Development Of Hypertension In Spontaneously Hypertensive Rats Research Articles

Hypertensive nephropathy treatment by heart-protecting musk pill: a study of anti-inflammatory therapy for target organ damage of hypertension

This study was designed to investigate the protective effect of the heart-protecting musk pill (HMP) on inflammatory injury of kidney from spontaneously hypertensive rat (SHR). Male SHRs aged 4 weeks were divided into SHR model group, HMP low-dosage group (13.5 mg/kg), and HMP high-dosage group (40 mg/kg). Age-matched Wistar–Kyoto rats were used as normal control. All rats were killed at 12 weeks of age. Tail-cuff method and enzyme-linked immunosorbent assay were used to determine rat systolic blood pressure and angiotensin II (Ang II) contents, respectively. Renal inflammatory damage was evaluated by the following parameters: protein expressions of inflammatory cytokines, carbonyl protein contents, nitrite concentration, infiltration of monocytes/macrophages in interstitium and glomeruli, kidney pathological changes, and excretion rate of urinary protein. HMP did not prevent the development of hypertension in SHR. However, this Chinese medicinal compound decreased renal Ang II content. Consistent with the change of renal Ang II, all the parameters of renal inflammatory injury were significantly decreased by HMP. This study indicates that HMP is a potent suppressor of renal inflammatory damage in SHR, which may serve as a basis for the advanced preventive and therapeutic investigation of HMP in hypertensive nephropathy.

Perinatal l-arginine and antioxidant supplements reduce adult blood pressure but not ameliorate the altered vascular function in spontaneously hypertensive rats

Spontaneously hypertensive rat (SHR) offspring from L-arginine- and antioxidant-supplemented SHR dams had persistent lower blood pressure in adulthood. We investigated the influence of vascular mechanism in this effect. We analyzed response to acetylcholine and phenylephrine in aorta and superior mesenteric arteries from Wistar-Kyoto (WKY), SHR, and SHR perinatally supplemented with L-arginine and 4-hydroxy-2,2,6,6-tetramethylpiperidinoxyl (TEMPOL; SHR-suppl). Supplements reduced blood pressure persistently in SHR. Relaxation to acetylcholine was greater in WKY than SHR and remained unmodified in SHR-suppl compared with SHR. Acute TEMPOL did not alter relaxation to acetylcholine in WKY but increased it similarly in SHR and SHR-suppl. Phenylephrine contraction was increased in SHR compared to WKY. In SHR-suppl, this response was similar to SHR. Endothelium removal or N-nitro-L-arginine methyl ester (L-NAME) increased contraction to phenylephrine more in WKY than SHR. In SHR-suppl, this was similar to SHR. In both SHR and SHR-suppl, TEMPOL similarly reduced phenylephrine response. This effect was prevented by L-NAME. Results exposed reinforce the concept that oxidative stress during perinatal period is a contributing factor to the development of hypertension in SHR. Results also reveal that the beneficial effect of this supplementation does not appear to be related to improved endothelial function, suggesting that other regulatory mechanisms of blood pressure may be involved.

Glutathione system in young spontaneously hypertensive rats

Glutathione (GSH) forms a part of the antioxidant system that plays a vital role in preventing oxidative stress, and an imbalance in the oxidant/antioxidant system has been linked to the pathogenesis of hypertension. The aim of this study was to investigate the status of the GSH system in the kidney of spontaneously hypertensive rats (SHR). Components of the GSH system, including glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), and total GSH content, were measured in the kidneys of 4, 6, 8, 12, and 16weeks old SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure of SHR was significantly higher from the age of 6weeks onwards compared with age-matched WKY rats. GPx activity in the SHR was significantly lower from the age of 8weeks onwards when compared to that in age-matched WKY rats. No significant differences were evident in the GPx-1 protein abundance, and its relative mRNA levels, GR, GST activity, and total GSH content between SHR and age-matched WKY rats. The lower GPx activity suggests of an impairment of the GSH system in the SHR, which might be due to an abnormality in its protein rather than non-availability of a cofactor. Its role in the development of hypertension in SHR however remains unclear.

