidic diet induced a reduction in TD (SHL: 82±0,6; SHLS: 83±0,5 vs. SC: 88±1,5 μm) and an increase of BS in SHL group (29,5%) and in SHLS group (43,4%), with no changes in AB, compared with SC. These results are associated with a reduction in glomerular filtration rate (creatinine clearance) (SHL: 0,7±0,1; SHLS: 0,8±0,2 vs. SC: 1,4±0,1 mL/min). In conclusion, our data suggests that hyperlipidic diet in hypertensive animals changed the renal morphometry with damage in renal function. However, when stimulated by NaCl consumption, there was no further impairment in renal function in hyperlipidic‐fed animals.Support or Funding InformationCAPES/Mackpesquisa

IL‐10 Supplementation Decreases BP in Male, But Not Female, Spontaneously Hypertensive Rats

Interleukin 10 (IL‐10) is an anti‐inflammatory cytokine that induces nitric oxide (NO) production. IL‐10 supplementation has previously been shown to lower blood pressure (BP) in male hypertensive mice, but the effect of exogenous IL‐10 in hypertensive females has not yet been studied. For the current study, we hypothesized that chronic infusion of IL‐10 in hypertensive rats would lower BP concomitant with an increase in NO synthase (NOS) activity. First, endogenous basal levels of renal IL‐10+ cells and the IL‐10 receptor were measured in a subset of male and female spontaneously hypertensive rats (SHR). In a second set of rats, baseline BP was recorded by tail cuff plethsmography, and rats were placed in metabolic cages for 24‐hr urine collection prior to initiating infusion of IL‐10. IL‐10 was infused by subcutaneous minipump (3.5 ug/kg/d) in half of the male and female SHR, with the remaining rats serving as sham controls (n=4–6 per treatment group per sex). After 2 weeks of treatment, final BP and metabolic cage timepoints were collected, and tissues were harvested. Female SHR had greater IL‐10+ renal cells than males (flow cytometry, 4.6±0.4 vs 1.9±0.4%, p=0.003, n=8) and greater expression of the IL‐10 receptor (Western blot, 0.4±0.1 vs 0.13±0.1 densitometric units, p=0.03, n=4). BP did not change in female SHR treated with IL‐10 (2‐way ANOVA, p=0.3), but BP significantly decreased following IL‐10 infusion in male rats (p=0.04, Table); BP was higher in males than females in both groups (p&lt;0.001). Urinary protein excretion (Bradford assay) did not differ between treatment and control groups in either sex (Table); but excretion was higher in males than in females (p=&lt;0.001). Contrary to our hypothesis, NOS enzymatic activity (measured by the conversion of radio‐labeled arginine to radio‐labeled citrulline) significantly decreased with IL‐10 treatment in both the inner medulla (p=0.004) and the renal cortex (p=0.003) of both sexes (Table). In conclusion, despite the finding that male SHR have less IL‐10 and IL‐10 receptor expression in the kidney compared to females, BP was selectively decreased in males. We hypothesize that the higher endogenous levels of IL‐10 in the female SHR contribute to the observed sex difference in BP and prevent further decreases in BP with exogenous IL‐10 infusion. Furthermore, our data suggests that decreases in BP in male SHR with IL‐10 is not dependent on upregulating NOS activity in the kidney, although the effect of IL‐10 on NO bioavailability was not assessed. Future studies will further explore the role of endogenous IL‐10 on BP control in female SHR. Baseline BP (mmHg) Final BP (mmHg) Baseline Proteinuria (mg/d) Final Proteinuria (mg/d) Inner Medulla NOS activity (pmol/mg) Cortex NOS activity (pmol/mg) Male CON 211±1 221±5 10±1 15±2 780±123 17287±42772 Male IL‐10 213±5 200±4* 12±1 16±2 284±29* 7316±1917* Female CON 160±8# 169±7# 2±0.4# 3±1# 1296±213# 20260±2207 Female IL‐10 163±2# 169±9# 1±0.3# 2±0# 650±65*# 8279±1215* p&lt;0.05 vs CON same sex, p&lt;0.05 vs male same treatment

EFFECT OF ADDITION OF CALCIUM AND MAGNESIUM IN DRINKING WATER ON STATE OF CARDIOVASCULAR SYSTEM IN SPONTANEOUSHYPERTENSIVE RATS

