[Assessment and truth -- how many cardio- and cerebrovascular events are in fact to be led back to taking rofecoxib].
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Cardiovascular Diseases↗
Biomedical subjects
Bernd Mühlbauer
Publications and source records attributed to Bernd Mühlbauer.
Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes.
Diabetic nephropathy is the leading cause of end-stage renal disease. Dopamine receptors are involved in the regulation of renal hemodynamics and may play a role in diabetes-induced hyperfiltration. To test this hypothesis, we investigated the renal effect of a dopamine D3 receptor antagonist (D3-RA) in hypertensive type II diabetic SHR/N-cp rats. Lean and obese SHR/N-cp rats were randomly assigned to D3-RA, angiotensin-converting enzyme inhibitor (ACE-i), or D3-RA+ACE-i treatment or control conditions. Treated animals were given the D3-RA A-437203 (10 mg/kg/body weight (BW)/day) or the ACE-i trandolapril (0.3 mg/kg BW/day) or a combination of both. At 6 months following perfusion, fixed kidneys were analyzed by morphological and stereological methods. Indices of renal damage (glomerulosclerosis, glomerulosclerosis damage index (GSI), tubulointerstitial and vascular damage), glomerular geometry and functional variables such as urinary albumin excretion, glomerular filtration rate, blood pressure, blood chemistry and BW were determined. The GSI (score 0-4) was significantly higher (P<0.05) in untreated diabetic animals (1.62+/-0.3) compared to nondiabetic controls (0.4+/-0.2) and the treatment groups (D3-RA: 0.31+/-0.12; ACE-i: 0.29+/-0.1; combination treatment: 0.12+/-0.01). Urinary albumin excretion (mg/24 h) was higher in untreated diabetic controls (102+/-19) compared to nondiabetic controls (31+/-12) and the treatment groups (D3-RA: 44+/-15; ACE-i: 41+/-13; combination treatment: 15+/-8). Mean glomerular volume was higher in untreated diabetic animals compared to nondiabetic controls and to the treatment groups. Desmin expression, a marker of podocyte damage, was elevated in untreated diabetic controls and diminished in all treatment groups. These data suggest that in a model of type II diabetes, the dopamine D3-RA had a beneficial effect on renal morphology and albuminuria, which was comparable in magnitude to that of ACE-i treatment.
Angiotensin-Converting Enzyme Inhibitors↗
Adenosine and kidney function.
In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.
Adenosine↗
Absence of amino acid-induced glomerular hyperfiltration in dopamine D3 receptor knockout mice.
Pharmacological inhibition of receptors of the dopamine D2-like family has been shown to abolish the glomerular hyperfiltration in response to amino acids. To further discriminate between the receptor subtypes within the D2-like family, we investigated the effects of amino acid infusion on renal function in dopamine D3 receptor knockout (-/-) mice. In clearance experiments pentobarbital-anesthetized D3 receptor (-/-) and wild-type (+/+) mice were infused with Ringer solution at baseline, followed by a continuous infusion of mixed amino acids (10%). Baseline glomerular filtration rate (GFR), assessed by renal clearance of [3H]-inulin, was the same in D3 receptor (-/-) mice (0.56+/-0.08 ml/min per g kidney weight) and wild-type animals (0.56+/-0.04 ml/min per g kw). During infusion of amino acids, GFR was significantly elevated by 50% in D3 receptor (+/+) mice. In contrast, this amino acid-induced response of GFR was abolished in D3 receptor (-/-) mice. Baseline urinary water and sodium excretion was not significantly different in both groups of mice. As observed in GFR, these renal excretory parameters were significantly elevated during amino acid infusion in D3 receptor (+/+) but not in D3 receptor (-/-) mice. Time controls, constantly infused with Ringer solution, did not show significant changes in GFR, renal water or sodium excretion during the entire experiment, indicating stable experimental conditions. Taken together, the data underline the involvement of dopamine D2-like receptors in the renal response to amino acid infusion and, in addition, attribute this effect to the dopamine D3 receptor subtype.