Effect of uric acid on hypertension progression in spontaneously hypertensive rats

Aims We investigated the effects of soluble uric acid (UA) on the development of hypertension in spontaneously hypertensive rats (SHRs), using Wistar–Kyoto rats (WKY) as normotensive controls. Main methods UA was prepared freshly as a suspension in saline solution and administered twice daily, intraperitoneally, at a dose of 250 mg/kg body weight for five weeks to SHR-UA ( n = 7) and WKY-UA rats ( n = 5). Controls for both strains were injected with saline solution (WKY-C and SHR-C, n = 5 each). Blood pressure, determined by tail-cuff plethysmography, levels of urine and blood biochemical parameters were monitored weekly. Oxidative stress, renal cytokines mRNA levels and immune cells infiltration were determined at the end of the study. Key findings UA did not alter blood pressure in the WKY rats, but markedly prevented the development of hypertension in SHRs. Urine volume was significantly increased in the SHR-UA group. UA protected against renal oxidative stress as indicated by a decrease in MDA content in the SHR-UA group when compared to the SHR-C group; MDA content was unchanged in the WKY animals. Plasma antioxidant capacity decreased significantly in the SHR-UA animals when compared to the other three groups. There was a significant decrease in renal infiltrating lymphocytes in the SHR-UA treated animals. Changes in the expression of TNF-α, IL-2 and IL-6 were detected in the SHR-UA group. Significance We conclude that UA protects against progression of hypertension in SHR rats.

Na+/H+ Exchanger NHE3 is differentially regulated in renal proximal tubules of pre‐hypertensive and hypertensive spontaneously hypertensive rats

The present work aimed to measure NHE3 in vivo transport activity and to define the mechanisms underlying NHE3 regulation in young pre‐hypertensive (5‐week‐old, systolic blood pressure (SBP) = 92 ± 2 mmHg) and adult hypertensive spontaneously hypertensive rats (SHR) (14‐week‐old, SBP = 187 ± 4 mmHg). NHE3 function was measured as the rate of bicarbonate reabsorption by means of in vivo microperfusion. NHE3‐mediated bicarbonate reabsorption was stimulated in 5‐week‐old SHR (44 ± 5%, P<0.01) and reduced in 14‐week‐old SHR (57 ± 4%, P<0.001) compared to Wistar Kyoto (WKY) rats at corresponding age. Stimulated NHE3 transport activity in young pre‐hypertensive SHR was associated with enhanced NHE3 microvillus expression, lower levels of phosphorylation at Ser552 and increased association with the enzyme dipeptidyl peptidase IV (DPPIV). Conversely, adult hypertensive SHR showed decreased NHE3 microvillus membrane content, higher relative ratio of phosphorylated Ser552, and lower amount of the NHE3‐DPPIV complex. No differences on renal cortical NHE3 protein content and mRNA levels were found between SHR and its WKY counterpart. We conclude that NHE3 is differentially regulated before and after development of hypertension in SHR by mechanisms that involve post‐translational modifications, subcellular redistribution and assembly with interacting proteins. Supported by FAPESP and CNPq

Kinetics of cardiac and vascular remodeling by spontaneously hypertensive rats after discontinuation of long-term captopril treatment

Angiotensin-converting enzyme inhibitors reduce blood pressure and attenuate cardiac and vascular remodeling in hypertension. However, the kinetics of remodeling after discontinuation of the long-term use of these drugs are unknown. Our objective was to investigate the temporal changes occurring in blood pressure and vascular structure of spontaneously hypertensive rats (SHR). Captopril treatment was started in the pre-hypertensive state. Rats (4 weeks) were assigned to three groups: SHR-Cap (N = 51) treated with captopril (1 g/L) in drinking water from the 4th to the 14th week; SHR-C (N = 48) untreated SHR; Wistar (N = 47) control rats. Subgroups of animals were studied at 2, 4, and 8 weeks after discontinuation of captopril. Direct blood pressure was recorded in freely moving animals after femoral artery catheterism. The animals were then killed to determine left ventricular hypertrophy (LVH) and the aorta fixed at the same pressure measured in vivo. Captopril prevented hypertension (105 + or - 3 vs 136 + or - 5 mmHg), LVH (2.17 + or - 0.05 vs 2.97 + or - 0.14 mg/g body weight) and the increase in cross-sectional area to luminal area ratio of the aorta (0.21 + or - 0.01 vs 0.26 + or - 0.02 microm(2)) (SHR-Cap vs SHR-C). However, these parameters increased progressively after discontinuation of captopril (22nd week: 141 + or - 2 mmHg, 2.50 + or - 0.06 mg/g, 0.27 + or - 0.02 microm(2)). Prevention of the development of hypertension in SHR by using captopril during the prehypertensive period prevents the development of cardiac and vascular remodeling. Recovery of these processes follows the kinetic of hypertension development after discontinuation of captopril.

