Activation of RAAS in a rat model of liver cirrhosis: no effect of losartan on renal sodium excretion.

BACKGROUND: Liver cirrhosis is characterized by avid sodium retention where the activation of the renin angiotensin aldosterone system (RAAS) is considered to be the hallmark of the sodium retaining mechanisms. The direct effect of angiotensin II (ANGII) on the AT-1 receptor in the proximal tubules is partly responsible for the sodium retention. The aim was to estimate the natriuretic and neurohumoral effects of an ANGII receptor antagonist (losartan) in the late phase of the disease in a rat model of liver cirrhosis. METHODS: Bile duct ligated (BDL) and sham operated rats received 2 weeks of treatment with losartan 4 mg/kg/day or placebo, given by gastric gavage 5 weeks after surgery. Daily sodium and potassium intakes and renal excretions were measured. RESULTS: The renal sodium excretion decreased in the BDL animals and this was not affected by losartan treatment. At baseline the plasma renin concentration (PRC) was similar in sham and BDL animals, but increased urinary excretion of ANGII and an increase P-Aldosterone was observed in the placebo treated BDL animals. The PRC was more than 150 times higher in the losartan treated BDL animals (p < 0.001) which indicated hemodynamic impairment. CONCLUSIONS: Losartan 4 mg/kg/day did not increase renal sodium excretion in this model of liver cirrhosis, although the urinary ANGII excretion was increased. The BDL animals tolerated Losartan poorly, and the treatment induced a 150 times higher PRC.

[Clinical application of combined hepatic artery resection and reconstruction in surgical treatment for hilar cholangiocarcinoma].

Objective: To clarify whether the surgical treatment for hilar cholangiocarcinoma combined with artery reconstruction is optimistic to the patients with hilar cholangiocarcinoma with hepatic artery invasion. Methods: There were 384 patients who received treatment in the First Affiliated Hospital to Army Medical University from January 2008 to January 2016 analyzed retrospectively. There were 27 patients underwent palliative operation, 245 patients underwent radical operation, radical resection account for 63.8%. Patients were divided into four groups according to different operation method: routine radical resection group(n=174), portal vein reconstruction group (n=47), hepatic artery reconstruction group (n=24), palliative group(n=27). General information of patients who underwent radical operation treatment was analyzed by chi-square test and analysis of variance. The period of operation time, blood loss, the length of hospital stay and hospitalization expenses of the radical operation patients were analyzed by one-way ANOVA. Comparison among groups was analyzed by LSD-t test. Results: The follow-up ended up in June first, 2016. Each of patients followed for 6 to 60 months, the median follow-up period was 24 months. 1-, 3-, and 5-year survival rates were 81.3%, 44.9% and 13.5% of routine radical operation group, and were 83.0%, 44.7% and 15.1% of portal vein reconstruction group, and were 70.8%, 27.7% and 6.9% of hepatic artery reconstruction group, respectively. And 1-, 3-, and 5-year survival rates of hepatic artery reconstruction group was lower than routine radical group and portal vein reconstruction group significantly (P<0.05). However, the rate of postoperative complications of the hepatic artery reconstruction group and the routine radical operation group and the portal vein reconstruction group were 62.5%(15/24), 55.3%(96/174) and 51.5%(24/47), respectively. There was no significant difference among them (P>0.05). The data shows that the ratio of lymphatic metastasis in hepatic artery reconstruction group (70.8%) is much higher than them in routine radical operation group (20.1%) and portal vein reconstruction group (19.1%) significantly (P<0.05). The presented data also indicate that hepatic artery resection prolongs survival time comparing with patients undergoing palliative therapy for hilar cholangiocarcinoma. Cox regression analysis indicate that hepatic artery resection and reconstruction is a protective factor compare with palliative therapy (RR=0.38, 95%CI: 0.22-0.67). The significant reason for shorter survival time is a positive correlation between hepatic artery invasion and lymph node metastasis. Conclusion: Hepatic artery resection and reconstruction has beneficial impact on oncologic long-term outcome in patients with advanced stage hilar cholangiocarcinoma.

The water channel AQP1 is expressed in human atherosclerotic vascular lesions and AQP1 deficiency augments angiotensin II-induced atherosclerosis in mice.

