D L Mattson

Medical College of Wisconsin, Milwaukee, Wisconsin, United States

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Publications (87)361.51 Total impact

  • Satarupa Das, David L Mattson
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    ABSTRACT: Administration of exogenous L-Arginine (L-Arg) attenuates Angiotensin II (AngII)-mediated hypertension and kidney disease in rats. The present study assessed renal hemodynamics and pressure-diuresis-natriuresis in anesthetized rats infused with vehicle, AngII (20 ng/kg/min, iv) or AngII + L-Arg (300 μg/kg/min, iv). Increasing renal perfusion pressure (RPP) from approximately 100 to 140 mmHg resulted in a 9-10 fold increase in urine flow and sodium excretion rate in control animals. In comparison, AngII infusion significantly reduced renal blood flow (RBF) and glomerular filtration rate (GFR) by 40-42% and blunted the pressure-dependent increase in urine flow and sodium excretion rate by 54-58% at elevated RPP. Supplementation of L-Arg reversed the vasoconstrictor effects of AngII and restored pressure-dependent diuresis to levels not significantly different from control rats.Experiments in isolated aortic rings were performed to assess L-Arg effects on the vasculature. Dose-dependent contraction to AngII (10(-10) M to 10(-7) M) was observed with a maximal force equal to 27±3% of the response to 10(-5) M phenylephrine. Contraction to 10(-7) M AngII was blunted by 75±3% with 10(-4) M L-Arg. The influence of L-Arg to blunt AngII mediated contraction was eliminated by endothelial denudation or incubation with nitric oxide synthase inhibitors. Moreover, the addition of 10(-3) M cationic or neutral amino acids, which compete with L-Arg for cellular uptake, blocked the effect of L-Arg. Anionic amino acids did not influence the effects of L-Arg on AngII-mediated contraction. These studies indicate that L-Arg blunts AngII-mediated vascular contraction by an endothelial- and NOS-dependent mechanism involving cellular uptake of L-Arg. This article is protected by copyright. All rights reserved.
    Clinical and Experimental Pharmacology and Physiology 01/2014; · 2.16 Impact Factor
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    ABSTRACT: Various stimuli, including hormones and growth factors, modulate epithelial sodium channels (ENaCs), which fine-tune Na(+) absorption in the kidney. Members of the EGF family are important for maintaining transepithelial Na(+) transport, but whether EGF influences ENaC, perhaps mediating salt-sensitive hypertension, is not well understood. Here, the ENaC inhibitor benzamil attenuated the development of hypertension in Dahl salt-sensitive rats. Feeding these salt-sensitive rats a high-salt diet led to lower levels of EGF in the kidney cortex and enhanced the expression and activity of ENaC compared with feeding a low-salt diet. To directly evaluate the role of EGF in the development of hypertension and its effect on ENaC activity, we infused EGF intravenously while continuously monitoring BP of the salt-sensitive rats. Infusion of EGF decreased ENaC activity, prevented the development of hypertension, and attenuated glomerular and renal tubular damage. Taken together, these findings indicate that cortical EGF levels decrease with a high-salt diet in salt-sensitive rats, promoting ENaC-mediated Na(+) reabsorption in the collecting duct and the development of hypertension.
    Journal of the American Society of Nephrology 04/2013; · 8.99 Impact Factor
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    ABSTRACT: Hypertension and renal damage in Dahl SS rats are associated with increased infiltrating immune cells in the kidney. To examine the role of infiltrating immune cells in this disease process, a zinc finger nuclease targeting bases 672-706 of recombination activating gene 1 (Rag1) was injected into the pronucleus of Dahl SS (SS/JrHsdMcwi) strain embryos and implanted in pseudopregnant females. This strategy yielded a rat strain with a 13 base frame-shift mutation in the target region of Rag1 and a deletion of immunoreactive Rag1 protein in the thymus. Flow cytometry demonstrated that the Rag1 null mutant rats have a significant reduction in T- and B-lymphocytes in the circulation and spleen. Studies were performed on SS and Rag1 null rats fed a 4.0% NaCl diet for three weeks. The infiltration of T-cells into the kidney following high salt was significantly blunted in the Rag1 null rats (1.7±0.6 x 10(5) cells/kidney) compared to the Dahl SS (5.6±0.9 x 10(5) cells/kidney). Accompanying the reduction in infiltration of immune cells in the kidney, mean arterial blood pressure and urinary albumin excretion rat were significantly lower in Rag1 null mutants (158±3 mmHg and 60±16 mg/day, respectively) than in SS rats (180±11 mmHg and 251±37 mg/day). Finally, a histological analysis revealed that the glomerular and tubular damage in the kidneys of the SS rats fed high salt was also attenuated in the Rag1 mutants. These studies demonstrate the importance of renal infiltration of immune cells in the pathogenesis of hypertension and renal damage in Dahl SS rats.