Changes in Arterial Blood Pressure of a Soluble Cocoa Fiber Product in Spontaneously Hypertensive Rats

The effect produced by long-term intake of a soluble cocoa fiber product (SCFP) on the development of hypertension of spontaneously hypertensive rats (SHR) was evaluated. Twenty male 3-week-old SHR were divided into two groups of 10 animals that drank either tap water (control) or a solution of SCFP (0.75 g/day SCFP) until the 20th week of life. Five 20-week-old rats of each group were sacrificed. Tap water as drinking fluid was given to all the animals from the 20th to 24th week of life. The 24-week-old rats were also sacrificed. Body weight, liquid and dry food intake, and arterial blood pressure (tail cuff) were recorded weekly. Malondialdehyde (MDA), glucose and angiotensin converting enzyme (ACE) activity in the plasma from the sacrificed rats were also obtained, and we evaluated the relaxation caused by acetylcholine in the aorta from these animals. SCFP attenuated the development of hypertension in SHR; however, the withdrawal of SCFP caused an increase in blood pressure in the rats. Body weight gain was slower in the group treated with SCFP. SCFP increased liquid intake but decreased dry food intake in the rats. SCFP decreased plasma MDA concentrations and slightly decreased plasma ACE activity, but no differences were observed in plasma glucose and in the aorta responses to acetylcholine in both groups of 20-week-old SHR. We have demonstrated the antihypertensive and antioxidant properties of SCFP. The control of body weight and the control of increased angiotensin II may be involved in the antihypertensive effect of this product.

Vascular oxidative stress, NF¿B activation and AT1 Receptor upregulation precede the development of hypertension in Spontaneously Hypertensive Rats (SHR)

Oxidative stress is strongly associated to hypertension. However, it is unclear whether oxidative stress is a cause or a consequence of hypertension and what role it plays in this disease. A hallmark of hypertension is abnormal vascular tone which is, in part, due to Angiotensin II type I receptor (AT1R) upregulation, the cause of which is unknown. We have previously shown that oxidative stress activates NF¿B, a redox sensitive transcription factor, via nuclear translocation which contributes to AT1R upregulation and subsequent hypertension. Here we report that vascular oxidative stress, NF¿B activation and AT1R upregulation precede the development of hypertension in SHR. The blood pressure in young SHR (3‐4 wk old) was similar to the age‐matched normotensive Wistar Kyoto rats (WKY). These SHR exhibited vascular oxidative stress as evidenced by increased oxidized glutathione levels, protein carbonylation and decreased superoxide dismutase activity as compared to WKY. The SHR vasculature also showed increased nuclear levels of NF¿B p65 subunit and increased AT1R protein levels. In conclusion, vascular oxidative stress via NF¿B activation may induce AT1R upregulation which precedes development of hypertension. This early evidence of oxidative stress suggests that it might be a cause of hypertension and may play a pivotal role in hypertension development by causing AT1R upregulationGrant AHA SDG 0835428N

Intrarenal Angiotensin III Infusion Induces Natriuresis and Angiotensin Type 2 Receptor Translocation in Wistar-Kyoto but not in Spontaneously Hypertensive Rats

