Goldblatt Hypertensive Rats Research Articles

Retraction Note: PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats.

Retraction Note: PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats.

Renal sympathetic activation triggered by the rostral ventrolateral medulla is dependent of spinal cord AT1 receptors in Goldblatt hypertensive rats

Spinal cord neurons contribute to elevated sympathetic vasomotor activity in renovascular hypertension (2K1C), particularly, increased actions of angiotensin II. However, the origin of these spinal angiotensinergic inputs remains unclear. The present study aimed to investigate the role of spinal angiotensin II type 1 receptor (AT1) receptors in the sympathoexcitatory responses evoked by the activation of the rostral ventrolateral medulla (RVLM) in control and 2K1C Goldblatt rats. Hypertension was induced by clipping of the left renal artery. After 6 weeks, a catheter (PE-10) filled with losartan was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anesthetized rats. The effects of glutamate microinjection into the RVLM on blood pressure (BP), heart rate (HR), and renal and splanchnic sympathetic nerve activity (rSNA and sSNA, respectively) were evaluated in the presence or absence of spinal AT1 blockade. Tachycardic, pressor, and renal sympathoexcitatory effects caused by RVLM activation were significantly blunted by losartan in 2K1C rats, but not in control rats. However, no differences were found in the gene expression of angiotensin-converting enzyme, angiotensinogen, and renin in the spinal cord segments between the groups. In conclusion, acute sympathoexcitation induced by RVLM activation is dependent on the spinal AT1 receptor in Goldblatt, but not in control, rats. The involvement of other central cardiovascular nuclei in spinal angiotensinergic actions, as well as the source of angiotensin II, remains to be determined in the Goldblatt model.

Peperomia pellucida (L.) Kunth as an angiotensin-converting enzyme inhibitor in two-kidney, one-clip Goldblatt hypertensive rats

BackgroudPeperomia pellucida (L.) Kunth has been used widely to treat headache, kidney disease, fever, and hypertension. Previous in vitro studies discovered that the flavonoid-rich extract of this plant has potential hypotensive effects, specifically angiotensin-converting enzyme (ACE)-inhibitory activity. However, there is insufficient scientific evidence to validate the result in vivo.PurposeThis study investigated the dose dependencies of the effects of the ethyl acetate fraction of the ethanolic extract of this plant on blood pressure and biomarkers associated with the renin–angiotensin–aldosterone systems (RAAS), such as angiotensin II (AII) and the plasma renin concentration (PRC).Study designIn total, 30 two-kidney, one-clip (2K1C) hypertensive model rats were divided into five groups (n = 6 each): model group, captopril 25 mg/kg BW group, and three different ethyl acetate groups (25, 50, and 100 mg/kg BW). Another six rats comprised the sham group.MethodsRenal hypertensive rats (RHRs) were generated using stainless steel modification clips. Drugs were administered via oral gavage for 2 consecutive weeks. Blood pressure was measured weekly prior to treatment. Blood samples were collected before treatment and after the last dose to measure AII and PRC. The left kidney was isolated for histopathological examination.ResultsBlood pressure, AII levels, and PRC were elevated after 6 weeks in RHRs. Treatment with captopril and the ethyl acetate fraction of P. pellucida (L.) Kunth decreased blood pressure, AII levels, and PRC. The ethyl acetate fraction at a dose of 50 mg/kg BW had similar ACE-inhibitory effects as captopril. Histopathological examination disclosed coagulative necrosis in clipped kidneys. Impairment was alleviated in a dose-dependent manner by P. pellucida (L.) Kunth, similarly as observed in the captopril group.ConclusionP. pellucida (L.) Kunth targets the renin–angiotensin–aldosterone system, which might explain its antihypertensive effects.

