Decreased levels of insulin-like growth factor-1 and vascular endothelial growth factor relevant to the ossification disturbance in femoral heads spontaneous hypertensive rats.

Ossification disturbance in femoral head reportedly is seen in the Spontaneously Hypertensive rats (SHR) between ages of 10 and 20 weeks. We investigated serum and tissue levels of insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) in SHR relevant to the ossification disturbance and osteonecrosis of the femoral head. Serum levels of IGF-1 and VEGF were significantly lower in SHR than in Wistar Kyoto rats (WKY) at weeks 5, 10, 15 and 20 (p<0.005). The incidence of histological ossification disturbance of the femoral head was higher in SHR (59%) than in WKY (40%) at week 20. Lower serum and local levels of VEGF in SHR appeared to be related to the incomplete ossification of the femoral heads. Immunohistochemical study showed significantly lower numbers of IGF-1 and VEGF positive chondrocytes in the femoral epiphyseal cartilage of SHR than in those of WKY at weeks 10, 15 and 20. Our results suggest that local and/or systemic levels of IGF-1 and VEGF between ages of 5 and 20 weeks might play roles in the pathogenesis of ossifi cation disturbance of the femoral head in SHR

Adolescent D-amphetamine treatment in a rodent model of ADHD: pro-cognitive effects during adolescence and cocaine abuse risk during adulthood

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar- Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d- Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model

Exercise training and detraining process affects plasma adiponectin level in healthy and spontaneously hypertensive rats

BACKGROUND: Adiponectin levels with long-term swimming exercise have been never investigated in spontaneously hypertensive rats (SHR). OBJECTIVE: This study was aimed to investigate the effects of exercise and detraining process on the adiponectin plasma levels of spontaneously hypertensive rats (SHR) and healthy Wistar-Kyoto rats (WKY). MATERIAL AND METHODS: The rats in the exercise groups were swimming for 10 weeks, 5 days/week, one hour in a day. The detraining rats were left to be sedentary in their cages for 5 weeks after 10 weeks of exercise period. RESULTS: The plasma adiponectin levels decreased in E and SHRE groups compared to the SC and the SHR groups, respectively. In addition, blood pressure was decreased in the exercise groups vs their controls. The adiponectin level was not found to be significantly different in ED and SHRED groups compared to their controls. The blood pressure did not differ between SDC and ED groups, although in the SHRED group it was found to be lower than in SHRSD group rats. CONCLUSION: The results of this study showed that exercise reduced plasma levels of adiponectin in healthy and spontaneously hypertensive rats. However, this difference disappeared at the end of the training processes. Our results suggest, that changes in plasma adiponectin levels are not responsible for changes in blood pressure

Effects of candesartan, an angiotensin II receptor type I blocker, on atrial remodeling in spontaneously hypertensive rats

Hypertension-induced structural remodeling of the left atrium (LA) has been suggested to involve the renin–angiotensin system. This study investigated whether treatment with an angiotensin receptor blocker, candesartan, regresses atrial remodeling in spontaneously hypertensive rats (SHR). Effects of treatment with candesartan were compared to treatment with a nonspecific vasodilatator, hydralazine. Thirty to 32-week-old adult male SHR were either untreated (n = 15) or received one of either candesartan cilexetil (n = 9; 3 mg/kg/day) or hydralazine (n = 10; 14 mg/kg/day) via their drinking water for 14 weeks prior to experiments. Untreated age- and sex-matched Wistar- Kyoto rats (WKY; n = 13) represented a normotensive control group. Untreated SHR were hypertensive, with left ventricular hypertrophy (LVH) compared to WKY, but there were no differences in systolic pressures in excised, perfused hearts. LA from SHR were hypertrophied and showed increased fibrosis compared to those from WKY, but there was no change in connexin-43 expression or phosphorylation. Treatment with candesartan reduced systolic tail artery pressures of conscious SHR below those of normotensive WKY and caused regression of both LVH and LA hypertrophy. Although hydralazine reduced SHR arterial pressures to those of WKY and led to regression of LA hypertrophy, it had no significant effect on LVH. Notably, LA fibrosis was unaffected by treatment with either agent. These data show that candesartan, at a dose sufficient to reduce blood pressure and LVH, did not cause regression of LA fibrosis in hypertensive rats. On the other hand, the data also suggest that normalization of arterial pressure can lead to the regression of LA hypertrophy

