Published online before print November 25, 2002, doi: 10.1161/01.HYP.0000042665.85720.A0
(Hypertension. 2003;41:37.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Tissue-Specific Response to Interstitial Angiotensin II in Humans
From the German Institute of Human Nutrition (M.B., F.A., S.K.), Potsdam, Germany; Franz-Volhard Clinical Research Center and HELIOS Klinikum Berlin, Medical Faculty of the Charité, Humboldt-University (J.J., J.T., G.F., M.S., A.M.S., F.C.L.), Berlin, Germany; and the Department of Internal Medicine and Endocrinology, Herlev Hospital, University of Copenhagen (N.-J.C.), Denmark.
Correspondence to Dr Michael Boschmann, German Institute for Human Nutrition, Department of Biochemistry and Physiology of Nutrition, Arthur-Scheunert-Allee 114–116, 14558 Bergholz-Rehbrücke, Germany. E-mail boschman{at}mail.dife.de
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Angiotensin II is synthesized locally in various tissues; however, the role of interstitial angiotensin II in the regulation of regional metabolism and tissue perfusion is not clear. We characterized the effect of interstially applied angiotensin II in skeletal muscle and subcutaneous adipose tissue of young, normal-weight, healthy subjects by using the microdialysis technique. Furthermore, we tested the hypothesis that the effect of interstitial angiotensin II is modulated by nitric oxide. Tissues were perfused with 0.01, 0.1, and 1 µmol/L angiotensin II in the presence of the L- or D-isomer of NG-nitro-arginine-methyl ester (L- or D-NAME), the effective and noneffective isomer, respectively, for blocking nitric oxide synthase. Dialysate ethanol, glycerol, glucose, lactate, and pyruvate concentrations were measured to assess changes in blood flow (ethanol dilution technique), lipolysis, and glycolysis, respectively. Baseline blood flow and dialysate concentrations of the metabolites were similar with L- and D-NAME in both tissues. Blood flow and dialysate glucose and lactate did not change significantly in both tissues during perfusion with angiotensin II. Dialysate glycerol dose-dependently increased in adipose tissue (P<0.0438) but decreased in muscle (P<0.007). In muscle, dialysate pyruvate increased (P<0.0002), whereas lactate/pyruvate ratio decreased (P<0.001), both dose-dependently. All effects were similar with L- and D-NAME and could be reversed by nitroprusside. We conclude that in contrast to the profound hemodynamic effect of intravascular angiotensin II, interstitial angiotensin II has a minimal acute effect on blood flow in both tissues. However, interstitial angiotensin II modulates lipid and carbohydrate metabolism in a tissue specific fashion. Thus, the physiology of interstitial angiotensin II cannot be predicted from intravascular studies.
Key Words: glucose • lactates • angiotensin II • microcirculation
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Angiotensin (Ang) II has a pivotal role in the regulation of vascular tone and of electrolyte and water homeostasis and may contribute to essential hypertension.1–4 Moreover, Ang II stimulates cell growth and differentiation and exerts metabolic effects that may contribute to cardiovascular disease.1–4 Ang II is generated in both the intravascular and interstitial space.5,6 The systemic and local constituents of the renin-angiotensin system are moderately increased in normotensive obese patients and dramatically increased in hypertensive obese patients.7 Intravascular and interstitial Ang II concentrations appear to be regulated in part independently from each other. In the rat, Ang II interstitial concentrations in the kidney are much higher than plasma concentrations.8 In this model, acute ACE inhibition markedly reduced plasma Ang II. In contrast, interstitial Ang II did not change. Similarly, acute volume expansion elicited a differential effect on intravascular and on interstitial Ang II.8 The fact that Ang II concentrations in the intravascular and in the interstitial space are independently regulated may suggest that Ang II has different physiological effects in both compartments. Intravascular Ang II, for example, elicits a profound increase in vascular tone through stimulation of Ang II type 1 (AT1) receptors.1–3 Interstitial Ang II, however, causes a moderate decrease in blood flow in adipose tissue, and this effect is clearly dependent on tissue location.9 Nevertheless, the physiology of interstitial Ang II in humans is still poorly understood. We sought to elucidate the effect of interstitial Ang II on tissue perfusion, metabolism, and interstitial norepinephrine in skeletal muscle (primarily energy consuming) and in adipose tissue (primarily energy storing). We used the microdialysis technique to apply Ang II locally to the interstitial space.9 Furthermore, we determined whether or not the effect of interstitial Ang II is modulated by nitric oxide (NO).10
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
The study population included 8 drug-free, nonsmoking male volunteers, 29±4 years of age, height of 1.82±0.02 m, and body mass index of 23.62±1.81 kg/m2. All were healthy as determined by medical history, physical examination, and routine blood and urine tests. The study was approved by the Institutional Review Board of Humboldt University, Berlin, and the subjects gave written informed consent.