Effects of Ovariectomy on Sex‐Dependent Differences in Hypertension and Renal Injury in 2‐Kidney 1‐Clip (2k1c) Goldblatt Hypertensive Rats

Previous studies demonstrated sex differences in hypertension in rats with unilateral renal artery stenosis (2K1C), with females developing a significantly lower degree of hypertension, urinary angiotensinogen (uAGT) and renal injury than males. The present study focused on the protective role estrogen may play in the development of hypertension by exploring the responses in 2K1C ovariectomized (OVX) female rats. A 0.2mm silver clip was placed on the left renal artery of OVX rats (n=4) with other rats left intact (n=4). Blood pressures (BP) of both groups were recorded on days -1, 3, 7, 14, and 21 using tail cuff plethysmography. Rats were placed in metabolic cages for 24 hours to measure water intake and urine volume. Rats were subjected to clearance studies on day 22. Following anesthesia with pentobarbital, the jugular vein was catheterized and infused with an inulin/PAH saline/albumin solution at a rate of 1.2mL/hour. A femoral artery catheter was used to continuously measure arterial pressure. The right and left ureters were catheterized, and urine flow was collected in 30min periods over 2 hours for uAGT ELISA and renal function analyses. Right and left kidneys were sectioned for RNA and histology to determine degree of kidney injury. BP in OVX 2K1C rats trended higher than BP in intact 2K1C females and were statistically higher by day 21. The OVX 2K1C rats did not show statistical differences in BP, urine volume, or uAGT compared to males. In OVX rats, clipped kidneys showed reduced kidney function as compared to intact 2K1C females, trending similar to male 2K1C data. Preliminary PAS data suggests that the degree of renal injury in OVX females is greater than in intact 2K1C females. In addition, nonclipped kidneys of OVX rats showed significantly greater uAGT excretion than the clipped kidneys, further supporting the role of intrarenal RAS in mediating hypertensive and renal injury responses in 2K1C rats. In conclusion, the increased uAGT in OVX rats indicate augmented intrarenal angiotensin II levels and are associated with decreased renal function in OVX rats vs. control and vs. intact 2K1C females. Our data suggests that removal of estrogen partially reduces its protective role against hypertension in females. Further tissue analysis will reveal the degree of renal injury. Our findings help explain sex-differences in hypertension and suggest the need for further research specifically focused on treatment and management of hypertension in women.

Differential effects of renal denervation on arterial baroreceptor function in Goldblatt hypertension model.

Sympathetic vasomotor activity is significantly increased in renovascular hypertension. Renal denervation (DnX) has emerged as a novel therapy for resistant hypertension to drug therapy. However, the underlying mechanisms regarding the reduction in blood pressure (BP) after DnX remain unclear. Thus, the aim of this study was to evaluate the effects of DnX of a clipped kidney on the baseline and baroreceptor reflex control of post-ganglionic sympathetic activity to the contralateral kidney (rSNA) and lumbar (lSNA) nerves in Goldblatt hypertensive rats (2K1C). Renal denervation of an ischaemic kidney (DxX - all visible bundles of nerves were dissected - 10% phenol) was performed 5weeks after clipping (gap width: 0.2mm). Ten days after DnX, BP was significantly reduced (16%) in the 2K1C compared with the undenervated 2K1C (p<0.05). DnX significantly reduced basal rSNA (control group (CT): 110±8, n=14; 2K1C: 150±8, n=12; 2K1C DnX: 89±7, spikes per second (spikes/s); p<0.05, n=8) and lSNA (CT: 137±8, n=8; 2K1C: 202±7, n=11; 2K1C DnX: 131±7, spikes/s; p<0.05, n=8) only in 2K1C rats. DnX significantly improved the arterial baroreceptor sensitivity of rSNA (CT: -2.3±0.2, n=11; 2K1C: -0.7±0.1, n=8; 2K1C DnX: -1.5±0.2, spikes/s/mmHg; p<0.05, n=5) and heart rate for tachycardic response (CT: -3.9±0.5, n=7; 2K1C: -1.9±0.1, n=8; 2K1C DnX: -3.3±0.4, bpm/mmHg; p<0.05, n=8), but not for lSNA in 2K1C rats. The results show that DnX normalized baseline sympathetic vasomotor activity to the lumbar and renal nerves, followed by a differential improvement in the arterial baroreceptor sensitivity. Whether the baroreceptor function sensitivity improvement induced by DnX is a cause or a consequence of BP reduction remains to be determined.

