Artigo Acesso aberto Revisado por pares

The intrarenal renin-angiotensin system in hypertension

2004; Elsevier BV; Volume: 65; Issue: 4 Linguagem: Inglês

10.1111/j.1523-1755.2004.00539.x

ISSN

1523-1755

Autores

L. Gabriel Navar,

Tópico(s)

Hormonal Regulation and Hypertension

Resumo

A 50-year-old woman with type 2 diabetes mellitus and hypertension was admitted to Brigham and Women's Hospital in Boston for entry into a clinical research protocol involving hemodynamic responses to angiotensin II (Ang II) receptor blockade. She presented to a local emergency room with severe headache at the age of 40. Her blood glucose at that time exceeded 800 mg/dL. After 1 year of failed therapy with oral hypoglycemic agents, insulin therapy was initiated. Her blood sugar control has been fair; she complains of twice nightly nocturia. She also has a burning and tingling neuropathy in her hands and feet, and she suffers from migraines related to stress. The patient's mother and father both died from complications of type 2 diabetes mellitus. One of her five siblings has diabetes that is treated with oral medications. The patient has three children who are well. The medical history is significant for hypertriglyceridemia and asthma; the most recent episode was 8 years ago. She also has angina. Thallium perfusion imaging was performed for chest pain 2 years prior to admission; both the stress and rest scan studies were normal. She had a tubal ligation at age 35, gastric stapling, and a cholecystectomy. Her current medications included lisinopril, 10 mg daily (held for 2 weeks prior to physiologic study); insulin, 46 units NPH, 8 regular every morning; and 32 NPH, 6 regular each evening; gemfibrozil, 1200 mg daily; nizatidine, 150 mg twice daily; amitriptyline, 100 mg at bedtime for neuropathy; and albuterol, 2 puffs as needed, but she hasn't required it in many months. Physical examination revealed: height, 158 cm; weight, 106.2 kg. Her blood pressures while seated with a thigh cuff were: 146/94 mm Hg, 144/94 mm Hg, and 146/94 mm Hg. The standing blood pressure was 142/90 mm Hg; pulse, 120 beats/min; and she reported feeling slightly dizzy. Her heart rate was 100 beats/min. Examination of the head, eyes, ears, nose, and throat was normal, with no carotid bruits and no jugular venous distention. Cardiac examination disclosed tachycardia, a regular S1 and S2, and no murmurs. The patient was morbidly obese and her abdomen was soft; bowel sounds were present. Her lungs were clear, and there was no costovertebral angle tenderness. No edema was present in her extremities. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined under low-salt conditions (after 1 week of a 10 mmol Na+ diet) from the p-aminohippuric acid (PAH) (Merck Sharp & Dohme, West Point, PA, USA) and inulin clearances after achieving metabolic balance on the low-salt diet. An intravenous catheter was placed in each of the patient's arms, one for the infusion, the other for blood sampling. Basal PAH and inulin clearances were calculated from their plasma levels and infusion rates for each substance. Plasma samples reflecting the control clearances were obtained 60 minutes after the start of the PAH infusion, when a steady state had been achieved, and 90 minutes thereafter following treatment with the Ang II type 1 (AT1) receptor antagonist irbesartan. Following 1 week on the low-salt diet, her basal plasma renin activity (PRA) was 2.8 ng/Ang I/mL/hour and her control arterial pressures during the equilibration phase averaged 123/72 mm Hg. Following treatment with 150 mg of irbesartan, her arterial pressure fell slightly to an average of 113/71 mm Hg. Basal RPF measured 596 mg mL/min/1.73 m2. Ninety minutes after receiving an acute dose of 150 mg irbesartan, the RPF was 786 mL/min/1.73 m2, for a response to the angiotensin receptor blocker of 190 mL/min/1.73 m2. The basal GFR was 122 mL/min/1.73 m2, and it increased to a peak GFR post irbesartan of 163 mL/min/1.73 m2, for an increase of 41 mL/min/1.73 m2. DR. L. GABRIEL NAVAR (Professor and Chairman, Department of Physiology; and Co-Director, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana, USA): This patient is a dramatic example of a metabolic syndrome of