In Sprague-Dawley rats, renal angiotensin (Ang) type 2 receptors (AT(2)Rs) mediate natriuresis in response to renal interstitial (RI) D(1)-like receptor stimulation or RI Ang III infusion. After D(1)-like receptor activation, apical membrane (AM) but not total renal proximal tubule cell AT(2)R expression is increased, suggesting that AM AT(2)R translocation may be important for natriuresis. The onset of hypertension in spontaneously hypertensive rats (SHRs) is preceded by defects in renal sodium excretion. The present study examines AT(2)R-mediated natriuresis in response to RI Ang III infusion in Wistar-Kyoto rats (WKYs) and SHRs. WKYs and SHRs received RI Ang III infusion after 24 hours of systemic AT(1)R blockade with candesartan. In WKYs, urine sodium excretion rate increased from 0.043+/-0.01 to 0.191+/-0.06 micromol/min (P<0.05) in response to Ang III infusion, but identical conditions failed to increase the urine sodium excretion rate in SHRs. The increase in the urine sodium excretion rate was blocked by coinfusion of PD-123319, a selective AT(2)R antagonist. On confocal microscopy images, Ang III-infused WKYs demonstrated greater renal proximal tubule cell AM AT(2)R fluorescence intensity compared with SHRs (5385+/-725 versus 919+/-35; P<0.0001), and Western blot analysis demonstrated increased AM (0.050+/-0.003 versus 0.038+/-0.003; P<0.01) but not total cell AT(2)R expression in WKYs. In SHRs, AM AT(2)R expression remained unchanged in response to RI Ang III infusion. Thus, RI Ang III infusion elicits natriuresis and renal proximal tubule cell AT(2)R translocation in WKYs. Identical manipulations fail to induce natriuresis or AT(2)R translocation in SHRs, suggesting that defects in AT(2)R-mediated natriuresis and trafficking may be important to the development of hypertension in SHRs.

High Salt Intake Enhances Blood Pressure Increase during Development of Hypertension via Oxidative Stress in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

High salt intake increases blood pressure (BP) in spontaneously hypertensive rats (SHR), and central neural mechanisms are suggested to be involved. Increased generation of reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM) contributes to the neural mechanism of hypertension in SHR. We sought to examine whether high salt intake increases hypertension in SHR and whether the increased ROS in the RVLM contributes to this mechanism. Male SHR and Wistar-Kyoto rats (WKY) (6 weeks old) were fed a high-salt diet (8%: HS-S; HS-W) or a regular-salt diet (0.5%: RS-S; RS-W) for 6 weeks. Systolic BP was significantly higher in HS-S than in RS-S at 12 weeks of age (244+/-5 vs. 187+/-7 mmHg, n=8; p<0.05). Urinary norepinephrine excretion was significantly higher in HS-S than in RS-S. Thiobarbituric acid-reactive substances levels in the RVLM were significantly higher in HS-S than in RS-S (9.9+/-0.5 vs. 8.1+/-0.6 mumol/g wet wt, n=5; p<0.05). Microinjection of tempol or valsartan into the RVLM induced significantly greater BP reduction in HS-S than in RS-S. The increase in angiotensin II type 1 receptor (AT(1)R) expression and the increase in reduced nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase activity in the RVLM were significantly greater in HS-S than in RS-S. These findings indicate that high salt intake exacerbates BP elevation and sympathetic nervous system activity during the development of hypertension in SHR. These responses are mediated by increased ROS generation that is probably due to upregulation of AT(1)R/NAD(P)H oxidase in the RVLM. (Hypertens Res 2008; 31: 2075-2083).