Right ventricular pressure elevated in one-kidney, one clip Goldblatt hypertensive rats

ABSTRACTBoth renal and respiratory diseases are common with high mortality rate around the world. This study was the first to compare effects of two kidneys, one clip (2K1C) and one-kidney, one clip (1K1C) Goldblatt hypertension on right ventricular pressure during normal condition and mechanical ventilation with hypoxia gas. Male Sprague–Dawley rats were subjected to control, 2K1C, or 1K1C groups. Twenty-eight days after the first surgery, animals were anesthetized, and femoral artery and vein, and right ventricle cannulated. Systemic arterial pressure and right ventricular systolic pressures (RVSP) were recorded during ventilation the animals with normoxic or hypoxic gas. RVSP in the 1K1C group was significantly more than the control and 2K1C groups during baseline conditions and ventilation the animals with hypoxic gas. Administration of antioxidant Trolox increased RVSP in the 1K1C and control groups compared with their baselines. Furthermore, there was no alteration in RVSP during hypoxia in the presence of Trolox. This study indicated that RVSP only increased after 28 days induction of 1K1C but not 2K1C model. In addition, it seems that the response to hypoxic gas and antioxidants in 1K1C is more than 2K1C. These data also suggest that effects of 1K1C may partially be related to reactive oxygen species (ROS) pathways.

Protective Cardiorenal Effects Of Tropaeolum majus L. In Rats With Renovascular Hypertension

: Background: Tropaeolum majus L. (Tropaeolaceae) is an important medicinal plant belonging to the Tropaeolaceae family, which has 80 species distributed in South and Central America. In Brazil, it is distributed practically throughout the entire territory and it is popularly known as “capuchinha”. In folk medicine its leaves are widely used for treatment of cardiovascular disorders. Despite consistent data showing some acute effects on renal and cardiovascular system, no study has investigated whether Tropaeolum majus extracts is able to exert cardiorenal protective effects after 30 days of treatment, i.e. in a sustained manner. Objective: Investigate the prolonged cardiorenal protective effects of ethanolic extract obtained from Tropaeolum majus (EETM) in rats with renovascular hypertension. Material and Methods: First, EETM was obtained and chemically characterized. Then, we investigated the possible antihypertensive and diuretics effects, including effects on renal haemodynamics, after prolonged treatment (30 days) with EETM (3, 30 and 300 mg/kg). Finally, we examined whether treatment with EETM may affect the angiotensin-converting enzyme (ACE) and oxidative stress, preventing heart and kidney damage in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats. Results: Prolonged treatment with EETM was able to prevent the evolution of renovascular hypertension in 2K1C rats, inducing important renoprotective effects and reducing systemic blood pressure and cardiac hypertrophy. Moreover, it was also identified that these effects may be directly related to significant ACE inhibitory activity and reduction of oxidative stress. Conclusion: This study has brought new scientific evidence of preclinical efficacy of EETM as a cardiorenal protective agent in rats with renovascular hypertension.Key words: Antihypertensive, Cardioprotective, Diuretic, Renoprotective, Tropaeolum majus L.

Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats.