Amino Acids↗
Effect of dopamine D3 receptor blockade on renal function and glomerular size in diabetic rats.
Dopamine D2-like receptors, including D2, D3, and D4 receptors, are involved in the regulation of glomerular hyperfiltration due to diabetes mellitus. These hemodynamic alterations represent a risk factor for the later development of diabetic nephropathy. The aim of the present study was to determine whether the D3 receptor subtype modulates the diabetes-induced increase in glomerular filtration rate (GFR) in rats. Renal function was studied in Sprague-Dawley rats 14 days after induction of a moderate diabetes mellitus (DM) by streptozotocin and in non-diabetic controls (CON). Rats were orally treated either with the peripherally acting, selective dopamine D3 receptor antagonist BSF 135170 (BSF, 10 mg/kg per day for 2 weeks) or with vehicle (VHC). Perfusion-fixed kidneys were used for estimation of glomerular volume. In conscious rats, which were treated with BSF, the DM-induced increase in fluid intake, urinary output, and renal sodium excretion was significantly less pronounced than in the vehicle group (DM-VHC). In the clearance experiments, GFR in CON was about 0.84+/-0.04 ml/min per 100 g body weight. The DM-VHC group presented a significant glomerular hyperfiltration (1.09+/-0.04 ml/min per 100 g body weight). Treatment with BSF significantly lowered GFR towards levels of CON. The estimated glomerular volume was 0.73+/-0.03 x 10(6) microm3 in the CON-VHC group and 0.86+/-0.04 x 10(6) microm3 in the DM-VHC animals. Interestingly, treatment with BSF decreased the glomerular volume in both groups. Irrespective of BSF treatment, kidney wet weight related to body weight was about 36% higher in DM animals compared with CON animals. We conclude that dopamine D3 receptors represent a target for the modulation of diabetes-induced glomerular hyperfiltration. Therefore, the results encourage the testing of the possible beneficial effects of long-term D3 receptor blockade on the development of diabetic nephropathy.
Animals↗
Regulation of renal adenosine excretion in humans--role of sodium and fluid homeostasis.
BACKGROUND: Adenosine is a vasoactive metabolite of ATP hydrolysis that is involved in the regulation of renal haemodynamics, tubular reabsorption and renin release. Elevated tissue levels are found under conditions of increased metabolic load, ischaemia or renal injury. Urinary adenosine excretion (EADO) may therefore provide a sensitive marker of renal functional impairment in allograft rejection and kidney disease. To provide a basis for evaluation of EADO in clinical settings, we investigated, in an intra-individual, crossover clinical trial the physiological variability and regulation of EADO in response to altered sodium and fluid balance. METHODS: Twelve healthy volunteers were randomized to normal (ad libitum), low (<5 g/day) or high (supplementation of 100 mg/kg/day) sodium chloride diets for 8 days prior to assessment of renal haemodynamics and tubular function in standard clearance investigations. Following baseline periods, fluid homeostasis was altered independently by acute oral water load. EADO was determined in 24 h urine collections and during clearance investigations. RESULTS: Mean EADO in humans was 3.2+/-0.2 micromol/ 24 h during euvolaemia and normal sodium intake. A weak correlation was found between sodium load and EADO. In clearance experiments, variation in EADO was <1.3-fold, despite profound alterations in sodium intake. EADO was independent of urinary flow rate. Renal haemodynamics were not significantly altered by dietary regimen or by acute volume load. CONCLUSION: In summary, the physiological variability of EADO is remarkably small in humans. We demonstrate that even profound alterations in sodium and fluid homeostasis do not significantly affect EADO. These data provide a basis for evaluation of elevated EADO as a marker of renal injury in various clinical settings.
Adenosine↗
Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats.