AIM: The water channel aquaporin 1 (AQP1) promotes endothelial cell migration. It was hypothesized that AQP1 promotes neovascularization and growth of atherosclerotic plaques. METHODS: AQP1 immunoreactivity and protein abundance was examined in human and murine atherosclerotic lesions and aortic aneurysms. Apolipoprotein E (ApoE) knockout (-/-) and AQP1-/-ApoE-/- mice were developed and fed Western diet (WD) for 8 and 16 weeks to accelerate the atherosclerosis process. In ApoE-/- and AQP1-/-ApoE-/- mice abdominal aortic aneurysms (AAA) were induced by angiotensin II (ANGII) infusion by osmotic minipumps for 4 weeks. RESULTS: In human atherosclerotic lesions and AAA, AQP1 immunoreactive protein was associated with intralesional small vessels. In ApoE-/- mouse aorta, APQ1 mRNA levels were increased with time on WD (n = 7-9, P < 0.003). Both in murine lesions at the aortic root and in the abdominal aortic aneurysmal wall, AQP1 immunoreactivity was associated with microvascular structures. The atherosclerotic lesion burden was enhanced significantly in ANGII-infused AQP1-/-ApoE-/- mice compared with ApoE-/- mice, but neither incidence nor progression of AAA was different. The aortic lesion burden increased with time on WD but was not different between ApoE-/- and AQP1-/-ApoE-/- mice at either 8 or 16 weeks (n = 13-15). Baseline blood pressure and ANGII-induced hypertension were not different between genotypes. CONCLUSION: AQP1 is expressed in atherosclerotic lesion neovasculature in human and mouse arteries and AQP1 deficiency augments lesion development in ANGII-promoted atherosclerosis in mice. Normal function of AQP1 affords cardiovascular protection.

Normotension, hypertension and body fluid regulation: brain and kidney.

The fraction of hypertensive patients with essential hypertension (EH) is decreasing as the knowledge of mechanisms of secondary hypertension increases, but in most new cases of hypertension the pathophysiology remains unknown. Separate neurocentric and renocentric concepts of aetiology have prevailed without much interaction. In this regard, several questions regarding the relationships between body fluid and blood pressure regulation are pertinent. Are all forms of EH associated with sympathetic overdrive or a shift in the pressure-natriuresis curve? Is body fluid homoeostasis normally driven by the influence of arterial blood pressure directly on the kidney? Does plasma renin activity, driven by renal nerve activity and renal arterial pressure, provide a key to stratification of EH? Our review indicates that (i) a narrow definition of EH is useful; (ii) in EH, indices of cardiovascular sympathetic activity are elevated in about 50% of cases; (iii) in EH as in normal conditions, mediators other than arterial blood pressure are the major determinants of renal sodium excretion; (iv) chronic hypertension is always associated with a shift in the pressure-natriuresis curve, but this may be an epiphenomenon; (v) plasma renin levels are useful in the analysis of EH only after metabolic standardization and then determination of the renin function line (plasma renin as a function of sodium intake); and (vi) angiotensin II-mediated hypertension is not a model of EH. Recent studies of baroreceptors and renal nerves as well as sodium intake and renin secretion help bridge the gap between the neurocentric and renocentric concepts.

The giraffe kidney tolerates high arterial blood pressure by high renal interstitial pressure and low glomerular filtration rate.

BACKGROUND: The tallest animal on earth, the giraffe (Giraffa camelopardalis) is endowed with a mean arterial blood pressure (MAP) twice that of other mammals. The kidneys reside at heart level and show no sign of hypertension-related damage. We hypothesized that a species-specific evolutionary adaption in the giraffe kidney allows normal for size renal haemodynamics and glomerular filtration rate (GFR) despite a MAP double that of other mammals. METHODS: Fourteen anaesthetized giraffes were instrumented with vascular and bladder catheters to measure glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal interstitial hydrostatic pressure (RIHP) was assessed by inserting a needle into the medullary parenchyma. Doppler ultrasound measurements provided renal artery resistive index (RI). Hormone concentrations as well as biomechanical, structural and histological characteristics of vascular and renal tissues were determined. RESULTS: GFR averaged 342 ± 99 mL min(-1) and ERPF 1252 ± 305 mL min(-1) . RIHP varied between 45 and 140 mmHg. Renal pelvic pressure was 39 ± 2 mmHg and renal venous pressure 32 ± 4 mmHg. A valve-like structure at the junction of the renal and vena cava generated a pressure drop of 12 ± 2 mmHg. RI was 0.27. The renal capsule was durable with a calculated burst pressure of 600 mmHg. Plasma renin and AngII were 2.6 ± 0.5 mIU L(-1) and 9.1 ± 1.5 pg mL(-1) respectively. CONCLUSION: In giraffes, GFR, ERPF and RI appear much lower than expected based on body mass. A strong renal capsule supports a RIHP, which is >10-fold that of other mammals effectively reducing the net filtration pressure and protecting against the high MAP.