    AJP Regulatory Integrative and Comparative Physiology 01/2013; · 3.28 Impact Factor
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    ABSTRACT: Multiple genes and pathways are involved in the pathogenesis of hypertension. Epigenomic studies of hypertension are beginning to emerge and hold great promise of providing novel insights into the mechanisms underlying hypertension. Epigenetic marks or mediators including DNA methylation, histone modifications, and noncoding RNA can be studied at a genome or near-genome scale using epigenomic approaches. At the single gene level, several studies have identified changes in epigenetic modifications in genes expressed in the kidney that correlate with the development of hypertension. Systematic analysis and integration of epigenetic marks at the genome-wide scale, demonstration of cellular and physiological roles of specific epigenetic modifications, and investigation of inheritance are among the major challenges and opportunities for future epigenomic and epigenetic studies of hypertension.
    Seminars in Nephrology 01/2013; 33(4):392–399. · 2.83 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) play important roles in biological development and disease. Much less is known about their role in normal adult physiology. The proximal convoluted tubule (PCT) and the medullary thick ascending limb (mTAL) in the kidney consist of epithelial cells with different transport activities. We identified 55 possible miRNA-target pairs of which the miRNAs and their predicted target proteins, many of which are involved in epithelial transport, were inversely enriched in PCT and mTAL. Some miRNAs appeared to have synergistic effects on shared targets. miR-192 and its predicted target the β-1 subunit of Na(+)/K(+)-ATPase (Atp1b1), an enzyme providing the driving force for tubular transport, were inversely enriched in kidney regions. In mice, knockdown of miR-192 led to up-regulation of Atp1b1 protein. When mice were fed with a high-salt diet, knockdown of miR-192 blunted the adaptational increase of urine output. Interestingly, miR-192 appeared to target Atp1b1 through the 5'-, rather than 3'-untranslated region. The study suggests a novel physiological mechanism in which miR-192 suppresses Na(+)/K(+)-ATPase and contributes to renal handling of fluid balance. It supports an important role of miRNAs in determining cellular characteristics that may appear subtle yet are physiologically critical.
    Nucleic Acids Research 12/2012; · 8.28 Impact Factor
  • Niwanthi W Rajapakse, David L Mattson
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    ABSTRACT: PURPOSE OF REVIEW: L-Arginine (L-Arg) is the substrate for nitric oxide (NO) formation. Reduced NO bioavailability, particularly within the renal circulation, has been identified as a key factor in the pathogenesis of hypertension. This review focuses on the pathogenic role of abnormal L-Arg transport, particularly within the kidney, in hypertension. RECENT FINDINGS: Most recent studies have attempted to restore NO bioavailability in cardiovascular diseases with the use of antioxidants to reduce NO inactivation, but this approach has failed to provide beneficial effects in the clinical setting. We argue that this may be due to reduced NO formation in hypertension, which has largely been overlooked as a means of restoring NO bioavailability in cardiovascular diseases. Recent data indicate that renal L-Arg transport plays an important role in regulating both renal perfusion and function and the long-term set point of arterial pressure in health. Perturbations in the renal L-Arg transport system can give rise to abnormal renal perfusion and function, initiating hypertension and related renal damage. SUMMARY: Accordingly, we propose that L-Arg transporters are a new treatment target in hypertension and in disease states where renal NO bioavailability is disturbed.