Peripheral chemoreflex sensitization is a feature of renovascular hypertension. Carotid sinus nerve denervation (CSD) has recently been shown to relieve hypertension and reduce sympathetic activity in other rat models of hypertension. We show that CSD in renovascular hypertension halts further increases in blood pressure. Possible mechanisms include improvements in baroreceptor reflex sensitivity and renal function, restoration of cardiac calcium signalling towards control levels, and reduced neural inflammation. Our data suggest that the peripheral chemoreflex may be a viable therapeutic target for renovascular hypertension. The peripheral chemoreflex is known to be hyper-responsive in both spontaneously hypertensive (SHR) and Goldblatt hypertensive (two kidney one clip; 2K1C) rats. We have previously shown that carotid sinus nerve denervation (CSD) reduces arterial blood pressure (ABP) in SHR. In the present study, we show that CSD ameliorates 2K1C hypertension and reveal the potential underlying mechanisms. Adult Wistar rats were instrumented to record ABP via telemetry, and then underwent CSD (n=9) or sham CSD (n=9) 5weeks after renal artery clipping, in comparison with normal Wistar rats (n=5). After 21days, renal function was assessed, and tissue was collected to assess sympathetic postganglionic intracellular calcium transients ([Ca2+ ]i ) and immune cell infiltrates. Hypertensive 2K1C rats showed a profound elevation in ABP (Wistar: 98±4mmHg vs. 2K1C: 147±8mmHg; P<0.001), coupled with impairments in renal function and baroreflex sensitivity, increased neuroinflammatory markers and enhanced [Ca2+ ]I in stellate neurons (P<0.05). CSD reduced ABP in 2K1C+CSD rats and prevented the further progressive increase in ABP seen in 2K1C+sham CSD rats, with a between-group difference of 14±2mmHg by week 3 (P<0.01), which was accompanied by improvements in both baroreflex control and spectral indicators of cardiac sympatho-vagal balance. Furthermore, CSD improved protein and albuminuria, decreased [Ca2+ ]i evoked responses from stellate neurons, and also reduced indicators of brainstem inflammation. In summary, CSD in 2K1C rats reduces the hypertensive burden and improves renal function. This may be mediated by improvements in autonomic balance, functional remodelling of post-ganglionic neurons and reduced inflammation. Our results suggest that the peripheral chemoreflex may be considered as a potential therapeutic target for controlling renovascular hypertension.

PP.LB02.15] RENAL DENERVATION NORMALIZES SYMPATHETIC VASOMOTOR ACTIVITY AND PRODUCES DIFFERENTIAL EFFECTS ON THE ARTERIAL BARORECEPTOR FUNCTION IN THE GOLDBLATT RENOVASCULAR HYPERTENSION

Objective: Sympathetic nerve activity is increased in renovascular hypertension. Renal denervation has shown promise in the treatment of patients with resistant hypertension to drug therapy, although the mechanisms underlying reduction in blood pressure remains uncertain. The aim of this study was to evaluate the effects of unilateral renal denervation (H+DnX) on efferent post-ganglionic sympathetic nerve activity to renal (rSNA) and lumbar (lSNA) sympathetic nerves in Goldblatt hypertensive rats (2K1C). Design and method: The baroreceptor sensitivity to rSNA, lSNA, heart rate (HR) and the cardiovascular autonomic function (by power spectral density analysis) were evaluated ten days after renal denervation. Denervation of clipped kidney (DnX – all visible bundles nerves were dissected – 10% phenol) was performed 5 weeks after clipping (gap width 0.2 mm). The rSNA and barorreceptor reflex control to rSNA was performed in the innervated contralateral kidney. Results: Ten days after DnX, blood pressure (BP) was significantly reduced (16%) in the 2K1C rats compared to 2K1C undenervated (H). DnX normalized rSNA (CT: 110 ± 8, n = 14; 2K1C:150 ± 8, n = 12; 2K1C DnX:89 ± 7, pps n = 8) and lSNA (CT: 137 ± 8, n = 8; 2K1C: 202 ± 7, n = 11; 2K1C DnX:131 ± 7, pps n = 8) in the 2K1C rats. DnX significantly improved the baroreceptor function for rSNA (CT: −2.3 ± 0.2, n = 11; 2K1C: −0.7 ± 0.1, n = 8; 2K1C DnX: −1.5 ± 0.2, pps/mmHg n = 5) and tachycardic response (CT: −3.9 ± 0.5, n = 7; 2K1C: −1.9 ± 0.1, n = 8; 2K1C DnX: −3.3 ± 0.4, bpm/mmHg n = 8), but not for lSNA in 2K1C rats. Furthermore, DnX significantly increased the high frequency (HF) component (CT: 1.4 ± 1, n = 10; 2K1C: 3.4 ± 2 n = 9; 2K1C DnX: 7.6 ± 3, ms2 n = 9) but not the very low frequency (VLF) and low frequency (LF) components (VLF = CT: 2.7 ± 1, n = 10; 2K1C: 13 ± 7, n = 9; 2K1C DnX: 9 ± 5, ms2 n = 8 / LF = CT: 2 ± 0.6, n = 9; 2K1C: 5 ± 3, n = 11; 2K1C DnX: 6 ± 4, ms2 n = 9) which remained elevated in the 2K1C rats. Conclusions: The results show that renal denervation normalized sympathetic vasomotor activity and increased the HF component of spectral analysis accompanied by a non uniform improvement in the arterial baroreceptor function. Whether the baroreceptor function sensitivity improvement induced by DnX is a cause or a consequence of BP reduction remains to be determined. Supported by FAPESP and CAPES.