Selective renal vasoconstriction, exaggerated natriuresis and excretion rates of exosomic proteins in essential hypertension.

AIM: In essential hypertension (EH), the regulation of renal sodium excretion is aberrant. We hypothesized that in mild EH, (i) abnormal dynamics of plasma renin concentration (PRC) and atrial natriuretic peptide (ANP) are responsible for the exaggerated natriuresis, and (ii) exosomic protein patterns reflect the renal tubular abnormality involved in the dysregulation of sodium excretion. METHODS: After 2-week drug washout and 4-day diet, systemic and renal hemodynamics, cardio-renal hormones, glomerular filtration and renal excretion were studied in male patients during saline loading (SL). Excretion rates of exosome-related urinary proteins including apical membrane transporters were determined by proteomics-based methods. RESULTS: In patients, baseline renal vascular conductance was reduced (-44%, P < 0.001), but non-renal vascular conductances were normal while PRC was reduced and ANP elevated (both P < 0.01). SL induced exaggerated natriuresis and reduced PRC (P < 0.01), at normal suppression rate. SL increased arterial pressure in patients (+11 mmHg, P < 0.001), but not in controls; however, during time control, patients showed identical increases (+10 mmHg, P < 0.005) apparently dissociating arterial pressure from natriuresis. At baseline, excretion rates of 438 proteins ranged from 0.07 to 49.8 pmol (mmol creatinine)(-1); 12 proteins were found in all subjects, and 21 proteins were found in two or more patients, but not in controls. In patients, the excretion rate of retinoic acid-induced gene 2 protein was reduced, and excretion rates of other proteins showed increased variances compatible with pathophysiological and clinical applicability. CONCLUSION: Essential hypertension patients exhibit selective renal vasoconstriction and individually varying excretion rates of several exosome-related proteins. Hormonal changes, rather than arterial pressure, seem to cause exaggeration of natriuresis.

Urinary concentration does not exclusively rely on plasma vasopressin. A study between genders. Gender and diurnal urine regulation.

AIM: We investigated the influence of gender on the diurnal regulation of urine production with special focus on vasopressin, oxytocin and prostaglandin E2. METHODS: Fifteen young women in mid-follicular phase and 22 young men (20-33 years) were included. All participants underwent a 24-h circadian inpatient study under standardized conditions for measurements of plasma vasopressin, oxytocin, sodium and osmolality. Urine was fractionally collected for measurements of electrolytes, aquaporin-2 and prostaglandin E2. RESULTS: Plasma vasopressin expressed a diurnal rhythm with a night-time increase in both genders (P < 0.001). The ratio between mean daytime and mean night-time was 1.57 [95% CI: 1.33-1.84] P < 0.001 in men and 1.35 [95% CI: 1.11-1.64] P = 0.002 in women. P-vasopressin was higher in males during the night (P < 0.05). There was no difference in diuresis (P = 0.43), urine osmolality (P = 0.12) or aquaporin-2 excretion (P = 0.80) between genders. We found a trend towards a higher reabsorption of free water in males (P = 0.07). The excretion of prostaglandin E2 was higher in males (P < 0.001). There was no diurnal rhythm in p-oxytocin (P = 0.37) and no correlation to diuresis, urine osmolality or aquaporin-2 excretions. CONCLUSION: Similar urinary flows and osmolalities are associated with levels of plasma vasopressin and renal PGE2, which are higher in males than in females. Oxytocin does not seem to play a role in the diurnal urine formation, whereas prostaglandin E2 could represent a mediator of the gender difference, not only as a mediator of the vasopressin response, but also as an independent factor. These findings need further elucidation.

TRAIL-secreting mesenchymal stem cells promote apoptosis in heat-shock-treated liver cancer cells and inhibit tumor growth in nude mice.