hypertension, diabetes, and obesity associated with hypertriglyceridemia. Even though this woman does not have severe hypertension, even moderately elevated arterial pressure in patients with diabetes can pose serious long-term risks for target organ damage, including the kidney. Treatment with angiotensin-converting enzyme (ACE) inhibitors or AT1 receptor blockers, however, can markedly retard the rate of loss of renal function [1.Bakris G.L. Williams M. Dworkin L. et al.Preserving renal function in adults with hypertension and diabetes: A consensus approach.Am J Kidney Dis. 2000; 36: 646-661Abstract Full Text Full Text PDF PubMed Scopus (1203) Google Scholar, 2.Brenner B.M. Nephrology Forum: Retarding the progression of renal disease.Kidney Int. 2003; 64: 369-378Abstract Full Text Full Text PDF Google Scholar]. She was given a low-salt diet for 1 week. Then an acute dose of irbesartan, an Ang II AT1 receptor blocker (ARB), was administered to determine the renal responsiveness to acute blockade of AT1 receptors. We should note that this patient did not exhibit an unusually large increase in PRA in response to the low-salt diet. Thus, the circulating renin activity did not suggest a particularly marked activation of the renin-angiotensin system (RAS). Nevertheless, in response to acute treatment with the ARB, she did manifest dramatic increases both in renal plasma flow, measured by PAH clearance, and GFR, measured by inulin clearance. This patient reflects a group of individuals who might have marked activation of the intrarenal RAS even though it is apparent neither from the PRA data nor from the responses in systemic arterial pressure to AT1 receptor blockade [3.Hollenberg N.K. Price D.A. Fisher N.D. et al.Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus.Kidney Int. 2003; 63: 172-178Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar]. After 1 week of a low-salt diet, this patient's arterial pressure had fallen to 123/72 mm Hg the day of the study and only decreased slightly in response to irbesartan treatment to 113/71 mm Hg. Nevertheless, RPF increased by 32%, and the GFR increased by 34%. Importantly, both the RPF and GFR increased proportionally to a similar extent, leaving the filtration fraction essentially unchanged (20% to 21%). Similar results have been reported using ACE inhibitors, ARBs, and renin inhibitors in normal subjects and in patients with essential hypertension [4.Fisher N.D.L. Price D.A. Litchfield W.R. et al.Renal response to captopril reflects state of local renin system in healthy humans.Kidney Int. 1999; 56: 635-641Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 5.Hollenberg N.K. Meggs L.G. Williams G.H. et al.Sodium intake and renal responses to captopril in normal man and in essential hypertension.Kidney Int. 1981; 20: 240-245Abstract Full Text PDF PubMed Scopus (164) Google Scholar, 6.Fisher N.D.L. Allan D. Kifor I. et al.Responses to converting enzyme and renin inhibition. Role of angiotensin in humans.Hypertension. 1994; 23: 44-51Crossref PubMed Scopus (82) Google Scholar]. On first impression, it would seem that this patient's response was paradoxical and at variance with the commonly held concept that high intrarenal Ang II levels primarily constrict efferent arterioles, while ACE inhibitors and ARBs primarily dilate efferent arterioles. This misconception resulted from the generalization of the effects of ACE inhibitors in patients with severe renal arterial lesions or stenosis or with long-standing structural damage of the preglomerular arteriolar vasculature. When the preglomerular vasculature loses its functional integrity, blockade of the RAS system can lead to predominant efferent arteriolar dilation and reductions in GFR. However, the bulk of the data both in patients and experimental animals indicates that Ang II elicits dose-dependent decreases in RPF but often with lesser falls in GFR, leading to increases in filtration fraction [7.Mitchell K.D. Navar L.G. Intrarenal actions of angiotensin II in the pathogenesis of experimental hypertension (chap 86).in: Laragh J.H. Brenner B.M. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. Raven, New York1995: 1437-1450Google Scholar, 8.Navar L.G. Inscho E.W. Majid S.A. et al.Paracrine regulation of the renal microcirculation [review].Physiol Rev. 1996; 76: 425-536PubMed Google Scholar, 9.Vos P.F. Koomans H.A. Boer P. Mees E.J.D. Effects of angiotensin II on renal sodium handling and diluting capacity in man pretreated with high-salt diet and enalapril.Nephrol Dial Transplant. 1992; 7: 991-996PubMed Google Scholar]. Likewise, blockade of Ang II receptors raises both RPF and GFR but decreases the filtration fraction [3.Hollenberg N.K. Price D.A. Fisher N.D. et al.Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus.Kidney Int. 2003; 63: 172-178Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 7.Mitchell K.D. Navar L.G. Intrarenal actions of angiotensin II in the pathogenesis of experimental hypertension (chap 86).in: Laragh J.H. Brenner B.M. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. Raven, New York1995: 1437-1450Google Scholar]. Unfortunately, the Ang II-induced increases in filtration fraction and the Ang II blockade-induced decreases in filtration fraction frequently have been interpreted as evidence supporting a predominant effect of Ang II on efferent arterioles. Let me emphasize that this interpretation is faulty in that changes in filtration fraction often occur as a consequence of parallel changes in afferent and efferent resistances [8.Navar L.G. Inscho E.W. Majid S.A. et al.Paracrine regulation of the renal microcirculation [review].Physiol Rev. 1996; 76: 425-536PubMed Google Scholar, 10.Carmines P.K. Perry M.D. Hazelrig J.B. et al.Effects of preglomerular and postglomerular vascular resistance alterations on filtration fraction.Kidney Int. 1987; 31: S229-S232Google Scholar]. A variety of studies both in normal and hypertensive models have shown that Ang II elicits reductions in single-nephron GFR and glomerular plasma flow because Ang II increases both afferent and efferent arteriolar resistances; direct microcirculation studies have shown dose-dependent afferent and efferent arteriolar vasoconstriction elicited by Ang II [11.Carmines P.K. Navar L.G. Disparate effects of Ca channel blockade on afferent and efferent arteriolar responses to ANG II.Am J Physiol (Renal Physiol). 1989; 256: F1015-F1020PubMed Google Scholar, 12.Ichihara A. Imig J.D. Inscho E.W. Navar L.G. Interactive nitric oxide-angiotensin II influences on renal microcirculation in angiotensin II-induced hypertension.Hypertension. 1998; 31: 1255-1260Crossref PubMed Scopus (38) Google Scholar]. This patient clearly demonstrated a robust increase in GFR as well as in RPF in response to irbesartan. These increases indicate that the preglomerular vasculature was highly responsive, not functionally impaired, and was under the substantial influence of high intrarenal levels of Ang II that elicited strong influences on the renal microvasculature. It is also possible that the increases in GFR were partly due to (1) the ability of AT1 receptor blockade to reverse Ang II-mediated decreases in the glomerular filtration coefficient, and (2) to a component of plasma flow dependency [3.Hollenberg N.K. Price D.A. Fisher N.D. et al.Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus.Kidney Int. 2003; 63: 172-178Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar]. The estimated changes in the determinants of glomerular dynamics are shown in Figure 1. Although the magnitude of the increases observed is greater than the responses generally observed, increases in RPF and GFR have been reported often. Thus, one important objective of this Forum is to correct a commonly held view that angiotensin antagonists predominantly dilate the efferent arterioles. The reason for the very robust responses to irbesartan in certain patients is not clear, but it is assumed that when intrarenal Ang II levels remain chronically elevated, various compensatory mechanisms such as vasodilator prostanoids and intrarenal nitric oxide activity are increased [13.Navar L.G. Ichihara A. Chin S.Y. Imig J.D. Nitric oxide-angiotensin II interactions in angiotensin II-dependent hypertension.Acta Physiol Scand. 