Gas chromatography/time‐of‐flight mass spectrometry based metabonomic approach to differentiating hypertension‐ and age‐related metabolic variation in spontaneously hypertensive rats

Metabonomics is a systematic approach to the study of in vivo metabolic profiles and therefore allows deep insight into and a better understanding of the pathogenesis of disease. To characterize the development of hypertension, a hypertensive animal model, the spontaneously hypertensive rat (SHR), and its normotensive control, the Wistar Kyoto (WKY) rat, were investigated and their blood plasma analyzed using the high-throughput metabolomic tool, gas chromatography/time-of-flight mass spectrometry (GC/TOFMS). A total of 187 peaks were quantitatively determined after deconvolution, and 78 of them were identified. Principal components analysis (PCA) and projection to latent structure partial least-squares discriminant analysis (PLS-DA) were used to process the GC/TOFMS data. The resulting mathematical models were further validated by cross-validation. Plasma compositional differences of many identified compounds showed hypertension-related variation between SHR and WKY rats, and age-related changes from 10 to 18 weeks for both the SHR and WKY rats. These compositional changes involved compounds such as hexadecanoic acid, linoleic acid, oleic acid, stearic acid, 3-hydroxybutyric acid, citric acid, threonic acid, tyrosine, tryptophan, threonine, phenylalanine, serine, ornithine, methionine, 3-hydroxyproline, creatinine, erythrose, myo-inositol, D-methylglucopyranoside, tocopherol, sitosterol, and nonesterified cholesterol. Significantly elevated free fatty acids (FFA) were observed in SHR relative to those in WKY rats, and their levels increased as the SHR aged from 10 to 18 weeks. The close correlation between FFA and hypertension suggests that FFA are potential biomarker candidates for hypertension and they may play an important role in the development of hypertension in SHR. It is also indicated that GC/TOFMS-based metabonomics is a powerful approach to identifying potential biomarkers and investigating the pathological processes of hypertension and the physiological developments of aging.

Is There a Relationship Between Blood Pressure and Intraocular Pressure? An Experimental Study in Hypertensive Rats

Purpose: Evaluation of relation between blood pressure (BP) and intraocular pressure (IOP) in two hypertensive rat strains: spontaneously hypertensive rats (SHR) and double transgenic (dTGR) (harboring human renin and angiotensinogen genes) rats, and in their normotensive control Wistar Kyoto and Sprague Dawley rats, respectively. Methods: Each rat strain was divided into medicated and non-medicated groups. Medicated rats were treated orally with an angiotensin II receptor type 1 blocker. IOP was measured using a specific rebound tonometer and BP by a tail-cuff method. Both parameters were determined in conscious animals every second week. For comparison, at the end of the study, IOP was measured in conscious and anesthetized rats. Results: The baseline IOP was higher in hypertensive rats vs their normotensive controls. Eight weeks of treatment with an angiotensin type 1 receptor blocker did not prevent a slight increase in IOP, although it abolished the development of hypertension in SHR. The markedly elevated IOP was reduced in medicated and non-medicated dTGR animals during the short follow-up period. General anesthesia reduced IOP significantly. Conclusion: The results suggest a positive relation between BP and IOP in hypertensive rats.

Abstract 181: Overexpression of Arachidonic Acid Cytochrome P450 Expoxygenases Prevents the Development of High Blood Pressure via Enhancing Atrial Natriuretic Peptide in Spontaneously Hypertensive Rats

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have potent vasodilatory and diuretic feature, and therefore potentially hypotensive effect. No in vivo studies, however, were performed to support it. This study investigated the hypothesis via overexpressing CYP epoxygense genes in spontaneously hypertensive rats (SHR). Recombinant adeno-associated virus vector (rAAV) was utilized to mediate long-term transfection of CYP2J2 and CYP2C11 genes, respectively, in adult SHR, and animal systolic blood pressure (SBP) was monitored using arterial caudilis indirect manometric method. Results showed that at 2 months the urinary excretion of stable hydrolysis metabolic product of 14, 15-EE, 14–15-DHET increased by 11 and 8.7 folds in rAAV-2J2 and rAAV-2C11 groups, respectively, compared with AAV-GFP-treated rats. (2) SBP in 2J2- and 2C11-treated rats decreased from 175.0 ± 2.8mHg to 163.5 ± 5.8mmHg and 161.2 ± 6.1 mmHg, respectively, ( p &lt;0.01) at month 2, and it is 165.0 ± 4.7 mmHg and 173.0 ± 12.8 mmHg at month 6 after gene injection (~30mmHg and ~23mmHg lowerer than that in control animals, respectively, p &lt;0.001). (3) Before the rats were sacrificed, cardiac function tests with Pressure-Volume System showed that maximum intracardiac pressure was 202.1 ± 30.0 &amp; 209.1 ± 17.1mmHg in two gene-treated rats, respectively, significantly lower than control (241.2 ± 18.2mmHg, p &lt;0.01) and cardiac output in treatment rats were significantly higher than control (p&lt;0.05). (4) Interestingly, atrial natriuretic peptide (ANP) mRNA were up-regulated 6–14 folds respectively in myocardium of 2J2 and 2C11 groups; furthermore, C-type receptor mRNA of ANP was increased in heart, lung, kidney and aorta. (5) in cultured atrial cells (HLB2G5), exogenous EETs stimulated ANP production. In conclusions, for first time our data indicates overexpression of CYP2J2 or CYP2C11 could prevent development of hypertension in SHR, improve cardiac functions, which may involve up-regulating ANP expression and its receptors in target tissues, which suppresses collagen deposition and cardiovascular remodeling.