Microdialysis
After an overnight fast, two microdialysis catheters each (distance, 2.5 cm) were inserted into abdominal subcutaneous adipose tissue (adipose) at the level of the umbilicus and into skeletal muscle (quadriceps femoris, vastus lateralis). Details of that technique are described elsewhere.11,12 Before insertion of the catheters, a local anesthetic (lidocaine) was given, either as a cream for adipose (EMLA, Astra GmbH) or as a subcutaneous injection for muscle (Xylocitin 1%, Jenapharm GmbH). After insertion of the probes, tissue perfusion was started at a flow rate of 2 µL/min with Ringer’s solution (Serumwerk Bernburg AG). The solution was supplemented with 50 mmol/L ethanol (EtOH, B. Braun Melsungen AG) and 100 µmol/L of either NG-nitro-L-arginine-methyl ester (L-NAME, effective in blocking NO synthase, NOS) or the D-isomer (D-NAME, ineffective in blocking NOS). CMA/60 microdialysis catheters and CMA/102 microdialysis pumps (both from CMA Microdialysis AB) were used. A period of 60 minutes was allowed for recovery of the tissues from insertional trauma and for baseline calibration of the perfusion system before commencement of the dialysis protocol. After the baseline perfusion was completed, 0.01, 0.1, and 1 µmol/l Ang II was added successively to the perfusion medium for testing the dose-response relation of Ang II on baseline blood flow and dialysate glycerol, glucose, and lactate concentrations. In a final perfusion step, the NO-donor nitroprusside (NP) was added to the highest Ang II concentration. Ang II and L- and D-NAME were purchased from Clinalfa and NP (Nipruss) from Schwarz Pharma AG. During each perfusion step, three 15-minute fractions of dialysates were collected and frozen at -80°C until analyses were performed.
Analyses
Ethanol concentration in the perfusate (inflow) and dialysate (outflow) was measured with a standard enzymatic assay.13 Dialysate concentrations of glycerol, glucose, lactate, and pyruvate were measured on a CMA/600 analyzer (CMA Microdialysis AB). Samples for norepinephrine were processed and analyzed as previously described.14
Calculations and Statistics
Changes in blood flow were determined by using the ethanol dilution technique, which is based on the Fick principle.15,16 Accordingly, a decrease in the outflow/inflow ratio is equivalent to an increase in blood flow and vice versa. For simplicity, the term ethanol ratio is substituted for the term ethanol outflow/inflow ratio. Changes in glycerol were used to assess changes in lipolysis and/or lipid mobilization; changes in glucose, lactate, and pyruvate were used to assess changes in carbohydrate metabolism.17,18 In situ recovery for glycerol, glucose, lactate, and pyruvate in the dialysate was assessed by near-equilibrium dialysis.19 For all four metabolites, we found recoveries of 
30% in adipose tissue and 50% in muscle. All data are given as mean±SEM. Statistical analyses were carried out by ANOVA with repeated measures, with pretreatment with L- or D-NAME and concentration of Ang II used as factors to determine the significance of differences in the hemodynamic and metabolic responses to Ang II either in the presence or absence of NOS blockade. For testing, a statistical program (InStat, Version 3.0, Graphpad Software Inc) was used. Significant F ratios from the ANOVA were followed by post hoc comparisons among means by use of the Bonferroni correction.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Resting heart rate was 56±6 bpm. Resting systolic and diastolic blood pressures were 118±7 and 63±10 mm Hg, respectively. These values did not change significantly during local perfusion of adipose tissue and muscle with Ang II by microdialysis (data not shown).