Liver cancer is one of the top six leading causes of cancer-related death. Radiofrequency ablation (RFA) is an important means of treating liver cancer. Residual cancer after RFA is the most frequent cause of recurrence in cases of liver cancer. The main difference between residual cancer cells and ordinary liver cancer cells is that residual cancer cells experience heat shock. The secretable form of trimeric human tumor necrosis factor-related apoptosis-inducing ligand (stTRAIL) induces apoptosis in a variety of human cancers but not in normal tissues. It has shown potent cancer-selective killing activity and has drawn considerable attention as a possible cancer therapy. In the present work, the therapeutic potential of this stTRAIL-based gene therapy was evaluated in hepatocellular carcinoma subjected to RFA. Rat bone marrow mesenchymal stem cells (BM-MSCs) were isolated and transduced with a lentiviral vector encoding stTRAIL (stTRAIL-MSCs, T-MSCs). Cells treated with heat treatment at 43 °C for 45 min served as simulated residual cancer cells. After treatment with T-MSCs, apoptosis in heat-shock-treated liver cancer cells increased significantly, and caspase-3 was upregulated. When T-MSCs were subcutaneously injected into nude mice, they localized to the tumors and inhibited tumor growth, significantly increasing survival. Collectively, the results of the present study indicate that BM-MSC can provide a steady source of stTRAIL and may be suitable for use in the prevention of the recurrence of hepatocellular carcinoma after RFA with secretable trimeric TRAIL.

Salt sensitivity of renin secretion, glomerular filtration rate and blood pressure in conscious Sprague-Dawley rats.

AIM: We hypothesized that in normal rats in metabolic steady state, (i) the plasma renin concentration (PRC) is log-linearly related to Na(+) intake (NaI), (ii) the concurrent changes in mean arterial pressure (MABP) and glomerular filtration rate (GFR) are negligible and (iii) the function PRC = f(NaI) is altered by ß1-adrenoceptor blockade (metoprolol) and surgical renal denervation (DNX). METHODS: In catheterized, conscious rats on low-Na(+) diet (0.004% Na(+)), NaI was increased by up to 120-fold, in four 3-day steps, by intravenous saline infusion. MABP was recorded continuously, PRC measured in arterial blood, and GFR estimated by inulin clearance. RESULTS: Steady states were achieved within 3 days. PRC [mIU L(-1)] was log-linearly related to NaI [mmol kg(-1) day(-1)]: PRC = -9.9 log (NaI) + 22. Set point (22 mIU L(-1) at NaI = 1) and slope (9.9 mIU per decade NaI) were independent of metoprolol administration and DNX. MABP and GFR were markedly salt-sensitive: MABP [mmHg] = 4.9 log (NaI) + 99 (P < 0.01), and GFR [mL min(-1)] = 1.4 log (NaI) + 8.3 (P < 0.01). MABP increased similarly (approx. 10%, P < 0.001) irrespective of pre-treatment. Metoprolol, but not DNX, reduced MABP, HR, and GFR (all P < 0.01). Salt sensitivity of GFR was not observed in DNX rats. CONCLUSION: Log-linear relations to sodium intake exist not only for PRC, but also for MABP and GFR, which per 10-fold increase in sodium intake rose by 5 mmHg and 1.4 mL min(-1) respectively. Steady-state levels of PRC appear independent of renal nerves. MABP and GFR seem markedly salt sensitive in normal rats.

Impact of cold ischemia on cytokines after partial liver transplantation in rats.

To study the impact of cold ischemia on tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) expression after liver transplantation, a stable model of partial liver transplantation in rats was established. The experimental animals were divided into the following groups: a partial hepatectomy control group, a group that received partial liver transplantation after 30 min of cold ischemia (experimental group A), and a group that received a partial liver transplantation after 10 h of cold ischemia (experimental group B). The survival rate was observed in each group. The liver tissue was sampled 1, 2, and 4 days after surgery, and immunohistochemical detection of proliferating cell nuclear antigen TNF-α and IL-10 was performed. The correlation between liver regeneration and TNF-α and IL-10 expression was analyzed, and the impact of the 2 cytokines on rat liver regeneration after liver transplantation was evaluated. The survival rates of rats in the partial hepatectomy control group, in the group that received a partial liver transplantation after 30 min of cold ischemia, and the group that received a partial liver transplantation after 10 h of cold ischemia were 100, 70, and 33.3%, respectively. The expression of proliferating cell nuclear antigen and TNF-α was decreased (P < 0.05), and IL-10 expression was increased (P < 0.05) in animals that received a partial liver transplant after 10 h of cold ischemia compared with that in the animals that received a partial liver transplant after 30 min of cold ischemia. We conclude that with the extension of cold ischemic time, liver regeneration and survival rate after liver transplantation decreased. TNF-α and IL-10 play important regulatory roles in the regeneration process of transplanted livers.