Decreased mRNA expression of ASIC2a in nodose sensory ganglia is associated with development of hypertension in SHR

We recently demonstrated Acid-Sensing Ion Channel 2 (ASIC 2), a putative mechanosensitive ion channel subunit, expressed in somata in nodose sensory ganglia (NG) and terminals of the aortic depressor nerve in aortic arch (FASEB J, 20:, 2006). In the present study, we tested the hypothesis that ASIC2a expression in NG is decreased in association with development of hypertension (HT) in spontaneously hypertensive rats (SHR). Total RNA was obtained from both NG of SHR and normotensive WKY rats at 1, 3 and 16 months of age (n = 5–6 male rats at each age). HT develops between 1 and 3 months of age in SHR, ASIC2a mRNA expression measured by qPCR was stable in NG of WKY rats from 1 to 16 months (m) of age (Table). ASIC2a expression was increased in SHR vs. WKY NG at 1 month of age (pre-HT), but was markedly reduced in SHR NG at 3 and 16 months of age when SHR are HT (∗ p < 0.01). We conclude that ASIC2a expression in NG is markedly decreased in SHR in association with development of HT. The decreased expression cannot be attributed to nonspecific genetic differences in SHR vs. WKY since ASIC2a expression was increased in young pre-HT SHR-NG. We speculate that the reduction of ASIC2a expression may contribute to decreased baroreceptor sensitivity and HT in SHR (HL14388).

Effects of electroacupuncture on the expression of iNOS in Nuclei of solitary tract and Rostral ventrolateral medulla in spontaneously hypertensive rats

Acupuncture has been used for the treatment of essential hypertension, but the efficacy and the mechanism of acupuncture in prevention of hypertension are still unclear. We tested the hypothesis that electroacupuncture (EA) applied to Baekhoe (GV20) changes NO/NOS system during development of hypertension in spontaneously hypertensive rats (SHR), and thereby causes the delay of development of hypertension in SHR. EA treatments (10Hz, 0.1mA, 0.1ms) were carried out for 25 min/day for five consecutive days. The systolic blood pressure (SBP) was determined in conscious rats by the tail-cuff method using automatic BP mornitoring system. We investigated the activations of inducible NO synthase (iNOS) in nuclei of solitary tract (NTS) and rostral ventrolateral medulla (RVLM) of SHR by the western blotting method. The SBP after the termination of EA stimulation applied to the GV20 was stabilized at 169.14±3.67 mmHg which is lower value than that of the control group. The SBP of control group was elevated to 178.14±3.49 mmHg. In addition, we evaluated NOS activity as well as iNOS protein expression of NTS and RVLM in both of SHR and WKY. The iNOS activity in NTS was significantly higher in SHR than in WKY. Furthermore, the iNOS activity of NTS showed significant decreases in EA groups compare to that of non treated SHR group. Although iNOS expression of RVLM showed non significant changes in SHR and WKY, EA significantly enhanced the iNOS expression in SHR. Our data support the hypothesis that delayed development of hypertension and altered iNOS expression of NTS and RVLM by EA stimulations in SHR rats. The findings demonstrate that acupuncture can change NO/NOS system in NTS and RVLM, and exert beneficial role on development of hypertension.