The aim. To assess the effect of enrichment of calcium and magnesium in drinking water on the level of arterial pressure (BP), myocardial remodeling processes, and autorhythmic contractile activity of the portal vein (PV) of spontaneously hypertensive SHR rats and control WKY rats. Material and methods . One group of SHR rats received drinking water enriched with calcium (120 mg/L) and magnesium (45 mg/L) from a 6-week-old age within 2 months. Two other groups of SHR and WKY rats received St. Petersburg tap water with a low content of Са 2+ (8 mg/L) and Mg 2+ (3 mg/L). All groups received a standard diet. At the end of the observation period, rats were assessed with blood pressure, myocardial mass index, urea level (UR), total cholesterol (Chol), total calcium (totalCa) and albumin (Alb) in blood. A contractile activity of PV was investigated by the method of myography (in vitro). The total and maximal amplitude and frequency of contractions of PV, as well as the work done by PV was determined. Results. In SHR rats, the enrichment of drinking water of Са 2+ and Mg 2+ , prevented the progressive rise BP to the level characteristic of the SHR, resulting in its stabilization at 18% lower than in the SHR of the mineral deficient group. Theincreaseinthecontent of Са 2+ and Mg 2+ in drinking water did not affect the degree of myocardial hypertrophy, as well as on the level of UR, totalCa and Alb of blood, but led to a decrease in the level of total cholesterol compared to animals that received low-mineralized water. The options of the autorhythmic contractile activity depended on the mineralization of drinking water. The addition of Са 2+ and Mg 2+ to the drinking water of SHR rats resulted in a decrease in both the amplitude of contractions of PV and the work performed by PV as compared with rats of mineral deficient groups. Conclusion. The researches have shown the important role of mineral composition of drinking water in processes of regulation of a level of arterial pressure. In spontaneously hypertensive SHR rats, the antihypertensive effect of drinking water enrichment with Са 2+ and Mg 2+ has been revealed. The increase in the intake of exogenous calcium and magnesium with water modifies the autorhythmic contractile activity of the portal vein of spontaneously hypertensive SHR rats, normalizing it to a level characteristic of normotensive WKY rats.

Modes of Hypotensive Action of Dihydroquercetin in Arterial Hypertension.

We studied the effect of dihydroquercetin (20 mg/kg/day intragastrically for 6 weeks) on mean BP and macro- and microrheological blood parameters in hypertensive SHR rats; in vitro effect of dihydroquercetin on the tone in thoracic aorta rings isolated from hypertensive SHR rats were also examined. At the end of the treatment course, the mean BP in the experimental rats decreased by 11%; the left ventricular mass index by 2%, and whole blood viscosity by 7-10% in comparison with control SHR rats; erythrocyte aggregation half-time increased by 15%; plasma viscosity, hematocrit, and erythrocyte deformability did not change. In in vitro experiments, dihydroquercetin (10-8-10-6M) induced relaxation of the isolated thoracic aorta rings in a dose-dependent manner. Hence, the antihypertensive effect of dihydroquercetin results from the decrease in blood viscosity and vasodilation.

Antioxidant and Antihypertensive Effect of Azadirachta Excelsa Leaf Extract in Spontaneously Hypertensive Rat (SHR) Model

A research was carried out to evaluate the antioxidant activities of Azadirachta excelsa and its antihypertensive effect in Spontaneously Hypertensive Rat (SHR). The Total Phenolic Content (TPC) and Total Flavonoid Content (TFC) was quantified and IC50 level of A. excelsa was determined. For the antihypertensive effect, the rats were randomly assigned into four treatment groups as followed: Group I (normotensive control from Wistar-Kyoto rats),Group II (hypertensive control from SHR), Group III (SHR receiving 250 mg/kg of A. excelsa extract), and Group IV (SHR receiving 40 mg/kg of captopril). The Systolic Blood Pressure (SBP) of these animals was performed by tail-cuff method. The average of TPC and TFC was 202 ± 0.42 mg Gallic Acid Equivalent (GAE)/g extract and 198 ± 0.67 mg rutin equivalent/g extract, respectively. Meanwhile, the IC50 value of free radical scavenging activity was about 308μg/ml. The systolic blood pressure level of the SHR treated with A.excelsa significantly reduced (153 mmHg; P <0.05) compared to the untreated SHR control (187 mm Hg; Group II). In conclusion, we found that A. excelsa extract at a dose of 250 mg/kg possesses phenolic properties that can be used as a potential treatment for hypertension due to its high antioxidant activities.