2000; 168: 139-147Crossref PubMed Google Scholar]. When the AT1 receptors were blocked acutely, the stimulated vasodilatory mechanisms were left unopposed and markedly raised RPF and GFR [8.Navar L.G. Inscho E.W. Majid S.A. et al.Paracrine regulation of the renal microcirculation [review].Physiol Rev. 1996; 76: 425-536PubMed Google Scholar]. With continued treatment, the activity of these compensatory mechanisms would be expected to abate and renal hemodynamic function would return toward normal. In general, elevated circulating renin levels in various hypertensive and diabetic conditions are certainly recognized as being indicative of a role for inappropriate activation of the RAS; but increased local activity of the RAS can occur even when the circulating indices are within the normal range. This increased activity could be due, in part, to increased expression of ACE on renal vascular endothelial cells in certain diseases, including diabetes and hypertension [14.Metzger R. Bohle R.M. Pauls K. et al.Angiotensin-converting enzyme in non-neoplastic kidney diseases.Kidney Int. 1999; 56: 1442-1454Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. In some organs, particularly the kidneys and adrenal glands, intrarenal Ang II, expressed as content per mass of tissue, is much greater than what can be explained on the basis of passive equilibration with the circulating components [15.Navar L.G. Imig J.D. Zou L. Wang C.-T. Intrarenal production of angiotensin II.Semin Nephrol. 1997; 17: 412-422PubMed Google Scholar, 16.Navar L.G. Lewis L. Hymel A. et al.Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats.J Am Soc Nephrol. 1994; 5: 1153-1158Crossref PubMed Google Scholar]. In the case of the kidney, the level of complexity might be even greater than was previously thought in that there is specific compartmentalization of renin and angiotensin levels with distinct regulatory mechanisms predominating in the separate compartments [17.Navar L.G. Harrison-Bernard L.M. Imig J.D. Compartmentalization of intrarenal angiotensin II (chap 16).in: Ulfendahl H.R. Aurell M. Renin-Angiotensin. Portland Press, London1998: 193-208Google Scholar]. Studies in human subjects have provided support for kidney-specific augmentation of the intrarenal RAS. Indeed, some of the earliest reports of the effects of ACE inhibition on renal function in humans demonstrated that administration of the first ACE inhibitor known as teprotide or SQ20881 to patients with essential hypertension significantly increased GFR and sodium excretion despite the associated decreases in arterial pressure [18.Hollenberg N.K. Swartz S.L. Passan D.R. Williams G.H. Increased glomerular filtration rate after converting-enzyme inhibition in essential hypertension.N Engl J Med. 1979; 301: 9-12Crossref PubMed Scopus (115) Google Scholar]. Sodium excretion increased in every patient, and neither the magnitude of the fall in blood pressure nor the change in creatinine clearance influenced the degree of natriuresis. Patients with essential hypertension treated with captropril had a similar or greater natriuretic response [5.Hollenberg N.K. Meggs L.G. Williams G.H. et al.Sodium intake and renal responses to captopril in normal man and in essential hypertension.Kidney Int. 1981; 20: 240-245Abstract Full Text PDF PubMed Scopus (164) Google Scholar]. These early findings set the stage for many subsequent studies that led to the recognition that the natriuretic responses to ACE inhibitors cannot be explained solely on the basis of the hemodynamic response but might include direct changes in tubular sodium reabsorption. That the responses to Ang II blockade in these patients could not be correlated with plasma Ang II levels again suggested independent regulation of intrarenal Ang II. Several experimental models of hypertension support an overactive RAS in the development and maintenance of hypertension [7.Mitchell K.D. Navar L.G. Intrarenal actions of angiotensin II in the pathogenesis of experimental hypertension (chap 86).in: Laragh J.H. Brenner B.M. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. Raven, New York1995: 1437-1450Google Scholar, 19.Ploth D.W. Angiotensin-dependent renal mechanisms in two-kidney one-clip renal vascular hypertension.Am J Physiol (Renal Physiol). 1983; 245: F131-F141PubMed Google Scholar, 20.Frohlich E.D. Influence of nitric oxide and angiotensin II on renal involvement in hypertension.Hypertension. 