Induction of Heme Oxygenase

Carbon monoxide (CO), produced within the body as a product of the catabolism of heme by the enzyme heme oxygenase (HO), has been reported to be a local vasodilator. One of its possible pathways is to stimulate guanylyl cyclase to produce cGMP as a second messenger.1 The parallel to NO, another gaseous signaling molecule that also works through cGMP-mediated pathways (although more potent), is obvious. In fact, the vasodilator actions of these 2 may be integrally linked. Both are endothelium derived.2 NO stimulation of cGMP may facilitate CO-mediated dilation of resistance vessels through calcium-activated potassium channels.3 However, the HO–CO story has not received the same interest and attention as NO, nor is it as generally well understood by those who work outside the field. In the present issue, we are presented with a provocative study by one of the well-established laboratories within the field of HO–CO. Wang et al4 focus on HO in the genetic model of hypertension, the spontaneously hypertensive rat (SHR). They report that 3 weeks of administration of hemin, the oxidation product of heme, which is both a substrate for and an inducer of HO, produced a profound 80-mmHg decrease in blood pressure that was sustained completely for 9 months after ceasing treatment (a duration in a rat’s life, which roughly translates into 17.5 human years). Although this is a remarkable, hopeful, and possibly profound observation, the study probably raises more questions than it answers. First, it is important to point out that this sustained decrease in blood pressure and reversal of hypertension is an unprecedented result. The potential importance of this observation is that a single 3-week treatment regimen induced a protracted reduction in blood pressure, long after treatment had ceased. To put this in perspective, treatment of virtually all forms of …

Increased expression of ENaC subunits and increased apical targeting of AQP2 in the kidneys of spontaneously hypertensive rats

In models of genetic hypertension, renal tubular dysfunction could be involved in the increased sodium and water reabsorption. However, the molecular basis for the increased renal sodium and water retention remains largely undefined in spontaneously hypertensive rats (SHR). We hypothesized that dysregulation of renal epithelial sodium channels (ENaC), sodium (co)transporters, or aquaporin-2 (AQP2) could be involved in the pathogenesis of hypertension in SHR. Six-week-old or twelve-week-old SHR and corresponding age-matched Wistar-Kyoto control rats (WKY) were studied. In both SHR groups, systolic blood pressure was markedly increased, whereas urine output, creatinine clearance, and urinary sodium excretion were decreased compared with corresponding WKY. Moreover, urine osmolality and urine-to-plasma osmolality ratio were increased compared with WKY. Semiquantitative immunoblotting demonstrated that the protein abundance of beta- and gamma-subunits of ENaC was increased in the cortex and outer stripe of the outer medulla and inner stripe of the outer medulla (ISOM) in SHR, whereas alpha-ENaC abundance was increased in ISOM. Immunoperoxidase microscopy confirmed the increased labeling of beta-ENaC and gamma-ENaC subunits in the late distal convoluted tubule, connecting tubule, and cortical and outer medullary collecting duct segments. In contrast, subcellular localization of alpha-ENaC, beta-ENaC, and gamma-ENaC was not changed. Expression of sodium/hydrogen exchanger type 3, bumetanide-sensitive Na-K-2Cl cotransporter, and thiazide-sensitive Na-Cl cotransporter was not altered in SHR. AQP2 levels were increased in the ISOM in SHR, and immunoperoxidase microscopy demonstrated an increased apical labeling of AQP2 in the inner medullary collecting duct in SHR. These results suggest that the increased protein abundance of ENaC subunits as well as the increased apical targeting of AQP2 may contribute to renal sodium and water retention observed during the development of hypertension in SHR.