Effects of Antihypertensive Agents on Intestinal Contractility in the Spontaneously Hypertensive Rat: Angiotensin Receptor System Downregulation by Losartan.

Hypertension is an inflammatory condition controlled by the renin angiotensin system and is linked to kidney disease, diabetes mellitus, and recently to dysfunction of the gut. The aim of this study was to determine what effect antihypertensive drug treatments may have on intestinal function of the spontaneously hypertensive rat (SHR). In the first experiment, SHRs were treated with enalapril, hydralazine, or with no treatment as a control. In the second experiment, SHRs were treated with losartan or with no treatment as a control. All drug treatments led to significant lowering of blood pressure after 16 weeks. At termination, intact tissue sections of the ileum and colon were induced to contract ex vivo by KCl; electrical stimulation; and agonists carbachol, angiotensin II, and prostaglandin E2 (PGE2). There were no differences in ileal or colonic contractility due to hydralazine or enalapril compared with no-treatment SHR control. However, for the ileum, the losartan group responded significantly more to KCl and carbachol while responding less to angiotensin II, with no difference for PGE2 compared with the no-treatment SHR control. In contrast, the colon responded similarly to KCl, electrical stimulation, and PGE2 but responded significantly less to angiotensin II. These results demonstrate that the ileum responds differently (with KCl and carbachol as agonists) to the colon after losartan treatment, whereas there is a reduced contractile response in both the ileum and colon following losartan treatment. Although there are few well documented major contraindications for angiotensin receptor blockers, the modulation of gut contractility by losartan may have wider implications for bowel health.

Adverse remodeling of the obtuse marginal artery in compensatory hypertrophied myocardium from spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) serve as a model of genetic hypertension. Adverse remodeling of a coronary artery has been reported in SHR. This model is used to study new therapies in regression vascular remodeling. However, no data are available that show remodeling of the intramyocardial branch of the obtuse marginal artery in 10-month-old SHR. This study was designed to assess remodeling (changes in vascular structure and fibrosis) of this coronary artery. The study was performed on 10-month-old male SHR (n=7) and normotensive control Wistar Kyoto rats (WKY) (n=7). Using histology, we show that the external diameter, lumen diameter, wall width, and cross-sectional area of the intramyocardial artery were significantly greater in SHR than in WKY. The wall-to-lumen ratio was similar in SHR and WKY. The collagen volume density of the intramyocardial artery in SHR was significantly greater than in WKY. Our results show hypertrophic outward remodeling in the intramyocardial branch of the obtuse marginal artery of the left ventricle in SHR. This artery can serve as a new vascular bed from adult SHR to study novel therapies in regression coronary artery remodeling.

TRPV1 attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation in hypertension.

The phenotypic modulation of contractile vascular smooth muscle cell (VSMC) is widely accepted as the pivotal process in the arterial remodeling induced by hypertension. This study aimed to investigate the potential role of transient receptor potential vanilloid type 1 (TRPV1) on regulating VSMC plasticity and intracranial arteriole remodeling in hypertension. Spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats and TRPV1-/- mice on a C57BL/6J background were used. By microscopic observation of the histopathological sections of vessels from hypertensive SHR and age-matched normotensive WKY control rats, we found that hypertension induced arterial remodeling. Decreased α-smooth muscle actin (α-SMA) and SM22α while increased osteopontin (OPN) were observed in aorta and VSMCs derived from SHR compared with those in WKY, and VSMCs derived from SHR upregulated inflammatory factors. TRPV1 activation by capsaicin significantly increased expression of α-SMA and SM22α, reduced expression of OPN, retarded proliferative and migratory capacities and inhibited inflammatory status in VSMCs from SHR, which was counteracted by TRPV1 antagonist 5'-iodoresiniferatoxin (iRTX) combined with capsaicin. TRPV1 activation by capsaicin ameliorated intracranial arteriole remodeling in SHR and deoxycorticosterone acetate (DOCA)-salt hypertensive mice. However, the attenuation of arteriole remodeling by capsaicin was not observed in TRPV1-/- mice. Furthermore, TRPV1 activation significantly decreased the activity of PI3K and phosphorylation level of Akt in SHR-derived VSMCs. Taken together, we provide evidence that TRPV1 activation by capsaicin attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation during hypertension, which may be at least partly attributed to the suppression PI3K/Akt signaling pathway. These findings highlight the prospect of TRPV1 in prevention and treatment of hypertension.