Interlobular Arteries From 2-Kidney, 1-Clip Goldblatt Hypertensive Rats’ Exhibit-Impaired Vasodilator Response to Epoxyeicosatrienoic Acids

BackgroundSmall renal arteries have a significant role in the regulation of renal hemodynamics and blood pressure (BP). To study potential changes in the regulation of vascular function in hypertension, we examined renal vasodilatory responses of small arteries from nonclipped kidneys of the 2-kidney, 1-clip Goldblatt hypertensive rats to native epoxyeicosatrienoic acids (EETs) that are believed to be involved in the regulation of renal vascular function and BP. A total of 2 newly synthesized EET analogues were also examined. Materials and MethodsRenal interlobular arteries isolated from the nonclipped kidneys on day 28 after clipping were preconstricted with phenylephrine, pressurized and the effects of a 14,15-EET analogue, native 14,15‐EET and 11,12‐ether-EET‐8ZE, an analogue of 11,12-EET, on the vascular diameter were determined and compared to the responses of arteries from the kidneys of sham-operated rats. ResultsIn the arteries from nonclipped kidneys isolated in the maintenance phase of Goldblatt hypertension, the maximal vasodilatory response to 14,15-EET analogue was 30.1 ± 2.8% versus 49.8 ± 7.2% in sham-operated rats; the respective values for 11,12-ther-EET-8ZE were 31.4 ± 6.4% versus 80.4 ± 6%, and for native EETs they were 41.7 ± 6.6% versus 62.8 ± 4.4% (P ≤ 0.05 for each difference). ConclusionsWe propose that reduced vasodilatory action and decreased intrarenal bioavailability of EETs combined with intrarenal angiotensin II levels that are inappropriately high for hypertensive rats underlie functional derangements of the nonclipped kidneys of 2-kidney, 1-clip Goldblatt hypertensive rats. These derangements could play an important role in pathophysiology of sustained BP elevation observed in this animal model of human renovascular hypertension.

Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats

This study examined the effects of a novel orally active 14,15-epoxyeicosatrienoic acid analog (EET-A) on blood pressure (BP) and myocardial infarct size (IS) in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats during sustained phase of hypertension. Between days 31 and 35 after clip placement the rats were treated with EET-A and BP was monitored by radiotelemetry; sham-operated normotensive rats were used as controls. Tissue concentrations of epoxyeicosatrienoic acids served as a marker of production of epoxygenase metabolites. The rats were subjected to acute myocardial ischemia/reperfusion (I/R) injury and IS was determined. We found that EET-A treatment did not lower BP in 2K1C rats and did not alter availability of biologically active epoxygenase metabolites in 2K1C or in sham-operated rats. The myocardial IS was significantly smaller in untreated 2K1C rats as compared with normotensive controls and EET-A reduced it in controls but not in 2K1C rats. Our findings suggest that during the phase of sustained hypertension 2K1C Goldblatt hypertensive rats exhibit increased cardiac tolerance to I/R injury as compared with normotensive controls, and that in this animal model of human renovascular hypertension short-term treatment with EET-A does not induce any antihypertensive and cardioprotective actions.

Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat.

What is the central question of this study? We examined, in hypertensive rats, whether the angiotensin-converting enzyme-independent enzymes generating angiotensin II in the tissues modulate blood pressure, peripheral circulation and renal function. What is the main finding and its importance? The results suggest that chymostatin-sensitive enzymes diminish vascular tone in renal and extrarenal vascular beds. Chymase or similar chymostatin-sensitive enzymes have a significant role in the synthesis of angiotensin II in different tissues but do not control blood pressure in the short term, similarly in salt-dependent or Goldblatt-type rat hypertension. In salt-dependent hypertension, chymase blockade protected renal outer medullary perfusion, probably by reducing the angiotensin II content in the kidney. Chymase is presumed to be a crucial enzyme of the non-angiotensin-converting enzyme pathway of angiotensin II (Ang II) generation in tissues, a process involved in vascular remodelling and development of hypertension. We examined the role of chymase in hypertension induced by exposure of uninephrectomized rats to high dietary salt intake (UNX HS) and in the Goldblatt renal artery stenosis (two-kidney, one-clip) model. In acute experiments with anaesthetized rats of either model, chymostatin at 2 mg kg(-1) h(-1) or 0.05% DMSO solvent was infused i.v. Mean arterial blood pressure, heart rate, iliac blood flow (a measure of hindlimb perfusion), total renal blood flow and intrarenal regional perfusion (laser-Doppler technique) were measured continuously, along with the glomerular filtration rate and renal excretion. In both models, chymase blockade distinctly decreased plasma and tissue Ang II without lowering mean blood pressure or consistently altering the other functional parameters measured. Unexpectedly, in Goldblatt hypertensive rats the blockade increased the renal and hindlimb vascular resistances by 51 and 33%, respectively (P < 0.05). In UNX HS hypertensive rats, chymase blockade abolished the solvent-induced decrease in outer medullary blood flow. We conclude that chymase or similar chymostatin-sensitive enzyme(s) has a significant role in the synthesis of Ang II in different tissues but does not participate in short-term control of blood pressure in salt-dependent or Goldblatt-type rat hypertension. In the Goldblatt model, chymase appeared to reduce the renal and hindlimb vascular resistances by an unknown mechanism. In salt-dependent hypertension, chymase blockade protected renal outer medullary perfusion, probably by reducing Ang II content in the kidney.

PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats.

Objective:Renin–angiotensin system (RAS) regulates adipogenic response with adipocyte hypertrophy by increasing oxidative stress. Recent studies have shown the role of peroxisome proliferator-activated receptor-δ (PPARδ) agonist in attenuation of angiotensin II-induced oxidative stress. The aim of this study was to explore a potential mechanistic link between PPARδ and the cytoprotective enzyme heme oxygenase-1 (HO-1) and to elucidate the contribution of HO-1 to the adipocyte regulatory effects of PPARδ agonism in an animal model of enhanced RAS, the Goldblatt 2 kidney 1 clip (2K1C) model.Method:We first established a direct stimulatory effect of the PPARδ agonist (GW 501516) on the HO-1 gene by demonstrating increased luciferase activity in COS-7 cells transfected with a luciferase-HO-1 promoter construct. Sprague-Dawley rats were divided into four groups: sham-operated animals, 2K1C rats and 2K1C rats treated with GW 501516, in the absence or presence of the HO activity inhibitor, stannous mesoporphyrin (SnMP).Results:2K1C animals had increased visceral adiposity, adipocyte hypertrophy, increased inflammatory cytokines, increased circulatory and adipose tisssue levels of renin and Ang II along with increased adipose tissue gp91 phox expression (P<0.05) when compared with sham-operated animals. Treatment with GW 501516 increased adipose tissue HO-1 and adiponectin levels (P<0.01) along with enhancement of Wnt10b and β-catenin expression. HO-1 induction was accompanied by the decreased expression of Wnt5b, mesoderm specific transcript (mest) and C/EBPα levels and an increased number of small adipocytes (P<0.05). These effects of GW501516 were reversed in 2K1C animals exposed to SnMP (P<0.05).Conclusion:Taken together, our study demonstrates, for the first time, that increased levels of Ang II contribute towards adipose tissue dysregulation, which is abated by PPARδ-mediated upregulation of the heme-HO system. These findings highlight the pivotal role and symbiotic relationship of HO-1, adiponectin and PPARδ in the regulation of metabolic homeostasis in adipose tissues.

