Early effects of renal denervation in the anaesthetised rat: natriuresis and increased cortical blood flow

A novel method of renal denervation was developed based on electro-coagulation of tissue containing most of the sympathetic fibres travelling towards the kidney. Kidney tissue noradrenaline was decreased to 4.7 % of the content measured in the contralateral innervated kidney when studied 3 days postdenervation.The method was utilised in anaesthetised rats to examine the effects of denervation within the heretofore unexplored first 75 min period postdenervation. Sodium excretion (UNaV) increased significantly (+82 %, P < 0.03) over the 25-50 min after denervation. In a parallel group, with a lower baseline UNaV, there was also a significant increase in UNaV (+54 %, P < 0.03) within the first 25 min. The renal perfusion pressure was maintained at a constant value and the glomerular filtration rate did not change after denervation.Renal cortical and medullary blood flows (CBF, MBF) were estimated as laser Doppler flux and medullary tissue ion concentration was estimated as electrical admittance (Y). Following denervation, in both groups CBF increased significantly within the first 25 min (+12 %, P < 0.01 and +8 %, P < 0.05, respectively) while MBF did not change or decreased slightly; Y did not change.The data document the development of natriuresis within the first 25-50 min after denervation. The increase in CBF indicated that, prior to denervation, the cortical, but not medullary, circulation was under a tonic vasoconstrictor influence of the renal nerves. Such a dissociation of neural effects on the renal cortical vs. medullary vasculature has not been previously described

Role of chymase in blood pressure control, plasma and tissue angiotensin II, renal Haemodynamics, and excretion in spontaneously hypertensive rats

Background: Chymase generates angiotensin II (ANG II) independently of angiotensin-converting enzyme in tissues and it contributes to vascular remodeling and development of hypertension, however the exact mechanism of its action is unclear. Methods: Hence, the effects of chymase inhibition were examined in anesthetized spontaneously hypertensive rats (SHR) in two stages of the disease development, ie. pre-hypertensive (SHR7) and with established hypertension (SHR16). Chymostatin, a commercial chymase inhibitor, was infused intravenously alone or in subsequent groups co-infused with captopril. Results: Mean blood pressure (MBP), total renal blood flow (RBF) and ANG II content (plasma and tissues) were measured. In SHR16 chymase blockade significantly decreased MBP (−6%) and plasma (−38%), kidney (−71%) and heart (−52%) ANG II levels. In SHR7 chymostatin did not influence MBP or RBF, but significantly decreased heart ANG II level. Conclusion: Jointly, functional studies and ANG II determinations support the evidence that in SHR chymase can raise plasma ANG II and contribute to blood pressure elevation. We propose that addition of chymase blockade to ACE inhibition could be a promising approach in the treatment of hypertensive patients resistant to therapy with ACE-inhibitors alone

Osmotic hypertonicity of the renal medulla during changes in renal perfusion pressure in the rat

The relationship between renal perfusion pressure (RPP) and ion concentration in renal medulla was studied in anaesthetized rats. RPP was changed in steps within the pressure range 130–80 mmHg, while tissue electrical admittance (Y, index of interstitial ion concentration) and medullary and cortical blood flow (MBF and CBF; laser Doppler flowmetry) were measured, along with glomerular filtration rate (Cin) and renal excretion.With a RPP reduction from 130 to 120 mmHg, tissue Y remained stable; at 100 and 80 mmHg, Y was 5 and 17 % lower, respectively, than at 120 mmHg.CBF fell less than RPP (partial autoregulation) in the range 130–100 mmHg only. MBF was autoregulated within 120–100 mmHg, but not above or below this range.Each step of RPP reduction was followed by a decrease in sodium and water excretion (UNaV and V). The osmolality of excised inner medulla fragments was similar at 120 and 105 mmHg (586 ± 45 and 618 ± 35 mosmol (kg H2O)−1, respectively) but lower at 80 mmHg (434 ± 31 mosmol (kg H2O)−1, P < 0.01); the ion concentration changed in parallel.The data show that medullary hypertonicity was well preserved during RPP fluctuations within 130–100 mmHg, but not below this range. RPP-dependent changes of UNaV and V were not clearly associated with changes in solute concentration in medullary tissue

Consequences of the loss of the Grainyhead-like 1 gene for renal gene expression, regulation of blood pressure and heart rate in a mouse model

Aim: The Grainyhead-like 1 (GRHL1) transcription factor is tissue-specific and is very highly expressed in the kidney. In humans the GRHL1 gene is located at the chromosomal position 2p25. A locus conferring increased susceptibility to essential hypertension has been mapped to 2p25 in two independent studies, but the causative gene has never been identified. Furthermore, a statistically significant association has been found between a polymorphism in the GRHL1 gene and heart rate regulation. The aim of our study was to investigate the physiological consequences of Grhl1 loss in a mouse model and ascertain whether Grhl1 may be involved in the regulation of blood pressure and heart rate. Experimental approach: In our research we employed the Grhl1 "knock-out" mouse strain. We analyzed renal gene expression, blood pressure and heart rate in the Grhl1-null mice in comparison with their "wild-type" littermate controls. Most important results: The expression of many genes is altered in the Grhl1-/- kidneys. Some of these genes have previously been linked to blood pressure regulation. Despite this, the Grhl1-null mice have normal blood pressure and interestingly, increased heart rate. Conclusions: Our work did not discover any new evidence to suggest any involvement of Grhl1 in blood pressure regulation. However, we determined that the loss of Grhl1 influences the regulation of heart rate in a mouse model

Endothelin type A receptor blockade increases renoprotection in congestive heart failure combined with chronic kidney disease: Studies in 5/6 nephrectomized rats with aorto-caval fistula

Background: Association of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient’s prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ETA) receptor antagonist to the angiotensin-converting enzyme inhibitor (ACEi) will bring additional beneficial effects in experimental rats. Methods: CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation. Results: The final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, however, the difference between the combination and either single treatment regimen was not significant. The combined treatment exerted best renoprotection, causing additional reduction in albuminuria and reducing renal glomerular and tubulointerstitial injury as compared with ACE inhibition alone. Conclusions: Our results show that treatment with ETA receptor antagonist attenuates the CKD- and CHF-related mortality, and addition of ETA receptor antagonist to the standard blockade of RAS by ACEi exhibits additional renoprotective actions

Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren‐2 transgenic hypertensive rats

1. The aim of the present study was to test the hypothesis that increasing kidney tissue concentrations of epoxyeicosatrienoic acids (EETs) by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH) would attenuate the progression of chronic kidney disease (CKD). 2. Ren-2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin (Ang) II-dependent hypertension. Soluble epoxide hydrolase was inhibited using cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB; 3 mg/L drinking water) for 20 weeks after 5/6 NX. Sham-operated normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. 3. When applied in TGR subjected to 5/6 NX, c-AUCB treatment improved survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury and reduced glomerular volume. All these organ-protective actions were associated with normalization of the intrarenal EETs : DHETEs ratio, an index of the availability of biologically active EETs, to levels observed in sham-operated HanSD rats. There were no significant concurrent changes of increased intrarenal AngII content. 4. Together, these results show that 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of AngII-dependent hypertension, and that restoration of intrarenal availability of EETs using long-term c-AUCB treatment exhibits substantial renoprotective actions