In a subset of experiments it was tested whether D-NAME, the isoform ineffective for blocking NOS, could elicit any unspecific effects on tissue blood flow and metabolism. Compared with baseline values in the absence of D-NAME, the presence of D-NAME in the perfusate did not influence ethanol ratio and dialysate concentrations of glucose, lactate, pyruvate, and glycerol (data not shown). Therefore, in the following, all baseline values in the presence of D-NAME can be considered as control values.
Blood Flow
Baseline ethanol ratio was 0.30 and 0.08 in adipose tissue and muscle, respectively, without any significant differences between L- and D-NAME (Figure 1). Ang II did not result in any significant change in ethanol ratio in both tissues, neither with L- nor with D-NAME. Final addition of NP to the medium induced a significant decrease in ethanol ratio down to 0.15 and 0.04 in adipose tissue and muscle, respectively (Figure 1).
|
Metabolites
Baseline dialysate concentration of glucose was 0.96 and 1.90 mmol/L, whereas that of lactate was 0.55 and 0.95 mmol/L in adipose tissue and muscle, respectively (L-NAME=D-NAME). There were no significant changes in the concentrations of glucose and lactate during Ang II perfusion, either in adipose tissue or in muscle (Figure 1). However, dialysate glucose concentration increased significantly to 1.7 mmol/L in adipose tissue and 2.6 mmol/L in muscle after NP administration (Figure 1). In both tissues, dialysate lactate concentration was not affected by NP (Figure 1). The response of dialysate glycerol to Ang II showed tissue-specific differences. In adipose tissue, dialysate glycerol increased dose-dependently from 115±9 and 100±12 µmol/L to 149±12 and 131±13 µmol/l in the presence of L- and D-NAME, respectively (P=0.0438, Figure 1). At all Ang II concentrations used, dialysate glycerol concentrations were higher in the presence of L-NAME compared with D-NAME; however, the difference did not reach a significant value (P=0.0531). The relative changes in dialysate glycerol did not differ between L- and D-NAME. Addition of NP was followed by a decrease in dialysate glycerol down to 50 µmol/L (L-NAME=D-NAME). In muscle, Ang II induced a dose-dependent decrease in dialysate glycerol from 34 to 22 µmol/L (P<0.007), with no differences between L-NAME and D-NAME (Figure 1). After addition of NP, dialysate glycerol returned back to baseline level. Dialysate pyruvate increased dose-dependently during Ang II perfusion in muscle from 0.020 to 0.045 mmol/L (P=0.0002, L-NAME=D-NAME) (Figure 2). Correspondingly, the lactate/pyruvate ratio decreased dose-dependently from 55 to 26 (P=0.001, L-NAME=D-NAME) (Figure 2). Addition of NP led to a return of dialysate pyruvate concentration and lactate/pyruvate ratio back to baseline levels.
|
Norepinephrine
To test if Ang II is able to facilitate sympathetic neurotransmission, adipose tissue and muscle were perfused with increasing doses of either Ang II or isoproterenol. In adipose tissue, dialysate norepinephrine concentration increased from 0.33±0.08 (baseline) to 0.52±0.04 nmol/L (P<0.05) during perfusion with 0.01 µmol/L Ang II (Figure 3). Higher Ang II concentration did not lead to a further increase in dialysate norepinephrine concentration. Perfusion with isoproterenol induced a dose-dependent increase in dialysate norepinephrine concentration from 0.42±0.04 (baseline) to 1.74±0.30 nmol/L at 1 µmol/L. In muscle, dialysate norepinephrine concentration did not change at any Ang II concentration used (Figure 3). However, during perfusion with isoproterenol, dialysate norepinephrine concentration increased from 0.84±0.14 (baseline) to 2.09±0.16 at 1 µmol/L.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The main finding in our study is that interstitially applied Ang II elicits hemodynamic and metabolic responses that are not predicted from intravascular studies. Ang II is a strong vasoconstrictor when applied to the intravascular space.2–4 In contrast, we observed that Ang II has a minimal effect on the perfusion of adipose tissue and of skeletal muscle when applied to the interstitial space. The absence of an important hemodynamic effect of Ang II in both tissues may indicate that interstitial Ang II is less important for blood flow regulation than intravascular Ang II, at least in skeletal muscle and in abdominal adipose tissue. We used the ethanol dilution technique, which is based on the Fick principle, to assess changes in tissue blood flow.15,16 Using this methodology, we have previously shown that in skeletal muscle, interstitial epinephrine elicits a dose related decrease in tissue blood flow.20 In contrast, in abdominal adipose tissue epinephrine and phenylephrine did not decrease blood flow when applied through the microdialysis probe.20,21 Obviously, resting adipose tissue is already at its minimum level, at least in men.20,21 Nitroprusside and isoproterenol elicited a marked increase in skeletal muscle and in adipose tissue blood flow.20 Moreover, we were able to show a subtle interaction between adrenergic stimulation and NO.20 Thus, absence of a change in ethanol ratio with Ang II is indeed consistent with absence of a major change in blood flow.