Reply to “Letter to the Editor: ‘How does potassium supplementation lower blood pressure?’”

to the editor: We appreciate Dr. McDonough's and Dr. Nguyen's valuable comments and interest (6a) in our study. They raised several interesting issues regarding our recent paper ([4][1]), which explored the molecular mechanisms responsible for the blood pressure-lowering effect of potassium

Irbesartan and Emodin on Myocardial Remodeling in Goldblatt Hypertensive Rats

Interactions between the renin-angiotensin system and transforming growth factor-beta 1 (TGF-β1) have been well documented. The aim was to explore the effect of irbesartan combining with emodin on myocardial remodeling in Goldblatt (2K-1C) hypertensive rats. All 60 Sprague-Dawley rats were randomly divided into 5 groups as follows: the sham-clipped without any drugs; 2K-1C without any drugs; the 2K-1C with irbesartan (50 mg/kg/day); the 2K-1C with emodin (80 mg/Kg/day); and the 2K-1C with irbesartan and emodin together for the last 8 weeks of a 12-week period of study. The outcome measures included left ventricular mass index, TGF-β1 and angiotensin II in the left ventricle, mRNA expression of TGF-β1, and connective tissue growth factor (CTGF). Compared with 2K1C group, the 2K1C/irbesartan group and 2K-1C/emodin plus irbesartan group had significantly lower systolic blood pressure and local angiotensin II (P < 0.05). The left ventricular mass index in each of the 3 treatment groups was significantly lower than that in the 2K1C group, especially in the combined group. The mRNA/protein TGF-β1 and the mRNA CTGF of 2K1C/irbesartan group, 2K1C/emodin group, and 2K-1C/emodin plus irbesartan group were significantly decreased compared with 2K-1C group (P < 0.05). Irbesartan or emodin or 2 drugs together can inhibit myocardial remodeling in renovascular hypertension rats probably by reducing TGF-β1 and CTGF expression. The combination of irbesartan and emodin is better than single drug application.

Reciprocal changes in renal ACE/ANG II and ACE2/ANG 1–7 are associated with enhanced collecting duct renin in Goldblatt hypertensive rats

Alterations in the balance between ANG II/ACE and ANG 1-7/ACE2 in ANG II-dependent hypertension could reduce the generation of ANG 1-7 and contribute further to increased intrarenal ANG II. Upregulation of collecting duct (CD) renin may lead to increased ANG II formation during ANG II-dependent hypertension, thus contributing to this imbalance. We measured ANG I, ANG II, and ANG 1-7 contents, angiotensin-converting enzyme (ACE) and ACE2 gene expression, and renin activity in the renal cortex and medulla in the clipped kidneys (CK) and nonclipped kidneys (NCK) of 2K1C rats. After 3 wk of unilateral renal clipping, systolic blood pressure and plasma renin activity increased in 2K1C rats (n = 11) compared with sham rats (n = 9). Renal medullary angiotensin peptide levels were increased in 2K1C rats [ANG I: (CK = 171 ± 4; NCK = 251 ± 8 vs. sham = 55 ± 3 pg/g protein; P < 0.05); ANG II: (CK = 558 ± 79; NCK = 328 ± 18 vs. sham = 94 ± 7 pg/g protein; P < 0.001)]; and ANG 1-7 levels decreased (CK = 18 ± 2; NCK = 19 ± 2 pg/g vs. sham = 63 ± 10 pg/g; P < 0.001). In renal medullas of both kidneys of 2K1C rats, ACE mRNA levels and activity increased but ACE2 decreased. In further studies, we compared renal ACE and ACE2 mRNA levels and their activities from chronic ANG II-infused (n = 6) and sham-operated rats (n = 5). Although the ACE mRNA levels did not differ between ANG II rats and sham rats, the ANG II rats exhibited greater ACE activity and reduced ACE2 mRNA levels and activity. Renal medullary renin activity was similar in the CK and NCK of 2K1C rats but higher compared with sham. Thus, the differential regulation of ACE and ACE2 along with the upregulation of CD renin in both the CK and NCK in 2K1C hypertensive rats indicates that they are independent of perfusion pressure and contribute to the altered content of intrarenal ANG II and ANG 1-7.