    Current opinion in nephrology and hypertension 10/2012; · 3.96 Impact Factor
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    ABSTRACT: Low renal nitric oxide (NO) bioavailability contributes to the development and maintenance of chronic hypertension. We investigated whether impaired l-arginine transport contributes to low renal NO bioavailability in hypertension. Responses of renal medullary perfusion and NO concentration to renal arterial infusions of the l-arginine transport inhibitor l-lysine (10 μmol·kg(-1)·min(-1); 30 min) and subsequent superimposition of l-arginine (100 μmol·kg(-1)·min(-1); 30 min), the NO synthase inhibitor N(G)-nitro-l-arginine (2.4 mg/kg; iv bolus), and the NO donor sodium nitroprusside (0.24 μg·kg(-1)·min(-1)) were examined in Sprague-Dawley rats (SD) and spontaneously hypertensive rats (SHR). Renal medullary perfusion and NO concentration were measured by laser-Doppler flowmetry and polarographically, respectively, 5.5 mm below the kidney surface. Renal medullary NO concentration was less in SHR (53 ± 3 nM) compared with SD rats (108 ± 12 nM; P = 0.004). l-Lysine tended to reduce medullary perfusion (-15 ± 7%; P = 0.07) and reduced medullary NO concentration (-9 ± 3%; P = 0.03) while subsequent superimposition of l-arginine reversed these effects of l-lysine in SD rats. In SHR, l-lysine and subsequent superimposition of l-arginine did not significantly alter medullary perfusion or NO concentration. Collectively, these data suggest that renal l-arginine transport is impaired in SHR. Renal l-[(3)H]arginine transport was less in SHR compared with SD rats (P = 0.01). Accordingly, we conclude that impaired arginine transport contributes to low renal NO bioavailability observed in the SHR kidney.
    AJP Renal Physiology 03/2012; 302(12):F1554-62. · 4.42 Impact Factor
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    ABSTRACT: NAD(P)H oxidase has been shown to be important in the development of salt-sensitive hypertension. Here, we show that the expression of a subunit of NAD(P)H oxidase, p67(phox), was increased in response to a high-salt diet in the outer renal medulla of the Dahl salt-sensitive (SS) rat, an animal model for human salt-sensitive hypertension. The higher expression of p67(phox), not the other subunits observed, was associated with higher NAD(P)H oxidase activity and salt sensitivity in SS rats compared with a salt-resistant strain. Genetic mutations of the SS allele of p67(phox) were found in the promoter region and contributed to higher promoter activity than that of the salt-resistant strain. To verify the importance of p67(phox), we disrupted p67(phox) in SS rats using zinc-finger nucleases. These rats exhibited a significant reduction of salt-sensitive hypertension and renal medullary oxidative stress and injury. p67(phox) could represent a target for salt-sensitive hypertension therapy.
    Cell metabolism 02/2012; 15(2):201-8. · 17.35 Impact Factor
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    ABSTRACT: The nephron number at birth is a quantitative trait that correlates inversely with the risk of hypertension and chronic kidney disease later in life. During kidney development, the nephron number is controlled by multiple factors including genetic, epigenetic, and environmental modifiers. Premature birth, which represents more than 12% of annual live births in the United States, has been linked to low nephron number and the development of hypertension later in life. In this report, we describe the development of a mouse model of prematurity-induced reduction of nephron number. Premature mice, delivered 1 and 2 days early, have 17.4 ± 2.3% (n = 6) and 23.6 ± 2% (n = 10) fewer nephrons, respectively, when compared with full-term animals (12,252 ± 571 nephrons/kidney, n = 10). After 5 weeks of age, the mice delivered 2 days premature show lower real-time glomerular filtration rate (GFR, 283 ± 13 vs 389 ± 26 μL/min). The premature mice also develop hypertension (mean arterial pressure [MAP], 134 ± 18 vs 120 ± 14 mm Hg) and albuminuria (286 ± 83 vs 176 ± 59 μg albumin/mg creatinine). This mouse model provides a proof of concept that prematurity leads to reduced nephron number and hypertension, and this model will be useful in studying the pathophysiology of prematurity-induced nephron number reductions and hypertension.