Adolescent D-amphetamine treatment in a rodent model of ADHD: pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood

Attention-deficit/hyperactivity disorder (ADHD) is comorbid with cocaine abuse. Whereas initiating ADHD medication in childhood does not alter later cocaine abuse risk, initiating medication during adolescence may increase risk. Preclinical work in the Spontaneously Hypertensive Rat (SHR) model of ADHD found that adolescent methylphenidate increased cocaine self-administration in adulthood, suggesting a need to identify alternatively efficacious medications for teens with ADHD. We examined effects of adolescent d-amphetamine treatment on strategy set shifting performance during adolescence and on cocaine self-administration and reinstatement of cocaine-seeking behavior (cue reactivity) during adulthood in male SHR, Wistar-Kyoto (inbred control), and Wistar (outbred control) rats. During the set shift phase, adolescent SHR needed more trials and had a longer latency to reach criterion, made more regressive errors and trial omissions, and exhibited slower and more variable lever press reaction times. d-Amphetamine improved performance only in SHR by increasing choice accuracy and decreasing errors and latency to criterion. In adulthood, SHR self-administered more cocaine, made more cocaine-seeking responses, and took longer to extinguish lever responding than control strains. Adolescent d-amphetamine did not alter cocaine self-administration in adult rats of any strain, but reduced cocaine seeking during the first of seven reinstatement test sessions in adult SHR. These findings highlight utility of SHR in modeling cognitive dysfunction and comorbid cocaine abuse in ADHD. Unlike methylphenidate, d-amphetamine improved several aspects of flexible learning in adolescent SHR and did not increase cocaine intake or cue reactivity in adult SHR. Thus, adolescent d-amphetamine was superior to methylphenidate in this ADHD model.R01 DA011716 - NIDA NIH HHS; DA011716 - NIDA NIH HH

729-2 Macrophage-Monocyte Invasion is Associated with Greater Cardiac Hypertrophy in Hypertensive Rats

Cardiac hypertrophy is an adaptive response to increased wall stress in hypertension. Although the mechanisms underlying this adaptive response are not clearly understood, a genetic predisposition appears to playa role. We sought to examine the hypothesis that an inflammatory response occurs in the heart early in the course of development of hypertension. We measured blood pressure, heart weight and cardiac macrophage-monocyte invasion in 6 week old SHR and WKY rats with renal hypertension (1 Kidney-1 Clip, 1K1C) or sham-operated controls (SHAM). Macrocyte-monophage invasion was measured as the extent of immunohistochemical staining with ED1, a cytoplasmic antigen in this cell type. Measurements were made at 7 and 21 days post procedure. Renal hypertensive rats, both SHR and WKY, had higher blood pressures at both time points than SHR sham, which in turn had higher blood pressures that WKY sham rats. Heart weight/body weight ratios were highest in SHR-1 K1 C rats, followed by SHR SHAM and WKY 1K1C, and least in WKY sham rats. ED1 staining was also highest in SHR 1K-lC rats, followed by SHR sham rats, and was considerably lower in WKY rats, 1K-1C or sham. Data atthe 21 day time point are shown below:BP (mmHg)Heart wt/body wt (mg/g)ED1 (counts/HPF)SHR 1K1C2054.320.0SHR SHAM1703.415.0WKY 1K1C2033.712.5WKY SHAM1432.812.5Thus, significant monocyte-macrophage invasion is a hitherto unrecognized feature of cardiac hypertrophy in SHR rats. We speculate that growth factors released by such cells may contribute to hypertensive cardiac hypertrophy

Vitamins Reverse Endothelial Dysfunction Through Regulation of eNOS and NAD(P)H Oxidase Activities