1997; 29: 188-193Crossref PubMed Google Scholar]. In Ang II-dependent forms of hypertension, the inappropriate activation of the intrarenal RAS limits the kidney's ability to maintain sodium balance when perfused at normal arterial pressures [7.Mitchell K.D. Navar L.G. Intrarenal actions of angiotensin II in the pathogenesis of experimental hypertension (chap 86).in: Laragh J.H. Brenner B.M. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. Raven, New York1995: 1437-1450Google Scholar, 21Navar L.G. Hamm L.L. The kidney in blood pressure regulation (chap 1).in: Wilcox C.S. Atlas of Diseases of the Kidney, Hypertension and the Kidney. vol 3. Current Medicine, Philadelphia1999: 1.1-1.22Google Scholar]. Overactivation of the intrarenal RAS leads to alterations in hemodynamic and transport function that contribute to the development and maintenance of hypertension. Persistence of this overactivation leads to long-term consequences, including cellular proliferation and renal injury. The complex and extensive actions of Ang II on renal function are mediated by the widespread distribution of Ang II receptors throughout the kidney in various nephron segments as well as in the vasculature and interstitium. The two major types of Ang II receptors are AT1 and AT2, but the hypertensinogenic actions of Ang II are primarily attributed to the AT1 receptor because of its multiple vascular and transport effects Figure 2. In addition to the vascular AT1 receptors, AT1 receptors have been localized to glomerular podocyte cells, proximal tubule brush border and basolateral membranes, interstitial cells, thick ascending limb epithelia, distal tubules, collecting ducts, and macula densa cells [22.Harrison-Bernard L.M. Navar L.G. Ho M.M. et al.Immunohistochemical localization of ANG II AT1 receptor in adult rat kidney using a monoclonal antibody.Am J Physiol (Renal Physiol). 1997; 273: F170-F177PubMed Google Scholar, 23.Wang Z.-Q. Millatt L.J. Heiderstadt N.T. et al.Differential regulation of renal angiotensin subtype AT1A and AT2 receptor protein in rats with angiotensin-dependent hypertension.Hypertension. 1999; 33: 96-101Crossref PubMed Scopus (77) Google Scholar, 24.Miyata N. Park F. Li X.F. Cowley JR, A.W. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney.Am J Physiol (Renal Physiol). 1999; 277: F437-F446PubMed Google Scholar]. Because of the extensive localization of AT1 receptors in luminal as well as basolateral membranes of proximal and distal nephron segments, interest is growing in the relative roles of Ang II in the renal interstitium and the tubular network. Much less AT2 receptor immunostaining occurs in adult kidneys, but it has been found in proximal tubules, collecting ducts, and some of the vasculature [23.Wang Z.-Q. Millatt L.J. Heiderstadt N.T. et al.Differential regulation of renal angiotensin subtype AT1A and AT2 receptor protein in rats with angiotensin-dependent hypertension.Hypertension. 1999; 33: 96-101Crossref PubMed Scopus (77) Google Scholar, 24.Miyata N. Park F. Li X.F. Cowley JR, A.W. Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney.Am J Physiol (Renal Physiol). 1999; 277: F437-F446PubMed Google Scholar]. Thus, it is now well recognized that Ang II has many other actions in addition to the more obvious hemodynamic responses. While some of these actions have obvious physiologic relevance, others, such as activation of cytokines and reactive oxygen species, occur primarily in a pathophysiologic setting and are linked to tissue injury, fibrosis, and proliferation [25Wolf G. The Renin-Angiotensin System and Progression of Renal Diseases.in: Berlyne G.M. Ronco C. Contributions in Nephrology. vol 135. Karger, Hamburg2002: 1-268Google Scholar]. In the final analysis, however, the local effects depend on the actual concentrations of the Ang II maintained within the corresponding compartment. Although direct measurements in human subjects are not available, experimental studies indicate that intrarenal Ang II tissue content is much higher than can be explained on the basis of non-specific equilibration between plasma Ang II concentrations and intrarenal extracellular fluid [26.Reams G. Villarreal D. Wu Z. Bauer J.H. Renal tissue angiotensin II: Response to infusions of angiotensin I and an angiotensin-converting enzyme inhibitor.Am J Kidney Dis. 1993; 22: 851-857Abstract Full Text PDF PubMed Scopus (15) Google Scholar, 27.Campbell D.J. Lawrence A.C. Towrie A. et al.Differential regulation of angiotensin peptide levels in plasma and kidney of the rat.Hypertension. 