    Translational research : the journal of laboratory and clinical medicine. 02/2012; 159(2):80-9.
  • Biophysical Journal 01/2012; 102(3):651-. · 3.67 Impact Factor
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    ABSTRACT: Sodium reabsorption via the epithelial Na(+) channel (ENaC) in the aldosterone-sensitive distal nephron plays a central role in the regulation of body fluid volume. Previous studies have indicated that arachidonic acid (AA) and its metabolite 11,12-EET but not other regioisomers of EETs inhibit ENaC activity in the collecting duct. The goal of this study was to investigate the endogenous metabolism of AA in cultured mpkCCD(c14) principal cells and the effects of these metabolites on ENaC activity. Liquid chromatography/mass spectrometry analysis of the mpkCCD(c14) cells indicated that these cells produce prostaglandins, 8,9-EET, 11,12-EET, 14,15-EET, 5-HETE, 12/8-HETE, and 15-HETE, but not 20-HETE. Single-channel patch-clamp experiments revealed that 8,9-EET, 14,15-EET, and 11,12-EET all decrease ENaC activity. Neither 5-, 12-, nor 15-HETE had any effect on ENaC activity. Diclofenac and ibuprofen, inhibitors of cyclooxygenase, decreased transepithelial Na(+) transport in the mpkCCD(c14) cells. Inhibition of cytochrome P-450 (CYP450) with MS-PPOH activated ENaC-mediated sodium transport when cells were pretreated with AA and diclofenac. Coexpression of CYP2C8, but not CYP4A10, with ENaC in Chinese hamster ovary cells significantly decreased ENaC activity in whole-cell experiments, whereas 11,12-EET mimicked this effect. Thus both endogenously formed EETs and their exogenous application decrease ENaC activity. Downregulation of ENaC activity by overexpression of CYP2C8 was PKA dependent and was prevented by myristoylated PKI treatment. Biotinylation experiments and single-channel analysis revealed that long-term treatment with 11,12-EET and overexpression of CYP2C8 decreased the number of channels in the membrane. In contrast, the acute inhibitory effects are mediated by a decrease in the open probability of the ENaC. We conclude that 11,12-EET, 8,9-EET, and 14,15-EET are endogenously formed eicosanoids that modulate ENaC activity in the collecting duct.
    AJP Renal Physiology 06/2011; 301(3):F672-81. · 4.42 Impact Factor
  • N W Rajapakse, D L Mattson
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    ABSTRACT: To examine whether reduced renal arginine transport increases the responsiveness of the renal circulation to angiotensin II in salt sensitivity, renal perfusion responses to angiotensin II were examined in the presence of L-arginine transport inhibitor, L-lysine and subsequent L-arginine in Sprague Dawley (SD) and Dahl salt-sensitive (Dahl S) rats. Laser Doppler probes and a transonic flow probe were used to measure regional renal perfusion and total renal perfusion respectively. Renal perfusion responses to intravenous (i.v.) angiotensin II were sequentially examined under control conditions and during i.v. infusion of L-lysine, L-arginine or nitric oxide synthase inhibitor, N(G)-nitro-L-arginine. Angiotensin II (10 and 100 ng kg(-1) min(-1) , i.v.) reduced total renal (-10 ± 3 and -36 ± 5%) and cortical (-10 ± 2 and -28 ± 4%) but not medullary perfusion in SD rats. In these rats L-lysine enhanced the renal perfusion response (P = 0.003), whereas subsequent L-arginine reversed this effect (P = 0.04). Angiotensin II reduced total renal, cortical and medullary perfusion in Dahl S rats. In Dahl S rats fed high salt, L-lysine did not affect renal perfusion responses to angiotensin II, but subsequent L-arginine blunted the renal blood flow response (P = 0.01) and increased the medullary perfusion during angiotensin II infusion (P = 0.006). Intact renal L-arginine transport attenuates the vasoconstrictor effects of circulating angiotensin II in the renal cortex in SD rats. L-arginine also plays an important role in protecting the renal medullary circulation from the ischemic effects of angiotensin II in Dahl S rats.