Antioxidant vitamins C and E have protective properties in genetic hypertension associated with enhanced oxidative stress. This study investigated whether vitamins C and/or E modulate vascular function by regulating enzymatic activities of endothelial nitric oxide synthase (eNOS) and NAD(P)H oxidase using thoracic aortas of 20- to 22-week-old male spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar-Kyoto rats (WKY). SHR aortas had impaired relaxant responses to acetylcholine but not to sodium nitroprusside, despite an 2-fold increase in eNOS activity and NO release. The levels of superoxide anion (O2 ), a potent NO scavenger, and NAD(P)H oxidase activity were also 2-fold higher in SHR aortas. Mechanical but not pharmacological inactivation of endothelium (by rubbing and 100 mol/L L-NAME, respectively) significantly abrogated O2 in both strains. Treatments of SHR aortas with NAD(P)H oxidase inhibitors, namely diphenyleneiodinium and apocynin, significantly diminished O2 production. The incubation of SHR aortas with different concentrations of vitamin C (10 to 100 mol/L) and specifically with high concentrations of vitamin E (100 mol/L) improved endothelial function, reduced superoxide production as well as NAD(P)H oxidase activity, and increased eNOS activity and NO generation in SHR aortas to the levels observed in vitamin C- and E-treated WKY aortas. Our results reveal endothelial NAD(P)H oxidase as the major source of vascular O2 in SHR and also show that vitamins C and E are critical in normalizing genetic endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities

PGC-1α mRNA Level and Oxidative Capacity of the Plantaris Muscle in Rats with Metabolic Syndrome, Hypertension, and Type 2 Diabetes

We examined the fiber profiles and the mRNA levels of peroxisome proliferator-activated receptors (PPARα and PPARδ/β) and of the PPARγ coactivator-1α (PGC-1α) in the plantaris muscles of 15-week-old control (WR), metabolic syndrome (CP), hypertensive (SHR), and type 2 diabetic (GK) rats. The deep regions in the muscles of SHR and GK rats exhibited lower percentages of high-oxidative type I and IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR and CP rats. The surface regions in the muscles of CP, SHR, and GK rats exhibited lower percentages of high-oxidative type IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR rats. The muscles of SHR and GK rats had lower oxidative enzyme activity compared with WR rats. The muscles of SHR rats had the lowest PPARδ/β mRNA level. In addition, the muscles of SHR and GK rats had lower PGC-1α mRNA level compared with WR and CP rats. We concluded that the plantaris muscles of rats with hypertension and type 2 diabetes have lower oxidative capacity, which is associated with the decreased level of PGC-1α mRNA

Diuretic action of exogenous hydrogen sulfide in spontaneously hypertensive diabetic rats

Purpose: To examine the hypothesis that in hypertensive diabetic rats hydrogen sulphide (H2S) reduces blood pressure through diuretic action in addition to its vasodilating effect.Methods: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were used. SHR were divided into three groups: SHR (II), SHR diabetic (III), and SHR diabetic NaHS-Treated (IV) with a group of WKY (I) rats serving as normotensive nondiabetic control. Diabetes was produced in two SHR groups using intraperitoneal streptozotocin (STZ). One diabetic group received NaHS, a donor of H2S (56 μM/kg i.p.) daily for five weeks. Blood pressure was measured in conscious and anesthetized states in surgically prepared animals. Plasma and urinary H2S levels and electrolytes were measured weekly throughout the 35-day period.Results: SHR and diabetic SHR had higher blood pressure and lower plasma and urinary H2S levels compared to WKY controls (p < 0.05). Moreover, the SHR diabetic group had higher plasma sodium, higher absolute and fractional sodium excretions (p < 0.05) but with similar blood pressure compared to SHR controls. NaHS treatment reduced blood pressure and restored H2S and plasma sodium (p < 0.05) levels. Moreover, SHR diabetic-NaHS treated group had higher urine output and absolute urinary sodium excretion compared to the untreated SHR diabetic group (p < 0.05).Conclusion: These results suggest a possible diuretic effect of exogenous H2S in spontaneously hypertensive diabetic rats.Keywords: Spontaneously hypertensive rats, Diabetes, Hydrogen sulphide, Diuretic, Sodium excretion, Urine outpu