Renal cortical and medullary blood flow during modest saline loading in humans.

AIM: Renal medullary blood flow (RMBF) is considered an important element of sodium homeostasis, but the experimental evidence is incongruent. Studies in anaesthetized animals generally support the concept in contrast to measurements in conscious animals. We hypothesized that saline-induced natriuresis is associated with changes in RMBF in humans. METHODS: After 4 days of low-sodium diet, healthy men were subjected to slow intravenous saline loading (12 µmol kg(-1) min(-1)) for 4 h. Renal medullary and cortical blood flow was determined by positron emission tomography with H(2)(15)O before and after saline infusion using two independent imaging processing methods. One based on a previously published algorithm (voxel peeling) and a novel method based on contrast-enhanced computed tomography (CT). Blood pressure was measured oscillometrically every 10 min. Cardiac output, heart rate and total peripheral resistance were recorded continuously. RESULTS: Saline loading increased the urinary sodium excretion by 3.6-fold (21-76 µmol min(-1) , P < 0.01). The RMBF was 2.6 ± 0.2 mL g(-1) tissue min(-1) before and 2.7 ± 0.1 mL g(-1) tissue min(-1) after saline (n.s.). Cortical blood flow was 3.6 ± 0.1 before and 3.4 ± 0.2 after saline (n.s.). Mean arterial blood pressure did not change measurably (90 vs. 90 mmHg). Bland-Altman analysis suggested agreement between results obtained with voxel peeling (2.6 ± 0.2 mL g(-1) tissue min(-1)) and contrast-enhanced CT (2.0 ± 0.1 mL g(-1) tissue min(-1)). CONCLUSION: In normal humans, changes in RMBF are not necessarily involved in the natriuretic response to modest saline loading. This result is in line with data from conscious rodents.

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms.

Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of ∼1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed.

Randomized clinical trial of splenic radiofrequency ablation versus splenectomy for severe hypersplenism.

BACKGROUND: Radiofrequency ablation (RFA) is a relatively new treatment for hypersplenism. The results of a randomized clinical trial comparing RFA and splenectomy with 5 years of follow-up are reported. METHODS: Fifty-seven patients with hypersplenism due to liver cirrhosis were assigned randomly (in a 1 : 2 ratio) to splenectomy (19 patients) or RFA (38). The RFA group was subdivided according to the percentage of the spleen ablated: less than 50 per cent (9 patients), 50-70 per cent (18) or over 70 per cent (11). Routine blood tests were performed before and after operation, and total spleen volume and ablated volume were measured by contrast-enhanced computed tomography. The primary endpoint of the trial was recurrence of hypersplenism, assessed as platelet and white cell counts, at 5 years after surgery. RESULTS: White cell and platelet counts increased rapidly after intervention in both groups. By 36 months after operation peripheral platelet and white cell counts had decreased significantly in the RFA group compared with the splenectomy group, and declined to baseline levels by 48 months. Hypersplenism recurred after 6 months in patients with less than 50 per cent of the spleen ablated. Blood cell count in the splenectomy group and in patients with more than 50 per cent of the spleen ablated decreased with time after operation, but to levels that remained significantly higher than those before operation (P < 0·050). Splenic volume reached its nadir 12 months after RFA and then increased with time. CONCLUSION: Splenic RFA represents an attractive alternative treatment for hypersplenism induced by liver cirrhosis, particularly when more than 50 per cent of the spleen is ablated.

Uridine adenosine tetraphosphate affects contractility of mouse aorta and decreases blood pressure in conscious rats and mice.