    Acta Physiologica 06/2011; 203(3):391-400. · 4.38 Impact Factor
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    ABSTRACT: The present studies examined the role and mechanism of action of infiltrating T lymphocytes in the kidney during salt-sensitive hypertension. Infiltrating T lymphocytes in the Dahl salt-sensitive (SS) kidney significantly increased from 7.2 ± 1.8 × 10(5) cells/2 kidneys to 18.2 ± 3.9 × 10(5) cells/2 kidneys (n = 6/group) when dietary NaCl was increased from 0.4 to 4.0%. Furthermore, the expression of immunoreactive p67(phox), gp91(phox), and p47(phox) subunits of NADPH oxidase was increased in T cells isolated from the kidneys of rats fed 4.0% NaCl. The urinary excretion of thiobarbituric acid-reactive substances (TBARS; an index of oxidative stress) also increased from 367 ± 49 to 688 ± 92 nmol/day (n = 8/group) when NaCl intake was increased in Dahl SS rats. Studies were then performed on rats treated with a daily injection of vehicle (5% dextrose) or tacrolimus (0.25 mg·kg(-1)·day(-1) ip), a calcineurin inhibitor that suppresses immune function, during the period of high-NaCl intake (n = 5/group). In contrast to the immune cell infiltration, increased NADPH oxidase expression, and elevated urine TBARS excretion in vehicle-treated Dahl SS fed high salt, these parameters were unaltered as NaCl intake was increased in Dahl SS rats administered tacrolimus. Moreover, tacrolimus treatment blunted high-salt mean arterial blood pressure and albumin excretion rate (152 ± 3 mmHg and 20 ± 9 mg/day, respectively) compared with values in dextrose-treated Dahl SS rats (171 ± 8 mmHg and 74 ± 28 mg/day). These experiments indicate that blockade of infiltrating immune cells is associated with decreased oxidative stress, an attenuation of hypertension, and a reduction of renal damage in Dahl SS rats fed high salt.
    AJP Renal Physiology 03/2011; 300(3):F734-42. · 4.42 Impact Factor
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    Carmen De Miguel, Hayley Lund, David L Mattson
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    ABSTRACT: The present study evaluated the influence and mechanism of action of dietary protein intake in Dahl SS hypertension and renal disease. Rats were fed isocaloric diets with low (6%), normal (18%), or high (30%) amounts of protein and 0.4% NaCl from 5 to 12 weeks of age; the NaCl content of the diets was then increased to 4.0% NaCl from 12 to 15 weeks of age. Rats fed the high-protein diet developed the highest mean arterial blood pressure and urine albumin-to-creatinine ratio when fed the 4.0% NaCl diet (153 ± 7 mm Hg and 8.0 ± 2.4, respectively) compared to rats fed normal protein (132 ± 3 mm Hg, 1.2 ± 0.3) or low-protein (132 ± 6 mm Hg, 0.3 ± 0.1) diets. Significantly greater numbers of infiltrating T lymphocytes were observed in kidneys of SS rats fed the high-protein diet (18.9 ± 3 × 10⁵ cells) than in rats fed the low-protein diet (9.1 ± 3 × 10⁵ cells). Furthermore, treatment of SS rats fed the high-protein diet with the immunosuppressant agent mycophenolate mofetil (20 mg/kg per day, ip) significantly reduced the number of infiltrating T cells in the kidneys (from 18.9 ± 2.7 to 10.6 ± 2.0 × 10⁵ cells) while decreasing blood pressure (from 133 ± 3 to 113 ± 4 mm Hg) and the albumin/creatinine ratio (from 10.9 ± 2.3 to 5.4 ± 1.2). These results demonstrate that restriction of protein intake protects the Dahl SS rats from hypertension and kidney disease and indicates that infiltrating immune cells play a pathological role in Dahl SS rats fed a high-protein diet. Moreover, the results show that hypertension in Dahl SS rats is sensitive to both NaCl and protein intake.