Even though interstitial Ang II did not have a major effect on tissue blood flow, it elicited marked metabolic changes in two functionally different tissues, namely white adipose tissue and skeletal muscle. Ang II can bind to plasma membrane receptors on adipocytes but also on presynaptic fibers of sympathetic neurons enhancing transmitter release during nerve stimulation.22,23 Therefore, Ang II could influence lipid and carbohydrate metabolism directly through an effect on receptors on adipocytes and indirectly through activation of receptors on presynaptic fibers of adrenergic neurons. A combination of both mechanisms could also occur. In our study, Ang II application did not lead to a major change in interstitial norepinephrine concentrations. In contrast, stimulation of presynaptic ß-2 adrenoreceptors increases interstitial norepinephrine markedly.20 However, the sensitivity of our method may not be sufficient enough to exclude a subtle effect of interstitial Ang II on norepinephrine turnover.
As indicated by the changes in dialysate glycerol concentrations, Ang II affected lipolysis in a tissue-specific manner: We observed a stimulation in adipose tissue but an inhibition in muscle, both dose-dependently. However, the increase in lipolysis with Ang II (+30%) was much weaker than the increase observed with isoproterenol (+300%).20 After binding of Ang II to its receptors, mainly Ang II type 1 (AT-1) receptors, various signal transduction systems are triggered, leading to an activation of phospholipases C, A2, and D, inhibition of adenylate cyclase, opening of calcium channels, or activation of tyrosine kinases.3 Inhibition of adenylate cyclase results in an inhibition of lipolysis and that could account for the antilipolytic effect of Ang II in muscle.24 Jones et al25 described a lipogenic effect of Ang II in differentiated murine 3T3-L1 preadipocytes and human adipocytes, along with increased expression and activity of the lipogenic enzymes glycerol-3-phosphate dehydrogenase and fatty acid synthase. The lipogenic effect of Ang II found in adipocytes in vitro contrasts with the small lipolytic effect found in adipose tissue in vivo. It is unclear, however, whether the lipolytic effect in vivo is the consequence of the small but significant increase in dialysate norepinephrine during perfusion with Ang II or whether it is the result of some unspecific effects.
Blocking of NOS with L-NAME did not significantly modulate the Ang II–induced effects. However, as has been demonstrated recently, the L-NAME concentration used is effective for blocking NOS.20 Obviously, endogenously produced NO is not sufficient to interact with Ang II. In contrast, the NO donor NP attenuated the Ang II–induced effects on lipolysis. However, the NP concentration used is in the millimolar range and is effective to achieve maximum vasodilation. Therefore, the NP-induced effects can mostly be attributed to the increased tissue perfusion. In adipose tissue, dialysate glycerol decreased below baseline values. In skeletal muscle, dialysate glycerol increased close to baseline values. The glycerol decrease in adipose tissue is in line with the increase in blood flow that we observed and may indicate increased glycerol clearance. However, the glycerol increase in muscle close to baseline levels despite an increased blood flow indicates that NO activates basal lipolysis and counteracts the antilipolytic effect of Ang II. Gaudiot et al26 reported that NO exogenously added to isolated rat adipocytes stimulates basal lipolysis but inhibits stimulated lipolysis through cGMP-independent mechanisms that are tightly linked to the redox state of NO. Dialysate glycerol concentrations in adipose tissue tended to be increased with NOS inhibition. The lipolytic effect of NOS inhibition in adipose tissue in vivo is in contrast to the antilipolytic effect observed in adipocytes in vitro.27 However, NO is a tonic inhibitor of sympathetic nerve traffic, and inhibition of NOS is accompanied by an increase in both basal and stimulated lipolysis in adipose tissue in vivo, as has been shown recently.20
In addition to the effects on lipolysis, Ang II markedly changed carbohydrate metabolism in skeletal muscle. Dialysate lactate did not change during perfusion with Ang II, whereas dialysate pyruvate increased and lactate/pyruvate ratio decreased dose-dependently. A decrease in lactate/pyruvate ratio is consistent with an increase in aerobic glycolysis. On the other hand, the changes in dialysate lactate, pyruvate, and lactate/pyruvate ratio are consistent with a hypoglycemic situation: The lower availability of glucose is compensated by a greater efficiency of glucose metabolism.28 Muscle blood flow and glucose supply were not significantly affected by Ang II. Obviously, Ang II moderately impaired glucose uptake into the muscle, leading to a metabolic response similar to a hypoglycemic situation. This interpretation is in line with a recent report by Frossard et al,29 who found an improved glucose uptake into muscle after treatment of volunteers with inhibitors of either ACE or Ang II receptors.
The Ang II doses used in our study may result in higher tissue levels of Ang II than will normally be encountered in vivo. Maximum perfusate concentration of Ang II used in our study was 10-6 mol/L, whereas normal plasma concentration is 10x10-12 mol/L.30,31 However, local generation of Ang II may result in higher Ang II concentrations in the interstitium than encountered in the circulation. In fact, interstitial concentrations of Ang II in rat kidney are much higher than plasma concentrations.8 Furthermore, in vitro recovery of Ang II is 20% at a flow rate of 2 µL/min when using CMA/60 catheters. Recovery could be even lower in vivo. We did not test for that. It is possible, however, that 10% of Ang II of the perfusate diffuses into the interstitial space. Taking this into account, a perfusate concentration of 0.1 µmol/L Ang II would correspond to an interstitial concentration of 0.01 µmol/L, a value that is already within the physiological range. Thus, although we cannot completely rule out that some of the effects observed at the higher Ang II doses in our study represent the pharmacological rather than the physiological action of Ang II, the magnitude of the Ang II effect probably corresponds to the physiological response of both tissues to Ang II.
In conclusion, interstitially applied Ang II elicits rather weak hemodynamic and metabolic effects in adipose tissue, whereas it dose-dependently inhibits lipolysis and glucose uptake in muscle, independent of its hemodynamic effects. The metabolic effects are not modulated by endogenously produced NO. However, most of the effects are reversible when NO–donor NP is added to the perfusate.
Perspectives
Our data suggest a tissue-specific effect of Ang II regarding the regulation of lipolysis and glucose metabolism. Ang II has no major effect on tissue perfusion in adipose tissue and muscle when applied interstitially. However, lipolysis is weakly stimulated in adipose tissue but strongly inhibited in muscle by Ang II. Furthermore, Ang II stimulates pyruvate production, whereas lactate production is unchanged, resulting in an increase in lactate/pyruvate ratio in muscle. This observation indicates an impaired glucose supply into muscle, possibly caused by a partial inhibited glucose uptake. Possibly, this effect is even more pronounced in obesity and can, therefore, promote the development of obesity-associated insulin resistance. All these effects are probably mainly but not exclusively related to activation of Ang II receptors on adipocytes or muscle cells/fibers rather than changes in norepinephrine release through stimulation of receptors on the presynaptic fibers. Our findings are consistent with the idea that interstitial and intravascular Ang II concentrations in humans are regulated in part independently and serve different physiological functions. The physiology of interstitial Ang II in humans may not be revealed with intravascular studies. Instead, tissue investigations such as reported in this article will play an increasing role in elucidating local Ang II–related effects.
|
Acknowledgments |
|---|
This study was supported in part by a grant-in-aid from Sanofi Synthelabo. The excellent, skillful technical assistance of Brigitte Geue, Carola Plaue, and Karin Schaller is gratefully acknowledged.
Received June 3, 2002; first decision July 29, 2002; accepted October 9, 2002.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993; 45: 205–251.[Medline] [Order article via Infotrieve]
- Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000; 52: 11–34.
[Abstract/Free Full Text] - Berry C, Touyz R, Dominiczak F, Webb RC, Johns DG. Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide. Am J Physiol. 2001; 281: H2337–H2365.
- Brunner HR. Experimental and clinical evidence that angiotensin II is an independent risk factor for cardiovascular disease. Am J Cardiol. 2001; 87: 3C-9C.[Medline] [Order article via Infotrieve]
- Campbell DJ. Circulating and tissue angiotensin systems. J Clin Invest. 1987; 79: 1–6.[Medline] [Order article via Infotrieve]
- Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension. 2000; 35: 1270–1277.
[Abstract/Free Full Text] - Engeli S, Sharma AM. The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension. J Mol Med. 2001; 79: 21–29.[CrossRef][Medline] [Order article via Infotrieve]
- Nishiyama A, Seth DM, Navar LG. Renal interstitial fluid concentrations of angiotensin I and II in anesthetized rats. Hypertension. 2002; 39: 129–134.
[Abstract/Free Full Text] - Boschmann M, Ringel J, Klaus S, Sharma AM. Metabolic and hemodynamic response of adipose tissue to angiotensin II. Obes Res. 2001; 9: 486–491.[Medline] [Order article via Infotrieve]
- Fernández-Alfonso MS, González C. Nitric oxide and the renin-angiotensin system: is there a physiological interplay between the systems? J Hypertens. 1999; 17: 1355–1361.[CrossRef][Medline] [Order article via Infotrieve]
- Lafontan M, Arner P. Application of in situ microdialysis to measure metabolic and vascular responses in adipose tissue. Trends Pharmacol Sci. 1996; 17: 309–313.[CrossRef][Medline] [Order article via Infotrieve]
- Lönnroth P. Microdialysis in adipose tissue and skeletal muscle. Horm Metab Res. 1997; 29: 344–346.[Medline] [Order article via Infotrieve]
- Bernt E, Gutmann I. Ethanol determination with alcohol dehydrogenase and NAD. In: Bergmeyer HU, ed. Methods of Enzymatic Analysis. Weinheim: Verlag Chemie; 1974: 1499–1505.
- Gronlund B, Astrup A, Bie P, Christensen NJ. Noradrenaline release in skeletal muscle and in adipose tissue studied by microdialysis. Clin Sci. 1991; 80: 595–598.[Medline] [Order article via Infotrieve]
- Hickner RC, Rosdahl H, Borg I, Ungerstedt U, Jorfeldt L, Henriksson J. The ethanol technique of monitoring local blood flow changes in rat skeletal muscle: implications for microdialysis. Acta Physiol Scand. 1992; 147: 87–97.
- Fellander G, Linde B, Bolinder L. Evaluation of the microdialysis ethanol technique for monitoring of subcutaneous adipose tissue blood flow in humans. Int J Obes. 1996; 20: 220–226.[Medline] [Order article via Infotrieve]
- Arner P, Liljeqvist L, Östman J. Metabolism of mono- and diacyl-glycerols in subcutaneous adipose tissue of obese and normal weight subjects. Acta Med Scand. 1976; 200: 187–194.[Medline] [Order article via Infotrieve]
- Rosdahl H, Ungerstedt U, Jorfeldt L, Henriksson J. Interstitial glucose and lactate balance in human skeletal muscle and adipose tissue studied by microdialysis. J Physiol. 1993; 471: 637–657.
[Abstract/Free Full Text] - Stahle L, Segersvard S, Ungerstedt U. A comparison between three methods for estimation of extracellular concentrations of exogenous and endogenous compounds by microdialysis. J Pharmacol Methods. 1991; 25: 41–52.[CrossRef][Medline] [Order article via Infotrieve]
- Jordan J, Tank J, Christensen NJ, Franke G, Stoffels M, Luft FC, Boschmann M. Interaction between beta-adrenergic receptor stimulation and nitric oxide release on tissue perfusion and metabolism. J Clin Endocrinol Metab. 2001; 86: 2803–2810.
[Abstract/Free Full Text] - Boschmann M, Krupp G, Luft FC, Klaus S, Jordan J. In vivo response on alpha-1 adrenoreceptor stimulation in human white adipose tissue. Obes Res. 2002; 10: 555–558.[Medline] [Order article via Infotrieve]
- Campbell WB, Jackson EK. Modulation of adrenergic transmission by angiotensins in the perfused rat mesentery. Am J Physiol. 1979; 236: H211–H217.[Medline] [Order article via Infotrieve]
- Cassis LA, Dwoskin LP. Presynaptic modulation of neurotransmitter release by endogeneous angiotensin II in brown adipose tissue. J Neural Transm. 1991; 34: 129–137.
- Lafontan M, Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res. 1993; 34: 1057–1091.[Abstract]
- Jones BH, Standridge MK, Moustaid N. Angiotensin II increases lipogenesis in 3T3-L1 and human adipose cells. Endocrinology. 1997; 138: 1512–1519.
[Abstract/Free Full Text] - Gaudiot N, Jaubert AM, Charbonnier E, Sabourault D, Lacasa D, Guidicelli Y, Ribière C. Modulation of white adipose tissue lipolysis by nitric oxide. J Biol Chem. 1998; 273: 13475–13481.
[Abstract/Free Full Text] - Gaudiot N, Ribière C, Jaubert AM, Guidicelli Y. Endogenous nitric oxide is implicated in the regulation of lipolysis through antioxidant-related effect. Am J Physiol. 2000; 279: C1603–C1610.
- Ungerstedt U. Microdialysis in normal and injured brain. In: Kinney JM, Tucker HN, eds. Physiology, Stress, and Malnutrition. New York: Lippincott-Raven Publishers; 1997: 361–374.
- Frossard M, Joukhadar C, Steffen G, Schmid R, Eichler HG, Müller M. Paracrine effects of angiotensin-converting enzyme and angiotensin II receptor inhibition on transcapillary glucose transport in humans. Life Sci. 2000; 66: 147–154.[CrossRef]
- Nussberger J, Brunner DB, Waeber B, Brunner HR. Specific measurement of angiotensin metabolites and in vitro generated angiotensin II in plasma. Hypertension. 1986; 8: 476–482.
[Abstract/Free Full Text] - Campbell DJ, Kladis A. Simultaneous radioimmunoassay of six angiotensin peptides in arterial and venous plasma of man. J Hypertens. 1990; 8: 165–172.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  S. Engeli, M. Boschmann, P. Frings, L. Beck, J. Janke, J. Titze, F. C. Luft, M. Heer, and J. Jordan Influence of Salt Intake on Renin-Angiotensin and Natriuretic Peptide System Genes in Human Adipose Tissue Hypertension, December 1, 2006; 48(6): 1103 - 1108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Boschmann, S. Engeli, F. Adams, G. Franke, F. C. Luft, A. M. Sharma, and J. Jordan Influences of AT1 receptor blockade on tissue metabolism in obese men Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R219 - R223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cabassi, P. Coghi, P. Govoni, E. Barouhiel, E. Speroni, S. Cavazzini, A. M. Cantoni, R. Scandroglio, and E. Fiaccadori Sympathetic Modulation by Carvedilol and Losartan Reduces Angiotensin II-Mediated Lipolysis in Subcutaneous and Visceral Fat J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2888 - 2897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Engeli, J. Bohnke, K. Gorzelniak, J. Janke, P. Schling, M. Bader, F. C. Luft, and A. M. Sharma Weight Loss and the Renin-Angiotensin-Aldosterone System Hypertension, March 1, 2005; 45(3): 356 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Engeli, J. Janke, K. Gorzelniak, J. Bohnke, N. Ghose, C. Lindschau, F. C. Luft, and A. M. Sharma Regulation of the nitric oxide system in human adipose tissue J. Lipid Res., September 1, 2004; 45(9): 1640 - 1648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Sharma Is There a Rationale for Angiotensin Blockade in the Management of Obesity Hypertension? Hypertension, July 1, 2004; 44(1): 12 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. H. Goossens, E. E. Blaak, W. H. M. Saris, and M. A. van Baak Angiotensin II-Induced Effects on Adipose and Skeletal Muscle Tissue Blood Flow and Lipolysis in Normal-Weight and Obese Subjects J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2690 - 2696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Schroeder, F. Adams, M. Boschmann, J. Tank, S. Haertter, A. Diedrich, I. Biaggioni, F. C. Luft, and J. Jordan Phenotypical evidence for a gender difference in cardiac norepinephrine transporter function Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2004; 286(5): R851 - R856. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||