1991; 18: 763-773Crossref PubMed Scopus (211) Google Scholar, 28.Imig J.D. Navar G.L. Zou L.X. et al.Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors.Am J Physiol (Renal Physiol). 1999; 277: F303-F311PubMed Google Scholar]. Variations in dietary sodium chloride intake are closely associated with changes in renal renin, Ang I, and Ang II content. However, the total renal levels of Ang I and Ang II remain higher than the corresponding plasma concentrations, so the intrarenal levels likely are not due to simple equilibration with circulating Ang II [27.Campbell D.J. Lawrence A.C. Towrie A. et al.Differential regulation of angiotensin peptide levels in plasma and kidney of the rat.Hypertension. 1991; 18: 763-773Crossref PubMed Scopus (211) Google Scholar, 28.Imig J.D. Navar G.L. Zou L.X. et al.Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors.Am J Physiol (Renal Physiol). 1999; 277: F303-F311PubMed Google Scholar, 29.Von Thun A.M. Vari R.C. El-Dahr S.S. Navar L.G. Augmentation of intrarenal angiotensin II levels by chronic angiotensin II infusion.Am J Physiol (Renal Physiol). 1994; 266: F120-F128PubMed Google Scholar, 30.Guan S. Fox J. Mitchell K.D. Navar L.G. Angiotensin and angiotensin converting enzyme tissue levels in two-kidney, one clip hypertensive rats.Hypertension. 1992; 20: 763-767Crossref PubMed Scopus (151) Google Scholar]. Renal Ang II levels in several experimental models of angiotensin-dependent hypertension are much higher than the plasma concentrations. This has been demonstrated in 2-kidney, 1-clip (2K1C) Goldblatt hypertension, Ang II-infused animals with hypertension, Ren2 TGR hypertension, and Dahl salt-sensitive rats fed a high-salt diet [29.Von Thun A.M. Vari R.C. El-Dahr S.S. Navar L.G. Augmentation of intrarenal angiotensin II levels by chronic angiotensin II infusion.Am J Physiol (Renal Physiol). 1994; 266: F120-F128PubMed Google Scholar, 30.Guan S. Fox J. Mitchell K.D. Navar L.G. Angiotensin and angiotensin converting enzyme tissue levels in two-kidney, one clip hypertensive rats.Hypertension. 1992; 20: 763-767Crossref PubMed Scopus (151) Google Scholar, 31.Zou L. Imig J.D. Von Thun A.M. et al.Receptor-mediated intrarenal ANG II augmentation in ANG II-infused rats.Hypertension. 1996; 28: 669-677Crossref PubMed Scopus (175) Google Scholar, 32.Kobori H. Nishiyama A. Abe Y. Navar L.G. Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet.Hypertension. 2003; 41: 592-597Crossref PubMed Scopus (199) Google Scholar, 33.Mitchell D.K. Jacinto S.M. Mullins J.J. Proximal tubular fluid, kidney, and plasma levels of angiotensin II in hypertensive ren-2 transgenic rats.Am J Physiol (Renal Physiol). 1997; 273: F246-F253PubMed Google Scholar]. In these models, the augmentation of intrarenal Ang II content is the consequence of several mechanisms. In addition to intrarenal formation of Ang II, the kidney accumulates Ang II from the circulation via an AT1 receptor-mediated process [31.Zou L. Imig J.D. Von Thun A.M. et al.Receptor-mediated intrarenal ANG II augmentation in ANG II-infused rats.Hypertension. 1996; 28: 669-677Crossref PubMed Scopus (175) Google Scholar, 34.Zou L. Imig J.D. Hymel A. et al.Renal uptake of circulating angiotensin II in Val5-angiotensin II infused rats is mediated by AT1 receptor.Am J Hypertens. 1998; 11: 570-578Crossref PubMed Scopus (79) Google Scholar]. Sustained elevations in circulating Ang II cause progressive accumulation of intrarenal Ang II levels even in the presence of marked suppression of renin formation. Of clinical relevance is the finding that even non-clipped kidneys of 2K1C Goldblatt rats have elevated intrarenal Ang II levels. Increased Ang II levels occur in renin-depleted kidneys of 2K1C Goldblatt hypertensive rats [29.Von Thun A.M. Vari R.C. El-Dahr S.S. Navar L.G. Augmentation of intrarenal angiotensin II levels by chronic angiotensin II infusion.Am J Physiol (Renal Physiol). 1994; 266: F120-F128PubMed Google Scholar, 30.Guan S. Fox J. Mitchell K.D. Navar L.G. Angiotensin and angiotensin converting enzyme tissue levels in two-kidney, one clip hypertensive rats.Hypertension. 1992; 20: 763-767Crossref PubMed Scopus (151) Google Scholar, 35.Cervenka L. Wang C.-T. Mitchell K.D. Navar L.G. Proximal tubular angiotensin II levels and renal functional responses to AT1 receptor blockade in nonclipped kidneys of Goldblatt hypertensive rats.Hypertension. 1999; 33: 102-107Crossref PubMed Scopus (94) Google Scholar, 36.Tokuyama H. Hayashi K. Matsuda H. et al.Differential regulation of elevated renal angiotensin II in chronic renal ischemia.Hypertension. 2002; 40: 34-40Crossref PubMed Scopus (45) Google Scholar], Ang II-infused hypertensive rats [29.Von Thun A.M. Vari R.C. El-Dahr S.S. Navar L.G. Augmentation of intrarenal angiotensin II levels by chronic angiotensin II infusion.Am J Physiol (Renal Physiol). 1994; 266: F120-F128PubMed Google Scholar, 31.Zou L. Imig J.D. Von Thun A.M. et al.Receptor-mediated intrarenal ANG II augmentation in ANG II-infused rats.Hypertension. 1996; 28: 669-677Crossref PubMed Scopus (175) Google Scholar], and Ren2 transgenic rats [33.Mitchell D.K. Jacinto S.M. Mullins J.J. Proximal tubular fluid, kidney, and plasma levels of angiotensin II in hypertensive ren-2 transgenic rats.Am J Physiol (Renal Physiol). 1997; 273: F246-F253PubMed Google Scholar]. In Ang II-infused rats, the augmentation of intrarenal Ang II is dependent on an AT1 receptor-mediated process, as it can be prevented by concomitant treatment with AT1 receptor blockers [31.Zou L. Imig J.D. Von Thun A.M. et al.Receptor-mediated intrarenal ANG II augmentation in ANG II-infused rats.Hypertension. 1996; 28: 669-677Crossref PubMed Scopus (175) Google Scholar, 34.Zou L. Imig J.D. Hymel A. et al.Renal uptake of circulating angiotensin II in Val5-angiotensin II infused rats is mediated by AT1 receptor.Am J Hypertens. 1998; 11: 570-578Crossref PubMed Scopus (79) Google Scholar]. These data demonstrate that intrarenal accumulation of Ang II occurs via an AT1 receptor-mediated mechanism and suggest the presence of receptor-mediated endocytosis and the existence of an intracellular pool of Ang II [28]. The intrarenal content of Ang II is not distributed in a homogeneous fashion but is compartmentalized in both a regional and segmental manner [17.Navar L.G. Harrison-Bernard L.M. Imig J.D. Compartmentalization of intrarenal angiotensin II (chap 16).in: Ulfendahl H.R. Aurell M. Renin-Angiotensin. Portland Press, London1998: 193-208Google Scholar]. Ang II levels in the deep medulla are much higher than cortical levels in normal rats and increase further in Ang II-infused hypertensive rats [15.Navar L.G. Imig J.D. Zou L. Wang C.-T. Intrarenal production of angiotensin II.Semin Nephrol. 1997; 17: 412-422PubMed Google Scholar, 37.Navar L.G. Harrison-Bernard L.M. Imig J.D. Mitchell K.D. Renal actions of angiotensin II at AT1 receptor blockers (chap 13).in: Epstein M. Brunner H.R. Angiotensin II Receptor Antagonists. Hanley & Belfus, Philadelphia2000: 189-214Google Scholar]. Ang II in the renal medulla might be particularly significant in regulating medullary hemodynamics [38.Pallone T.L. Zhang Z. Rhinehart K. Physiology of the renal medullary microcirculation.Am J Physiol (Renal Physiol). 2003; 284: F253-F266Crossref PubMed Scopus (175) Google Scholar]. Also, Ang II receptor density is much greater in the medulla than in the cortex [39.Zhuo J. Alcorn D. Allen A.M. Mendelsohn F.A.O. High resolution localization of angiotensin II receptors in rat renal medulla.Kidney Int. 1992; 42: 1372-1380Abstract Full Text PDF PubMed Scopus (71) Google Scholar]. Within the cortex, Ang II is distributed in the interstitial and tubular fluid as well as within the cells. The interstitial fluid contributes to the disproportionately high total intrarenal Ang II levels. Studies using microdialysis probes implanted in the renal cortex have shown that Ang II and Ang I concentrations in interstitial fluid are much higher than plasma concentrations [40.Siragy H.M. Carey R.M. Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model.Hypertension. 1999; 33: 1237-1242Cros

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