AIM: in the anaesthetized rat, uridine adenosine tetraphosphate (Up(4) A) is a circulating, endothelium-derived vasoconstrictor presumably operating as such in un-anaesthetized animals. The present study investigated the in vivo effects of Up(4) A in conscious mice and rats, and its direct vascular effects in the mouse aorta in vitro. METHODS: in vivo, Up(4) A was given as step-up infusion at rates of 8-512 nmol min(-1) kg(-1) for 30 min periods in chronically catheterized rodents. In vitro, the effect of Up(4) A on rings of mouse aortae mounted in a myograph was tested. RESULTS: high doses of Up(4) A (mice: 512 nmol min(-1) kg(-1) ; rats: 128 nmol min(-1) kg(-1) ) caused hypotension (99 (+/-)4 to 64 7(+/-) mmHg and 114 (+/-) 3 to 108 (+/-) 3 mmHg, respectively, both P < 0.01). In rats, Up(4) A significantly decreased sodium excretion by >75% and potassium excretion by approximately 60% without significant changes in urine flow. Exposure of phenylephrine-contracted rings to increasing concentrations of Up(4) A elicited contraction at 10(-7) and 10(-6) molL(-1) (18 ± 2% and 76 (+/-) 16% respectively); unexpectedly, 10(-5) molL(-1) caused a biphasic response with a contraction (19 6(+/-)2%) followed by a relaxation (-46 (+/-) 6%). No relaxation was observed when the concentration was increased further. Bolus exposure to 10(-5) molL(-1) of Up(4) A caused contraction (+80 (+/-) 2%). Added successively to untreated vessels, increasing concentrations of Up(4) A (10(-7) -10(-5) molL(-1) ) induced a biphasic response of contraction followed by relaxation. CONCLUSION: up(4) A has direct biphasic effects on vascular smooth muscle of the mouse aorta but vasoconstriction dominates at low concentrations. In conscious rodents, step-up infusions of Up(4) A elicit hypotension and electrolyte retention.

Systemic nitric oxide clamping in normal humans guided by total peripheral resistance.

AIM: We wanted to stabilize the availability of nitric oxide (NO) at levels compatible with normal systemic haemodynamics to provide a model for studies of complex regulations in the absence of changes in NO levels. METHODS: Normal volunteers (23-28 years) were infused i.v. with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) at 0.5 mg kg(-1) h(-1). One hour later, the NO donor sodium nitroprusside (SNP) was co-infused in doses eliminating the haemodynamic effects of l-NAME. Haemodynamic measurements included blood pressure (MABP) and cardiac output (CO) by impedance cardiography. RESULTS: l-NAME increased MABP and total peripheral resistance (TPR, 1.02 + or - 0.05 to 1.36 + or - 0.07 mmHg s mL(-1), mean + or - SEM, P < 0.001). With SNP, TPR fell to a stable value slightly below control (0.92 + or - 0.05 mmHg s mL(-1), P < 0.05). CO decreased with l-NAME (5.8 + or - 0.3 to 4.7 + or - 0.3 L min(-1), P < 0.01) and returned to control when SNP was added (6.0 + or - 0.3 L min(-1)). A decrease in plasma noradrenaline (42%, P < 0.01) during l-NAME administration was completely reversed by SNP. Plasma renin activity decreased during l-NAME administration and returned towards normal after addition of SNP. In contrast, plasma aldosterone was increased by l-NAME and remained elevated. CONCLUSIONS: Concomitant NOS inhibition and NO donor administration can be adjusted to maintain TPR at control level for hours. This approach may be useful in protocols in which stabilization of the peripheral supply of NO is required. However, the dissociation between renin and aldosterone secretion needs further investigation.

Blood volume, blood pressure and total body sodium: internal signalling and output control.

Total body sodium and arterial blood pressure (ABP) are mutually dependent variables regulated by complex control systems. This review addresses the role of ABP in the normal control of sodium excretion (NaEx), and the physiological control of renin secretion. NaEx is a pivotal determinant of ABP, and under experimental conditions, ABP is a powerful, independent controller of NaEx. Blood volume is a function of dietary salt intake; however, ABP is not, at least not in steady states. A transient increase in ABP after a step-up in sodium intake could provide a causal relationship between ABP and the regulation of NaEx via a hypothetical integrative control system. However, recent data show that subtle sodium loading (simulating salty meals) causes robust natriuresis without changes in ABP. Changes in ABP are not necessary for natriuresis. Normal sodium excretion is not regulated by pressure. Plasma renin is log-linearly related to salt intake, and normally, decreases in renin secretion are a precondition of natriuresis after increases in total body sodium. Renin secretion is controlled by renal ABP, renal nerve activity and the tubular chloride concentrations at the macula densa (MD). Renal nerve activity is related to blood volume, also at constant ABP, and elevates renin secretion by means of beta(1)-adrenoceptors. Recent results indicate that renal denervation reduces ABP and renin activity, and that sodium loading may decrease renin without changes in ABP, glomerular filtration rate or beta(1)-mediated nerve activity. The latter indicates an essential role of the MD mechanism and/or a fourth mediator of the physiological control of renin secretion.

Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes.

The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper-transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein-protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders.