Role of Adenosine in Contrast Media—Induced Acute Renal Failure in Diabetes Mellitus
2000; Elsevier BV; Volume: 75; Issue: 12 Linguagem: Inglês
10.4065/75.12.1275
ISSN1942-5546
AutoresAxel Pflueger, Timothy S. Larson, Karl A. Nath, Bernard F. King, Jennifer M. Gross, Franklyn G. Knox,
Tópico(s)Renal Transplantation Outcomes and Treatments
ResumoIncreased release of renal adenosine and stimulation of renal adenosine receptors have been proposed to be major mechanisms in the development of contrast media—induced acute renal failure (CM-ARF). Patients with diabetes mellitus or preexisting renal disease who have reduced renal function have a markedly increased risk to develop CM-ARF. This increased risk to develop CM-ARF in patients with diabetes mellitus is linked to a higher sensitivity of the renal vasculature to adenosine, since experimental studies have shown increased adenosine-induced vasoconstriction in the kidneys of diabetic animals. Furthermore, recent evidence suggests that administration of adenosine receptor antagonists reduces the risk of development of CM-ARF in both diabetic and nondiabetic patients. The purpose of this review is to discuss the role of adenosine in the development of CM-ARF, particularly in the kidneys of diabetic patients, and to evaluate the therapeutic potential of adenosine receptor antagonists in the prevention of CM-ARF. Selective adenosine Al receptor antagonists may provide a therapeutic tool to prevent CM-ARF in patients with diabetes mellitus and reduced renal function. Increased release of renal adenosine and stimulation of renal adenosine receptors have been proposed to be major mechanisms in the development of contrast media—induced acute renal failure (CM-ARF). Patients with diabetes mellitus or preexisting renal disease who have reduced renal function have a markedly increased risk to develop CM-ARF. This increased risk to develop CM-ARF in patients with diabetes mellitus is linked to a higher sensitivity of the renal vasculature to adenosine, since experimental studies have shown increased adenosine-induced vasoconstriction in the kidneys of diabetic animals. Furthermore, recent evidence suggests that administration of adenosine receptor antagonists reduces the risk of development of CM-ARF in both diabetic and nondiabetic patients. The purpose of this review is to discuss the role of adenosine in the development of CM-ARF, particularly in the kidneys of diabetic patients, and to evaluate the therapeutic potential of adenosine receptor antagonists in the prevention of CM-ARF. Selective adenosine Al receptor antagonists may provide a therapeutic tool to prevent CM-ARF in patients with diabetes mellitus and reduced renal function. Administration of contrast media is common in radiologic studies, including coronary angiography, peripheral and central vascular angiography, and computed tomography. Contrast agents can have adverse effects on renal function, including prolonged decrease of renal blood flow (RBF), decrease of glomerular filtration rate (GFR), and induction of contrast media-induced acute renal failure (CM-ARF).1Bohle A Christensen J Kokot F et al.Acute renal failure in man: new aspects concerning pathogencsis: a morphomelric study.Am J Nephrol. 1990; 10: 374-388Crossref PubMed Scopus (41) Google Scholar, 2Larson T Hudson K Mcrtz JI Romero JC Knox FG. Renal vasoconstrictive response to contrast medium; the role of sodium balance and the renin-angiotensin system.J lab Clin Med. 1983; 101: 385-391PubMed Google Scholar, 3Rudnick MR Berns JS Cohen RM Goldfarb S Contrast media-associated nephrotoxicity.Curr Opin Nephrol Hypertens. 1996; 5: 127-133Crossref PubMed Scopus (50) Google Scholar Patients undergoing these radiologic examinations often suffer from multiple disorders with reduced renal function. In particular, patients with diabetes mellitus and coexisting renal impairment are vulnerable to CMARF, which can lead to substantial morbidity and even mortality.3Rudnick MR Berns JS Cohen RM Goldfarb S Contrast media-associated nephrotoxicity.Curr Opin Nephrol Hypertens. 1996; 5: 127-133Crossref PubMed Scopus (50) Google Scholar, 4Barrett BJ Carlisle FJ Mctaanalysis of the relative nephrotoxicity of high- and low-osmolalily iodinatcd contrast media.Radiology. 1993; 188: 171-178PubMed Google Scholar, 5Morcos SK Contrast media-induced nephrotoxicity-questions and answers.RrJ Radiol. 1998; 71: 357-365Google Scholar, 6Rudnick MR Goldfarb S Wexler L et al.Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial: the lohcxol Cooperative Study.Kidney Int. 1995; 47: 254-261Crossref PubMed Scopus (854) Google Scholar The pathophysiology of CM-ARF, while not completely understood, is thought to be related, at least in part, to direct stimulation of renal vasoconstrictor receptors or indirectly to the contrast media-induced release of renal vasoconstrictors.3Rudnick MR Berns JS Cohen RM Goldfarb S Contrast media-associated nephrotoxicity.Curr Opin Nephrol Hypertens. 1996; 5: 127-133Crossref PubMed Scopus (50) Google Scholar,4,7–10 Several mediators have been proposed to participate in the pathogenic mechanism of this renal vasoconstriction, including release of renal vasoconstrictors such as adenosine, endothelin, angiotensin II, and serotonin; formation of oxygen-derived free radicals; and inhibition of renal vasodilators such as nitric oxide, atrial natriuretic factor, and prostaglandins.3Rudnick MR Berns JS Cohen RM Goldfarb S Contrast media-associated nephrotoxicity.Curr Opin Nephrol Hypertens. 1996; 5: 127-133Crossref PubMed Scopus (50) Google Scholar, 4Barrett BJ Carlisle FJ Mctaanalysis of the relative nephrotoxicity of high- and low-osmolalily iodinatcd contrast media.Radiology. 1993; 188: 171-178PubMed Google Scholar Evidence is accumulating to implicate adenosine as a key mediator of contrast media-induced renal vasoconstriction and thus CM-ARF.1,7,8.11-14 This review focuses on the pathogenesis of CM-ARF with regard to adenosine release, stimulation of renal adenosine receptors, and the potential role of adenosine receptor antagonists as therapeutic tools to prevent CM-ARF, particularly in patients with diabetes mellitus and reduced renal function. Contrast media-induced ARF is one of the most common causes of drug-induced ARF.4Barrett BJ Carlisle FJ Mctaanalysis of the relative nephrotoxicity of high- and low-osmolalily iodinatcd contrast media.Radiology. 1993; 188: 171-178PubMed Google Scholar,15 It has a low incidence in patients with renal sufficiency, ranging from 0% to 7% (average about 3%), when ARF is defined as an increase of baseline serum creatinine of at least 25%.16Cramer BC Parfrey PS Hutchinson HA et al.Renal function following infusion of radiologie contrast material: a prospective controlled study.Arch Intern Med. 1985; 145: 87-89Crossref PubMed Scopus (112) Google Scholar, 17Parfrey PS Griffiths SM Barrett BJ et al.Contrast material induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study.N Engl J Med. 1989; 320: 143-149Crossref PubMed Scopus (891) Google Scholar However, the risk of developing CM-ARF increases in patients with preexisting renal disease (baseline serum creatinine level ∼1.5 mg/dL) and, in particular, in patients with diabetes mellitus and renal insufficiency.3Rudnick MR Berns JS Cohen RM Goldfarb S Contrast media-associated nephrotoxicity.Curr Opin Nephrol Hypertens. 1996; 5: 127-133Crossref PubMed Scopus (50) Google Scholar, 15Morcau JF Hclenon O Kinkel K Melki P Assessment of the patient with renal disease: conventional uroradiology and contrast media.in: Davison AM Cameron JS Grünfeld JP Kerr DNS Ritz E Wincarls CO 2nd ed. Oxford Textbook of Clinical Nephrology. Vol I. Oxford University Press, New York, NY1998: 93-132Google Scholar, 18Heyman SN Rosen S Brezis M Radioeontrast nephropathy: a paradigm for the synergism between toxic and hypoxic insults in the kidney.Exp Nephrol. 1994; 2: 153-157PubMed Google Scholar, 19Wcisberg LS Kurnik PB Kurnik BR Risk of radioeontrast nephropathy in patients with and without diabetes mellitus.Kidnex Int. 1994; 45: 259-265Crossref PubMed Scopus (335) Google Scholar Chronic renal failure and diabetes mellitus in association with decreased renal function are the most common risk factors for the development of CM-ARF.15Morcau JF Hclenon O Kinkel K Melki P Assessment of the patient with renal disease: conventional uroradiology and contrast media.in: Davison AM Cameron JS Grünfeld JP Kerr DNS Ritz E Wincarls CO 2nd ed. Oxford Textbook of Clinical Nephrology. Vol I. Oxford University Press, New York, NY1998: 93-132Google Scholar Other reported risk factors such as dehydration, cardiovascular disease, the use of diuretics, advanced age (≤70 years), multiple myeloma, hypertension, and hyperuricemia are most likely epiphenomena for reduced GFR.20Katzberg RW Contrast medium-induced nephrotoxicity.in: Kalzbcrg RW The Contrast Media Manual. Williams & Wilkins, Baltimore, Md1992: 28-35Google Scholar With CM-ARF defined as an increase in baseline serum creatinine of 1.0 mg/dL or more, or 25%, it occurs in 9% to 40% of patients with diabetes mellitus and mild to moderate chronic renal insufficiency (baseline serum creatinine ≥1.4 mg/dL)17Parfrey PS Griffiths SM Barrett BJ et al.Contrast material induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study.N Engl J Med. 1989; 320: 143-149Crossref PubMed Scopus (891) Google Scholar, 19Wcisberg LS Kurnik PB Kurnik BR Risk of radioeontrast nephropathy in patients with and without diabetes mellitus.Kidnex Int. 1994; 45: 259-265Crossref PubMed Scopus (335) Google Scholar, 21Barrett BJ Parfrey PS Vavasour HM et al.Contrast nephropathy in patients with impaired renal function: high versus low osmolar media.Kidney Int. 1992; 41: 1274-1279Crossref PubMed Scopus (207) Google Scholar and in 50% to 95% of diabetic patients with severe chronic renal insufficiency (baseline serum creatinine ≥2.0 mg/dL).22Shaft T Chou SY Porush JG Shapiro WB Infusion intravenous pyelography and renal function: effects in patients with chronic-renal insufficiency.Arch Intern Med. 1978; 138: 1218-1221Crossref PubMed Scopus (75) Google Scholar, 23Manske CL Sprafka JM Strony JT Wang Y Contrast nephropathy in azotemic diabetic patients undergoing coronary angiog-raphy.Am J Med. 1990; 89: 615-620Abstract Full Text PDF PubMed Scopus (468) Google Scholar, 24Harkoncn S Kjcllstrand CM Exacerbation of diabetic renal failure following intravenous pyelography.Am J Med. 1977; 63: 939-946Abstract Full Text PDF PubMed Scopus (117) Google Scholar Furthermore, contrast media volume and osmolality have been reported to correlate with the incidence of CM-ARF. 4Barrett BJ Carlisle FJ Mctaanalysis of the relative nephrotoxicity of high- and low-osmolalily iodinatcd contrast media.Radiology. 1993; 188: 171-178PubMed Google Scholar, 6Rudnick MR Goldfarb S Wexler L et al.Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial: the lohcxol Cooperative Study.Kidney Int. 1995; 47: 254-261Crossref PubMed Scopus (854) Google Scholar The serum creatinine level is the most commonly used marker in clinical settings to monitor renal function. However, the serum creatinine level is an insensitive measure in patients with normal kidney function, as more than 50% reduction in GFR may occur before any increases are observed. Creatinine clearance is a more sensitive marker to monitor GFR; however, it requires serum and urine creatinine concentrations and a 24-hour urine collection for accurate measurement. In clinical studies, CM-ARF has been defined as an increase of serum creatinine by either 25% or 50% or a rise of the serum creatinine level of at least 0.5 mg/dL. 5Morcos SK Contrast media-induced nephrotoxicity-questions and answers.RrJ Radiol. 1998; 71: 357-365Google Scholar, 6Rudnick MR Goldfarb S Wexler L et al.Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial: the lohcxol Cooperative Study.Kidney Int. 1995; 47: 254-261Crossref PubMed Scopus (854) Google Scholar, 17Parfrey PS Griffiths SM Barrett BJ et al.Contrast material induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study.N Engl J Med. 1989; 320: 143-149Crossref PubMed Scopus (891) Google Scholar, 20Katzberg RW Contrast medium-induced nephrotoxicity.in: Kalzbcrg RW The Contrast Media Manual. Williams & Wilkins, Baltimore, Md1992: 28-35Google Scholar, 23Manske CL Sprafka JM Strony JT Wang Y Contrast nephropathy in azotemic diabetic patients undergoing coronary angiog-raphy.Am J Med. 1990; 89: 615-620Abstract Full Text PDF PubMed Scopus (468) Google Scholar, 24Harkoncn S Kjcllstrand CM Exacerbation of diabetic renal failure following intravenous pyelography.Am J Med. 1977; 63: 939-946Abstract Full Text PDF PubMed Scopus (117) Google Scholar, 25Harnish PP Fountainc H Fbrahimi R [odixanol: experience in 1259 patients in the United States.Invest Radiol. 1994; 29: S236-S237Crossref PubMed Scopus (9) Google Scholar, 26Vari RC Natarajan LA Whitescarvcr SA Jackson BA Ott CE Induction, prevention and mechanisms of contrast media-induced acute renal failure.Kidney Int. 1988; 33: 699-707Crossref PubMed Scopus (85) Google Scholar Contrast agents are hypertonic relative to serum. Iodinated contrast media can be high-osmolality or low-osmolality agents.27King Jr, BF lnlravascular contrast media and premedication.in: Bush Jr, Wll Krccke KN King Jr., BF Bcttmann MA Radiology Life Support (Rad-lS); A Practical Approach. Oxford University Press, New York, NY1999: 1-21Google Scholar High-osmolality agents are ionic, have an osmolality up to 5 times greater than plasma osmolality, and induce marked diuresis.15Morcau JF Hclenon O Kinkel K Melki P Assessment of the patient with renal disease: conventional uroradiology and contrast media.in: Davison AM Cameron JS Grünfeld JP Kerr DNS Ritz E Wincarls CO 2nd ed. Oxford Textbook of Clinical Nephrology. Vol I. Oxford University Press, New York, NY1998: 93-132Google Scholar Low-osmolality agents generally are nonionic and have an osmolality about twice that of plasma and a small osmotic diuretic effect. Some studies show that nonionic low-osmolality agents are associated with a lower incidence of CM-ARF compared with conventionally high-osmolality agents.4Barrett BJ Carlisle FJ Mctaanalysis of the relative nephrotoxicity of high- and low-osmolalily iodinatcd contrast media.Radiology. 1993; 188: 171-178PubMed Google Scholar, 6Rudnick MR Goldfarb S Wexler L et al.Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial: the lohcxol Cooperative Study.Kidney Int. 1995; 47: 254-261Crossref PubMed Scopus (854) Google Scholar whereas other studies failed to show a benefit of low-osmolality agents.21Barrett BJ Parfrey PS Vavasour HM et al.Contrast nephropathy in patients with impaired renal function: high versus low osmolar media.Kidney Int. 1992; 41: 1274-1279Crossref PubMed Scopus (207) Google Scholar, 28Gomes AS Lois JF Baker JD McGlade CT Bunnell DH Hartzmun S Acute renal dysfunction in high-risk patients after angiography: comparison of ionic and nonionic contrast media.Radiology. 1989; 170: 65-68PubMed Google Scholar, 29Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar, 30Schwab SJ Hlatky MA Pieper KS et al.Contrast nephrotoxicity: a randomized controlled trial of a nonionic and an ionic radiographie contrast agent.N tlngl J Med. 1989; 320: 149-153Crossref PubMed Scopus (377) Google Scholar Numerous studies have shown that the risk is similar between the 2 contrast agents and depends more on the patient population.17Parfrey PS Griffiths SM Barrett BJ et al.Contrast material induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study.N Engl J Med. 1989; 320: 143-149Crossref PubMed Scopus (891) Google Scholar, 21Barrett BJ Parfrey PS Vavasour HM et al.Contrast nephropathy in patients with impaired renal function: high versus low osmolar media.Kidney Int. 1992; 41: 1274-1279Crossref PubMed Scopus (207) Google Scholar, 30Schwab SJ Hlatky MA Pieper KS et al.Contrast nephrotoxicity: a randomized controlled trial of a nonionic and an ionic radiographie contrast agent.N tlngl J Med. 1989; 320: 149-153Crossref PubMed Scopus (377) Google Scholar, 31Taliercio CP Vlielslra RF Llstrup DM et al.A randomized comparison of the nephrotoxicity of iopamidol and diatrizoate in high risk patients undergoing cardiac angiography.J Am Coll Cardiol. 1991; 17: 384-390Abstract Full Text PDF PubMed Scopus (135) Google Scholar Currently, the "third generation"of low-osmolality contrast agents, which are isotonic to plasma, is being evaluated25Harnish PP Fountainc H Fbrahimi R [odixanol: experience in 1259 patients in the United States.Invest Radiol. 1994; 29: S236-S237Crossref PubMed Scopus (9) Google Scholar; it is unknown whether these agents have a more favorable nephrotoxic profile. The overall prevalence of CM-ARF remains a common cause of acute renal failure in hospitalized patients with preexisting renal dysfunction.17Parfrey PS Griffiths SM Barrett BJ et al.Contrast material induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study.N Engl J Med. 1989; 320: 143-149Crossref PubMed Scopus (891) Google Scholar, 22Shaft T Chou SY Porush JG Shapiro WB Infusion intravenous pyelography and renal function: effects in patients with chronic-renal insufficiency.Arch Intern Med. 1978; 138: 1218-1221Crossref PubMed Scopus (75) Google Scholar, 23Manske CL Sprafka JM Strony JT Wang Y Contrast nephropathy in azotemic diabetic patients undergoing coronary angiog-raphy.Am J Med. 1990; 89: 615-620Abstract Full Text PDF PubMed Scopus (468) Google Scholar, 24Harkoncn S Kjcllstrand CM Exacerbation of diabetic renal failure following intravenous pyelography.Am J Med. 1977; 63: 939-946Abstract Full Text PDF PubMed Scopus (117) Google Scholar, 25Harnish PP Fountainc H Fbrahimi R [odixanol: experience in 1259 patients in the United States.Invest Radiol. 1994; 29: S236-S237Crossref PubMed Scopus (9) Google Scholar Adenosine, a nucleoside generated from the energy metabolism of adenosine triphosphate (ATP) hydrolysis, is widely recognized as a regulator of physiologic functions, including cardiac rate and contractility, smooth muscle tone, neurotransmitter release, lipolysis, white blood cell function, platelet function, and renal function." Because of its ubiquity, its role in the regulation of cellular function, its close metabolic relationship to fundamental cellular events such as bioenergetics, gene expression, and signal transduction, and its modulation of vascular tone, adenosine is thought to be among the best examples of autocrine/paracrine regulation. Formation of adenosine occurs by 2 pathways: (1) a transmethylation pathway in which S-adenosylhomocysteine is hydrolyzed to adenosine and homocysteine by S-adenosylhomocysteine hydrolase (intracellularly); and (2) dephosphorylation of 5′-adenosine monophosphate (5′AMP) by 5′-nucleotidase enzymes and nonspecific phosphatases (intra- and extracellularly). The major source of adenosine is via 5′ nucleotidase, which is activated by low levels of ATP during conditions that lower energy levels such as hypoxemia and ischemia. Adenosine stimulates adenosine receptors, is taken up by cells (eg, erythrocytes), and is metabolized by adenosine deaminase to inosine 5Morcos SK Contrast media-induced nephrotoxicity-questions and answers.RrJ Radiol. 1998; 71: 357-365Google Scholar,32–34 (Figure 1). Adenosine receptors have been characterized in the kidney, heart, lungs, liver, and brain. Adenosine receptors are subdivided into 4 identified subtypes, A1, A2α, A2β and A3.5Morcos SK Contrast media-induced nephrotoxicity-questions and answers.RrJ Radiol. 1998; 71: 357-365Google Scholar Adenosine Al and A2α are high-affinity adenosine receptors, which adenosine activates in physiologic concentrations of 10-8 to 10-7 mol/L, while A2β and A3 are lowaffinity adenosine receptors, with adenosine activating only in micromolar concentration, ranging from 10-6 to 10-5 mol/L. While basal adenosine concentrations are around 10-7 mol/L, they can increase to 10-5 mol/L under hypoxic conditions. Thus, high-affinity adenosine receptors A1 and A2α appear to be constitutively stimulated at physiologic adenosine concentrations, while A2β and A3 receptors are activated only under extreme pathological conditions associated with much higher adenosine levels.35Müller CE Stein B Adenosine receptor antagoniste: structures and potential therapeutic applications.Curr Pharm Res. 1996; 2: 501-530Google Scholar, 36Millier CE A-adenosinc receptor antagonists.Expert Opin Ther Patents. 1997; 7: 419-440Crossref Scopus (92) Google Scholar Table 1 summarizes the renal effects of adenosine related to specific receptor types. In the kidney, adenosine modulates vascular and tubular function primarily via Al and A2α adenosine receptors.32McCoy DE Bhattacharya S Olson BA Levier DG Arend LJ Spiclman WS The renal adenosine system: structure, function, and regulation.Semin Nephrol. 1993; 13: 31-40PubMed Google Scholar, 35Müller CE Stein B Adenosine receptor antagoniste: structures and potential therapeutic applications.Curr Pharm Res. 1996; 2: 501-530Google Scholar These receptors are found throughout the kidney with a predominance of A1 receptors present on the afferent arteriole and renal tubules, and A2α receptors primarily located on the efferent arteriole.32McCoy DE Bhattacharya S Olson BA Levier DG Arend LJ Spiclman WS The renal adenosine system: structure, function, and regulation.Semin Nephrol. 1993; 13: 31-40PubMed Google Scholar Medullary capillaries have been shown to possess both A1 and A2α receptors.37Silldorff EP Kreisberg MS Pallone TL Adenosine modulates vasomotor tone in outer medullary descending vasa recta of the rat.J Clin Invest. 1996; 98: 18-23Crossref PubMed Scopus (52) Google Scholar Stimulation of Al receptors (Alα, A1β), which are coupled to G-inhibitory protein, and another G protein (not yet identified) causes vasoconstriction by subsequently increasing intracellular calcium of the smooth muscle cell (Figure 1). In contrast, stimulation of A2α receptors, which are coupled to G-stimulatory protein, causes vasodilation.32McCoy DE Bhattacharya S Olson BA Levier DG Arend LJ Spiclman WS The renal adenosine system: structure, function, and regulation.Semin Nephrol. 1993; 13: 31-40PubMed Google ScholarTable 1Functional Effects of Renal Adenosine A1 and A2a Receptors*cAMP = cyclic adenosine monophosphate.LocationEffectsReceptor typeReferencesGlomcrular filtrationIncreaseA2α29Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar, 37Silldorff EP Kreisberg MS Pallone TL Adenosine modulates vasomotor tone in outer medullary descending vasa recta of the rat.J Clin Invest. 1996; 98: 18-23Crossref PubMed Scopus (52) Google ScholarDecreaseA129Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar, 38Pflueger AC Schenk F Osswald H Increased sensitivity of the renal vasculature to adenosine in streptozotocin-induced diabetes mcllilus rats.Am J Physiol. 1995; 269: F529-F535PubMed Google Scholar, 39Pflucger AC Osswald H Knox FG Adenosine-induccd renal vasoconstriction in diabetes mellitus rats: role of nitric oxide.Am J Physiol. 1999; 276: F340-F346PubMed Google Scholar, 40Melin J Hellberg O Akyurek LM Kallskog O Larsson E Fellstrom BC. Ischemia causes rapidly progressive nephropathy in the diabetic rat.Kidney Int. 1997; 52: 985-991Crossref PubMed Scopus (75) Google ScholarAfferent artcrioleVasoconstrictionA121Barrett BJ Parfrey PS Vavasour HM et al.Contrast nephropathy in patients with impaired renal function: high versus low osmolar media.Kidney Int. 1992; 41: 1274-1279Crossref PubMed Scopus (207) Google Scholar, 29Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar, 33Pflueger A Renale Wirhingen von Adenosin bei Ratten mit experimentellem Diabetes mellitus. Medical Faculty of Tübingen, Tübingen, Germany1997: 1-201Google Scholar, 34Osswuld H Adenosine and renal function.in: Berne RM Rall TW Rubio R Regulatory Function of Adenosine. Martinus Nijho'f Publishers, The Hague, Netherlands1983: 399-415Crossref Google Scholar, 36Millier CE A-adenosinc receptor antagonists.Expert Opin Ther Patents. 1997; 7: 419-440Crossref Scopus (92) Google Scholar, 38Pflueger AC Schenk F Osswald H Increased sensitivity of the renal vasculature to adenosine in streptozotocin-induced diabetes mcllilus rats.Am J Physiol. 1995; 269: F529-F535PubMed Google ScholarEfferent arterioleVasodilationA2α29Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar, 37Silldorff EP Kreisberg MS Pallone TL Adenosine modulates vasomotor tone in outer medullary descending vasa recta of the rat.J Clin Invest. 1996; 98: 18-23Crossref PubMed Scopus (52) Google ScholarMedullary capillariesVasoconstriclionA132McCoy DE Bhattacharya S Olson BA Levier DG Arend LJ Spiclman WS The renal adenosine system: structure, function, and regulation.Semin Nephrol. 1993; 13: 31-40PubMed Google ScholarVasodilalionA2α32McCoy DE Bhattacharya S Olson BA Levier DG Arend LJ Spiclman WS The renal adenosine system: structure, function, and regulation.Semin Nephrol. 1993; 13: 31-40PubMed Google ScholarJuxtaglomerular apparatusDecrease renin releaseA129Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar, 37Silldorff EP Kreisberg MS Pallone TL Adenosine modulates vasomotor tone in outer medullary descending vasa recta of the rat.J Clin Invest. 1996; 98: 18-23Crossref PubMed Scopus (52) Google ScholarIncrease renin releaseA2α29Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar, 37Silldorff EP Kreisberg MS Pallone TL Adenosine modulates vasomotor tone in outer medullary descending vasa recta of the rat.J Clin Invest. 1996; 98: 18-23Crossref PubMed Scopus (52) Google ScholarErythropoietin synthesisInhibitionA129Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google ScholarStimulationA2α29Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google ScholarPresynaptic neurotransmitter releaseInhibitionA2α29Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google ScholarCollecting ductsDecrease cAMPA129Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google ScholarIncrease cAMPA2129Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar, 37Silldorff EP Kreisberg MS Pallone TL Adenosine modulates vasomotor tone in outer medullary descending vasa recta of the rat.J Clin Invest. 1996; 98: 18-23Crossref PubMed Scopus (52) Google ScholarProximal tubuleIncrease phosphate transportA139Pflucger AC Osswald H Knox FG Adenosine-induccd renal vasoconstriction in diabetes mellitus rats: role of nitric oxide.Am J Physiol. 1999; 276: F340-F346PubMed Google ScholarAscending limb of loop of Henle (sodium transport)Decrease cAMPA129Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google ScholarIncrease cAMPA2α29Moore RD Steinberg EP Powe NR et al.Nephrotoxicity of high-osmolality versus low-osmolality contrast media: randomized clinical trial.Radiology. 1992; 182: 649-655PubMed Google Scholar* cAMP = cyclic adenosine monophosphate. Open table in a new tab Despite the presence of both A1 and A2α adenosine receptors, the infusion of adenosine into the renal artery or lower abdominal aorta causes a reduction in total renal blood flow. 33Pflueger A Renale Wirhingen von Adenosin bei Ratten mit experimentellem Diabetes mellitus. Medical Faculty of Tübingen, Tübingen, Germany1997: 1-201Google Scholar,34,38,39,41,42 In contrast to other vascular beds (eg, coronary capillaries, cerebral vasculature, and gastrointestinal vasculature) in which adenosine acts as a vasodilator,32McCoy DE Bhattacharya S Olson BA Levier DG Arend LJ Spiclman WS The renal adenosine system: structure, function, and regulation.Semin Nephrol. 1993; 13: 31-40PubMed Google Scholar, 33Pflueger A Renale Wirhingen von Adenosin bei Ratten mit experimentellem Diabetes mellitus. Medical Faculty of Tübingen, Tübingen, Germany1997: 1-201Google Scholar, 34Osswuld H Adenosine and renal function.in: Berne RM Rall TW Rubio R Regulatory Function of Adenosine. Martinus Nijho'f Publishers, The Hague, Netherlands1983: 399-415Crossref Google Scholar, 38Pflueger AC Schenk F Osswald H Increased sensitivity of the renal vasculature to adenosine in str
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