    Hypertension 02/2011; 57(2):269-74. · 6.87 Impact Factor
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    David L Mattson
    AJP Renal Physiology 12/2010; 299(6):F1257. · 4.42 Impact Factor
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    ABSTRACT: This study examined mechanisms by which immune cells participate in the development of hypertension and renal disease in Dahl salt-sensitive (SS) rats. Increasing dietary salt from 0.4% to 4.0% NaCl significantly increased renal infiltration of T lymphocytes from 8.8 +/- 1.2 x 10(5) to 14.4 +/- 2.0 x 10(5) cells/2 kidneys, increased arterial blood pressure from 131 +/- 2 to 165 +/- 6 mmHg, increased albumin excretion rate from 17 +/- 3 to 129 +/- 20 mg/day, and resulted in renal glomerular and tubular damage. Furthermore, renal tissue ANG II was not suppressed in the kidneys of SS rats fed 4.0% NaCl. Administration of the immunosuppressive agent mycophenolate mofetil (MMF; 20 mg.kg(-1).day(-1)) prevented the infiltration of T lymphocytes and attenuated Dahl SS hypertension and renal disease. In contrast to vehicle-treated rats, Dahl SS rats administered MMF demonstrated a suppression of renal tissue ANG II from 163 +/- 26 to 88 +/- 9 pg/g of tissue when fed high salt. Finally, it was demonstrated that the T lymphocytes isolated from the kidney possess renin and angiotensin-converting enzyme activity. These data indicate that infiltrating T cells are capable of participating in the production of ANG II and are associated with increased intrarenal ANG II, hypertension, and renal disease. The suppression of T-cell infiltration decreased intrarenal ANG II and prevented Dahl SS hypertension and kidney damage. As such, infiltrating cells are capable of participating in the established phase of Dahl SS hypertension.
    AJP Regulatory Integrative and Comparative Physiology 02/2010; 298(4):R1136-42. · 3.28 Impact Factor
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    ABSTRACT: The present studies evaluated intrarenal hemodynamics, pressure natriuresis, and arterial blood pressure in rats following recovery from renal ischemia-reperfusion (I/R) injury. Acute I/R injury, induced by 40 min of bilateral renal arterial occlusion, resulted in an increase in plasma creatinine that resolved within a week. Following 5 wk of recovery on a 0.4% NaCl diet, the pressure-natriuresis response was assessed in anesthetized rats in which the kidney was denervated and extrarenal hormones were administered intravenously. Increasing renal perfusion pressure (RPP) from 107 to 141 mmHg resulted in a fourfold increase in urine flow and sodium excretion in sham control rats. In comparison, pressure diuresis and natriuresis were significantly attenuated in post-I/R rats. In sham rats, glomerular filtration rate (GFR) averaged 1.6 +/- 0.2 mlxmin(-1)xg kidney weight(-1) and renal blood flow (RBF) averaged 7.8 +/- 0.7 mlxmin(-1)xg kidney weight(-1) at RPP of 129 mmHg. Renal cortical blood flow, measured by laser-Doppler flowmetry, was well autoregulated whereas medullary blood flow and renal interstitial hydrostatic pressure increased directly with elevated RPP in sham rats. In contrast, GFR and RBF were significantly reduced whereas medullary perfusion and interstitial pressure demonstrated an attenuated response to RPP in post-I/R rats. Further experiments demonstrated that conscious I/R rats develop hypertension when sodium intake is increased. The present data indicate that the pressure-natriuretic-diuretic response in I/R rats is blunted because of a decrease in GFR and RBF and the depressed pressure-dependent increase in medullary blood flow and interstitial pressure.
    AJP Regulatory Integrative and Comparative Physiology 09/2009; 297(5):R1358-63. · 3.28 Impact Factor
  • David L Mattson
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    ABSTRACT: Mice lacking or over-expressing a gene of experimental interest have become important tools to understand the regulation of kidney function and water and electrolyte homeostasis. The use of mice in physiological studies is becoming more widespread, but there are still a number of technical limitations that preclude the full utilization of mouse models in renal research. The present chapter focuses upon a set of methods developed in our laboratory to quantify renal function in conscious mice. These measurements are based upon surgical instrumentation of mice with chronic indwelling arterial and venous catheters. This preparation permits direct measurement of arterial blood pressure, direct sampling of arterial and/or venous blood, intravenous or intra-arterial infusion of substances, and quantification of daily sodium balance. The advantage of these techniques is that all of these procedures can be performed in conscious mice freely moving in their home cages. As such, this in vivo preparation provides an assessment of physiological function in mice in their native state.