Enhanced Intrarenal Angiotensinogen Contributes to Early Renal Injury in Spontaneously Hypertensive Rats

This study was performed to determine whether augmented intrarenal angiotensinogen may contribute to the enhanced renal angiotensin II (Ang II) and associated tissue injury in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were maintained on a normal diet and killed at either 7 or 14 wk of age. Two groups of SHR received either an Ang II type 1 receptor blocker (ARB; olmesartan, 5 mg/d) or a triple therapy (hydralazine 7.5 mg/d, reserpine 0.15 mg/d, and hydrochlorothiazide 3 mg/d [HRH]) during weeks 7 through 14. Systolic BP and renal Ang II were significantly increased in SHR-14 (n = 8) compared with WKY-7, WKY-14, and SHR-7 (n = 8 each), and ARB treatment prevented these increases (n = 8). However, whereas HRH treatment prevented the development of hypertension in SHR, this combination therapy failed to decrease renal Ang II (n = 8). With the use of urine samples or fixed renal sections, renal injuries in rats were quantified in a semiautomated manner by the following six parameters: (1) urinary excretion rate of total protein, (2) glomerular sclerosis, (3) interstitial expansion, (4) and (5) numbers of monocytes/macrophages in interstitium or glomeruli, and (6) arterial proliferation. Angiotensinogen mRNA and protein levels in kidney cortex, measured by real-time reverse transcriptase-PCR and Western blot analysis, respectively, and all six parameters of renal damage were changed in parallel, and ARB treatment also prevented these increases. However, HRH treatment failed to prevent these increases. These results indicate that SHR have enhanced intrarenal angiotensinogen production that contributes to increased Ang II levels leading to the development of hypertension and renal injury in this strain.

Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney

To determine the effects of chronic denervation on renal vascular structure and function in young adult spontaneously hypertensive rats (SHRs). Unilateral renal denervation (SHRUDx) or sham-operation (SHRS) was performed in SHRs at 6 weeks of age. At 10 weeks, rats were allocated to one of three procedures designed to examine renal vascular structure and function. A further group underwent bilateral renal denervation. In SHRUDx or SHRS groups, either the kidneys were perfusion-fixed for stereological estimates of artery wall and lumen dimensions or for vascular casting to determine arteriole lumen diameters, or the rats were anaesthetized for estimation of glomerular capillary pressure. Chronic unilateral renal denervation had no significant effect on the development of hypertension between 6 and 10 weeks of age, as previously reported, but resulted in luminal narrowing of the interlobular artery (denervated group 52 +/- 2 mum, sham-operated group 64 +/- 1 mum; P < 0.01 for interaction between strain and treatment), without alterations in interlobular or arcuate artery wall dimensions. There were no significant effects on either afferent or efferent arteriole lumen diameters. Estimated glomerular capillary pressure was significantly lower in the denervated kidneys of SHRUDx (47 +/- 1 mmHg) compared with kidneys of the SHRS (50 +/- 1 mmHg; P < 0.04). Mean arterial pressure was approximately 12 mmHg lower in the bilaterally denervated SHRs than in the sham-operated SHRs. Although bilateral denervation attenuated the development of hypertension in SHRs, unilateral denervation did not, indicating that one neurally intact kidney was sufficient to drive the normal development of SHR hypertension, but only with apparent prohypertensive compensatory changes in the denervated kidney.

Sympatho‐renal interactions in the determination of arterial pressure: role in hypertension

Renal mechanisms and the sympathetic nervous system contribute to the development of arterial hypertension. Renal transplantation experiments in spontaneously hypertensive rats (SHRs) were performed to investigate how the sympathetic nervous system and the kidneys interact during the development and maintenance of hypertension. Our findings indicate that the rise in arterial pressure that occurs after transplantation of a kidney from a SHR into normotensive recipients is not mediated by elevations in sympathetic activity. However, chronic reductions in sympathetic tone reduce the rise in arterial pressure which can be induced by SHR renal grafts in normotensive recipients. Untreated SHRs transplanted with a kidney from sympathectomized donors have lower arterial pressure and reduced sodium sensitivity of arterial pressure compared to SHRs transplanted with a kidney from hydralazine-treated donors. It is concluded that chronic non-adapting changes in sympathetic activity modulate the degree to which renal mechanisms can cause hypertension in SHRs. Severe reduction in sympathetic tone during early ontogeny causes long-term changes in renal function that mitigate hypertension development in SHRs even when the extrarenal neuro-hormonal environment is restored.