BACKGROUND: The increase in glomerular filtration rate (GFR) induced by amino acid infusion is attenuated in rats with chronic renal denervation. The aim of the present study was to investigate whether renal denervation abrogates glomerular hyperfiltration occurring in the early state of diabetes mellitus. METHODS: Sprague-Dawley rats were subjected to bilateral renal denervation before induction of diabetes mellitus (DM) by streptozotocin. Clearance experiments were performed 2 weeks after onset of moderate DM. Glomerular volume was estimated following paraformaldehyde fixation in rat kidney slices from measurement of cross-sectional area of Bowman's capsule. RESULTS: GFR in non-diabetic rats with intact nerves (CON-INN) was 0.82+/-0.03 ml.min(-1).100 g(-1) body weight. Diabetic animals with innervated kidneys presented a significant glomerular hyperfiltration (1.13+/-0.03 ml.min(-1).100 g(-1) body weight), while renal denervation in diabetic rats lowered GFR towards levels of CON-INN (0.88+/-0.03 ml.min(-1).100 g(-1) body weight). Estimated glomerular volume amounted to 0.69+/-0.03.10(6) micro m(3) in the CON-INN group and was significantly higher in diabetic animals with intact renal nerves (0.86+/-0.04.10(6) microm(3)). Interestingly, renal denervation prevented the glomerular enlargement due to DM. CONCLUSIONS: Renal nerves appear to be significantly involved in the mediation of glomerular hyperfiltration in experimental DM. If the kidney is prevented from sympathetic nerve stimulation, structural changes due to early diabetic nephropathy, i.e. glomerular enlargement, are abolished.
Analysis of Variance↗
Subapical localization of the dopamine D3 receptor in proximal tubules of the rat kidney.
The dopamine D3 receptor (D3R), intensively studied in neuroscience, also plays an important role in the regulation of renal and cardiovascular function. In contrast to functional findings, less information is available on its localization in the kidney. Neither RT-PCR studies nor radioligand binding assays are suitable to selectively determine the distribution of renal D3R at the level of cellular or even subcellular structures. We studied the renal D3R distribution in Sprague-Dawley rats by a polyclonal antiserum directed against an epitope in the third intracytoplasmic loop. D3R immunoreactivity was detected by indirect immunofluorescence and confocal laser scanning microscopy. D3R staining was confined to the renal cortex and occurred in proximal convoluted tubules near or in direct connection with the urinary pole of the glomeruli. The fluorescent spots were restricted to the subapical portion of the proximal tubular cells. Double staining with the F-actin marker phalloidin revealed a localization of the D3R below the brush border region. However, staining by anti-beta1/beta2-adaptins, recognizing clathrin-coated compartments, did not correspond to the distribution of the D3R signal. This is the first description of a D3R accumulation in a cytoplasmic pool in the kidney, probably corresponding to a recycling mechanism or storage compartment.
Animals↗
Role of the renin-angiotensin system in the compensation of quinpirole-induced blood pressure decrease.
The dopamine D(2)-like receptor agonist quinpirole has been reported to lower blood pressure. This effect appears to be mediated via activation of presynaptic D(2)-like receptors inhibiting the stimulated neural norepinephrine release. The aim of the present study was to investigate the role of renal nerves and the renin-angiotensin system (RAS) in the blood pressure lowering effect of quinpirole. Therefore, clearance experiments using different doses of quinpirole (0.3 to 100 microg/kg/min) were performed in thiopental-anesthetized rats with intact kidneys (INN) or 5 to 7 days after bilateral renal denervation (DNX). The functional involvement of the RAS in the blood pressure lowering effect of quinpirole was determined in rats pretreated with a subpressor dose of angiotensin II (10 microg/kg/min) or in rats pretreated with the angiotensin II (AT(1)) receptor antagonist losartan, in a subdepressor dose (10 microg/kg/min). Quinpirole dose-dependently decreased mean arterial blood pressure (MAP) by up to 29%. This blood pressure lowering effect of quinpirole was observed at lower doses in DNX rats when compared with INN animals (ED(50): 0.98 microg/kg/min in DNX vs. 6.02 microg/kg/min in INN animals). Quinpirole in a dose of 3 microg/kg/min, which did not affect MAP in vehicle treated INN rats, significantly reduced MAP in rats with losartan pretreatment. In DNX rats pretreated with angiotensin II the MAP-response to the infusion of 3 microg/kg/min quinpirole was clearly attenuated in comparison with untreated DNX animals. Our data show that stimulation of dopamine D(2)-like receptors dose-dependently decreased blood pressure, which was potentiated by both interruption of the renal innervation and AT(1) receptor blockade, while exogenous ANG II restored the enhancement of the blood pressure response to quinpirole. We conclude that the increased vasodilatory effect of quinpirole after renal denervation might depend on a decreased activity of the RAS.