    Methods in molecular biology (Clifton, N.J.) 01/2009; 573:75-94.
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    ABSTRACT: Experiments were performed to determine whether exogenous L-arginine could ameliorate angiotensin II-induced hypertension and renal damage. Rats were instrumented with chronic indwelling femoral venous and arterial catheters for infusions of drugs and measurement of conscious arterial pressure. Arterial blood pressure significantly increased from 124+/-1 to 199+/-4 mm Hg, after 9 days of continuous infusion of angiotensin II (20 ng/kg per minute; IV; n=6 to 9). In contrast, the increase in arterial pressure after 9 days of angiotensin II infusion was significantly blunted by 45% (P=0.0003) in rats coadministered L-arginine (300 microg/kg per minute; IV; n=7 to 9). The glomerular injury index was significantly greater in rats administered angiotensin II in comparison with rats administered saline vehicle (P<0.001). Coinfusion of L-arginine significantly increased plasma nitrate/nitrite concentrations (P<0.001) and completely prevented angiotensin II-induced glomerular damage (P<0.001). Angiotensin II infusion alone and combined angiotensin II plus L-arginine infusion significantly increased urinary albumin excretion. Albuminuria in rats administered angiotensin II plus L-arginine is likely to be because of increased intraglomerular pressure. Our experiments demonstrate that L-arginine can blunt angiotensin II-induced hypertension and associated renal damage. This latter observation is most exciting because it indicates that increasing NO bioavailability, in addition to lowering arterial pressure, can greatly reduce hypertension-induced renal damage.
    Hypertension 12/2008; 52(6):1084-90. · 6.87 Impact Factor
  • Niwanthi W Rajapakse, David L Mattson
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    ABSTRACT: 1. l-Arginine is the substrate for vascular nitric oxide (NO) formation. Under normal physiological conditions, intracellular l-arginine levels far exceed the K(m) of NO synthase for l-arginine. However, endogenous NO formation is dependent on extracellular l-arginine concentrations, giving rise to the concept of the 'l-arginine paradox'. 2. Nitric oxide production in epithelial and endothelial cells is closely coupled to cellular l-arginine uptake, indicating that l-arginine transport mechanisms play a major role in the regulation of NO-dependent function. 3. Consistent with the data in endothelial and epithelial cells are functional data indicating that exogenous l-arginine can increase renal vascular and tubular NO bioavailability and thereby influence kidney perfusion, function and arterial pressure. The integrated effect of increased cellular l-arginine transport is to lower arterial pressure. Therefore, the use of l-arginine in the treatment of hypertension warrants investigation. 4. Low NO bioavailability is central to the development and maintenance of hypertension and to related endothelial dysfunction and target organ damage. We propose that l-arginine can interrupt the vicious cycle that initiates and maintains low NO in hypertension by increasing the formation of NO.
    Clinical and Experimental Pharmacology and Physiology 12/2008; 36(3):249-55. · 2.16 Impact Factor

Publication Stats

2k Citations
361.51 Total Impact Points


  • 1993–2013
    • Medical College of Wisconsin
      • Department of Physiology
      Milwaukee, Wisconsin, United States
  • 2012
    • Baker IDI Heart and Diabetes Institute
      Melbourne, Victoria, Australia
  • 2008
    • Monash University (Australia)
      • Department of Physiology
      Melbourne, Victoria, Australia
  • 2004–2006
    • University of North Carolina at Chapel Hill
      • Department of Pathology and Laboratory Medicine
      Chapel Hill, NC, United States
  • 2002
    • University of Maryland, Baltimore
      • Division of Nephrology
      Baltimore, MD, United States
  • 2000–2002
    • Semmelweis University
      Budapeŝto, Budapest, Hungary
  • 1997
    • University of São Paulo
      San Paulo, São Paulo, Brazil
  • 1995
    • University of Greifswald
      • Institute of Physiology
      Greifswald, Mecklenburg-Vorpommern, Germany