Counterpoint: Activation of the Intrarenal Renin-Angiotensin System is the Dominant Contributor to Systemic Hypertension

Our discussion regarding the dominant mechanism responsible for hypertension calls to mind the famous poem, “The Blind Men and the Elephant,” by John Godfrey Saxe based on an ancient fable from India. In essence, the blind men described the elephant based on their specific encounter, thus

Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-β mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-β mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

Intrarenal cytochrome P-450 metabolites of arachidonic acid in the regulation of the nonclipped kidney function in two-kidney, one-clip Goldblatt hypertensive rats

The contribution of epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) as cytochrome P-450 metabolites of arachidonic acid in the regulation of the nonclipped kidney function in two-kidney, one-clip (2K1C) Goldblatt hypertensive rats was investigated during the phases of initial and stable hypertension, that is, 7 or 27 days after clipping, respectively. Male Hannover Sprague-Dawley rats had the right renal artery clipped or underwent sham operation. Urinary excretion of EETs, their inactive metabolites dihydroxyeicosatrienoic acids and of 20-HETE was measured. Intrarenal cytochrome P-450 protein expression and the activities of epoxygenase, omega-hydroxylase and soluble epoxide hydrolase were also determined. The responses of renal hemodynamics and electrolyte excretion of the nonclipped kidney to left renal artery infusions of inhibitors of EETs or 20-HETE formation (MS-PPOH and DDMS, respectively) were measured. In 2K1C rats, urinary excretion of EETs was significantly lower and that of 20-HETE was higher than that in sham-operated animals only on day 27 after clipping. Intrarenal inhibition of EETs significantly decreased renal hemodynamics and sodium excretion in sham-operated but not in 2K1C rats. Intrarenal inhibition of 20-HETE decreased sodium excretion in sham-operated rats but elicited increases in renal hemodynamics and sodium excretion in 2K1C rats. Our results indicate that the nonclipped kidney of Goldblatt 2K1C rats in the phase of sustained hypertension exhibits decreased intrarenal EETs and elevated 20-HETE levels as compared with the kidney of sham-operated animals. This suggests that altered production and action of cytochrome P-450-derived metabolites during this stable phase contributes to the mechanism of Goldblatt 2K1C hypertension.

Blood Pressure, Blood Flow, and Oxygenation in the Clipped Kidney of Chronic 2-Kidney, 1-Clip Rats

Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls. Twelve months after left renal artery clipping or sham, mean arterial pressure, renal cortical blood flow, and renal cortical and medullary oxygen tension were measured after acute administration of Tempol followed by enalaprilat or candesartan followed by enalaprilat. The mean arterial pressure of the 2K,1C rat was reduced by candesartan (−9%) and, more effectively, by Tempol (−35%). All of the applied treatments had similar blood pressure-lowering effects in sham rats (average: −21%). Only Tempol increased cortical blood flow (+35%) and cortical and medullary oxygen tensions (+17% and +94%, respectively) in clipped kidneys of 2K,1C rats. Administration of enalaprilat had no additional effect, except for a modest reduction in cortical blood flow in the clipped kidney of 2K,1C rats when coadministered with candesartan (−10%). In conclusion, acute administration of Tempol is more effective than candesartan in reducing the mean arterial blood pressure and improving renal blood perfusion and oxygenation in the clipped kidney of chronic 2K,1C rats.