Anesthesia↗
Dopamine D3 receptor mRNA and renal response to D3 receptor activation in spontaneously hypertensive rats.
Defective dopamine receptors may be involved in the development of hypertension. Recently, it has been shown that gene expression and function of the renal dopamine D3 receptor is impaired in salt-sensitive Dahl rats, a model of salt-dependent hypertension. Here, the functional response to D3 receptor activation was investigated in spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto rats (WKY). In addition, expression of the D3 receptor gene was studied in both rat strains. In clearance experiments, Ringer solution was infused at baseline in thiopental-anesthetized SHR and WKY (each n = 8), followed by an infusion of R(+)-7-hydroxy-dipropylaminotetralin (DPAT), a specific D3 receptor agonist. DPAT was infused in two consecutive doses of 0.01 and 0.1 microg/min per kg body weight. During the entire experiment mean arterial blood pressure was significantly higher (1.5-fold) in adult SHR when compared to age-matched WKY. In both groups DPAT infusion induced a similar dose-dependent increase in urinary flow rate and sodium excretion by a maximum of 2.3-fold and 3.5-fold, respectively. DPAT also increased the glomerular filtration rate in both SHR and WKY. Reverse transcription-polymerase chain reaction studies of whole kidney samples showed no significant differences between young prehypertensive and adult hypertensive SHR when compared to age-matched normotensive WKY. In summary, pharmacological dopamine D3 receptor activation induces a uniform renal response in SHR and WKY. Together with the similar D3 receptor gene expression in both rat strains, which is independent of age or blood pressure levels, the results do not support the notion that the dopamine D3 receptor system is involved in the pathogenesis of hypertension in the SHR model.
Animals↗
Tissue levels of S-adenosylhomocysteine in the rat kidney: effects of ischemia and homocysteine.
Most S-adenosylmethionine (AdoMet)-dependent methyltransferases are regulated in vivo by the AdoMet/S-adenosylhomocysteine (AdoHcy) ratio, also termed as "methylation potential." Since adenosine inhibits in vitro AdoHcy hydrolysis and since adenosine tissue levels increase during hypoxia, it can be predicted that AdoHcy levels may increase in the rat kidney in parallel of those of adenosine. Therefore, the present investigation was performed to assess changes of renal AdoHcy and AdoMet tissue contents during ischemia and after administration of adenosine and homocysteine or both in the ischemic rat kidney. In anesthetized rats ischemia of the kidney was induced by renal artery occlusion for various time intervals. Adenosine and homocysteine were infused into the renal artery of the ischemic kidney. To induce a hyperhomocysteinemia homocysteine was continuously infused. The kidneys were removed and immediately snap-frozen. Tissue contents of AdoHcy, AdoMet, adenosine and adenine nucleotides were analyzed by means of HPLC. Under normoxic condition the tissue contents of AdoHcy, AdoMet and adenosine were 0.7+/-0.05, 44.1+/-1.0 and 3.8+/-0.1nmol/g wet weight, respectively. Renal ischemia for 30min resulted in an increase of AdoHcy levels from 0.7+/-0.05 to 9.1+/-0.6nmol/g wet weight and in a dramatic decrease of the AdoMet/AdoHcy ratio and energy charge from 65.1+/-5.6 to 2.8+/-0.2 and from 0.87+/-0.01 to 0.25+/-0.01, respectively. Application of exogenous adenosine into the ischemic kidney did not result in further AdoHcy accumulation. However, when homocysteine was infused into the ischemic kidney, AdoHcy increased five-fold above control levels, during 5min ischemia. Systemic infusion of homocysteine leads to a reduction of the methylation potential also in the normoxic kidney. We conclude that (i) the methylation potential in the kidney is markedly reduced during ischemia, mainly due to accumulation of AdoHcy; (ii) elevation of AdoHcy tissue content during ischemia is the result of the inhibition of AdoHcy hydrolysis; (iii) homocysteine is rate limiting for AdoHcy synthesis in the ischemic kidney; (iv) under normoxic conditions hyperhomocysteinemia can affect the methylation potential in the renal tissue.
Adenosine↗
Age dependency of renal function in CD-1 mice.
Renal function was studied in mice of different ages. In metabolic cage experiments, the renal electrolyte excretion was similar in young (n = 8; 5- to 7-wk-old) and adult (n = 6; 20- to 22-wk-old) CD-1 (ICR) BR mice, whereas spontaneous drinking volume and urinary flow rate were significantly higher in the adult compared with the young mice. Subsequently, the renal functional reserve was investigated by amino acid (AA) infusion (10%) in anesthetized young (n = 8) and adult (n = 6) mice. Because the body weight of adult mice was significantly higher than that of young animals, one group of adult mice (n = 8) received 12.5% AA to ensure that the dose of AA related to body weight was similar in both groups. Young animals constantly infused with Ringer solution served as time controls (n = 8). Glomerular filtration rate (GFR) at baseline was similar in each group. Because of AA, GFR significantly increased in young mice but not in both groups of adult animals, whereas in time controls GFR remained constant. Urinary flow rate and sodium excretion were elevated by AA in young and adult mice. We conclude that in CD-1 mice the first signs of age-related changes in kidney function concern alterations in renal hemodynamics, whereas renal tubular function appears to be preserved.
Aging↗
Dopamine D(3) receptors and salt-dependent hypertension.
Alterations in the dopaminergic system may contribute to the pathogenesis of hypertension. Dopamine D(3) receptors have been shown to be involved in the regulation of sodium balance and hemodynamics in rodents. For determining the role of D(3) receptors in salt-dependent hypertension, clearance experiments were performed in anesthetized salt-sensitive (DS) and salt-resistant (DR) Dahl rats that were fed a standard diet with either normal (0.2%) or high (4%) sodium content for 21 to 26 d, which induced hypertension in DS but not in DR rats. The D(3) receptor agonist R(+)-7-hydroxydipropyl-aminotetralin (7-OH-DPAT) increased GFR by up to 35% and urinary sodium excretion by up to 4.4-fold in DR rats that were on both normal and high-sodium diet. 7-OH-DPAT-induced natriuresis also was observed in DS rats that were on normal diet but not in hypertensive DS rats that were on high-salt diet. No GFR response to 7-OH-DPAT was found in DS rats, irrespective of sodium diet. The diminished functional response to D(3) receptor stimulation in DS rats was associated with a significantly lower [(3)H]-7-OH-DPAT binding to renal membrane protein when comparing DS with DR rats. Consequently, DR rats were treated with BSF 135170, a novel, highly selective D(3) receptor antagonist, for 29 d. Whereas no change in systolic BP was observed during normal diet, high sodium intake significantly increased BP by almost 40 mmHg. In summary, both expression and function of the renal dopamine D(3) receptor are impaired in salt-sensitive Dahl rats. Together with the induction of salt-dependent hypertension in genetically salt-resistant Dahl rats by D(3) receptor blockade, the data strongly suggest that the deficiency in dopamine D(3) receptors represents an important pathophysiological factor in the development of salt-dependent hypertension.
Animals↗