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• W1980809339 abstract "The association between hypertension and chronic renal disease is well known. The pathogenesis of hypertension in patients with chronic kidney disease (CKD) is complex and multifactorial, which may explain why it is resistant to treatment. The traditional paradigm is that hypertension in CKD is due either to an excess of intravascular volume (volume dependent) or to excessive activation of the renin–angiotensin system in relation to the state of sodium/volume balance (renin-dependent hypertension). This review focuses on the importance of less established mechanisms, such as increased activity of the sympathetic nervous system, increased endothelin production, decreased availability of endothelium-derived vasodilators and structural changes of the arteries, renal ischemia, and sleep apnea. The association between hypertension and chronic renal disease is well known. The pathogenesis of hypertension in patients with chronic kidney disease (CKD) is complex and multifactorial, which may explain why it is resistant to treatment. The traditional paradigm is that hypertension in CKD is due either to an excess of intravascular volume (volume dependent) or to excessive activation of the renin–angiotensin system in relation to the state of sodium/volume balance (renin-dependent hypertension). This review focuses on the importance of less established mechanisms, such as increased activity of the sympathetic nervous system, increased endothelin production, decreased availability of endothelium-derived vasodilators and structural changes of the arteries, renal ischemia, and sleep apnea. The association between hypertension and chronic renal disease is well known and renal diseases are by far the most common cause of secondary hypertension. The pathogenesis of hypertension in patients with chronic kidney disease (CKD) is complex and multifactorial, which may explain why it is resistant to treatment. The traditional paradigm is that hypertension in CKD is due either to an excess of intravascular volume (volume dependent) or to excessive activation of the renin–angiotensin system in relation to the state of sodium/volume balance (renin-dependent hypertension) (Table 1). In recent years, this concept has been challenged owing to the recognition that interventions aimed at reducing blood volume and inhibiting the renin–angiotensin system often do not normalize blood pressure (BP), and the unraveling of alternative pathogenic mechanisms (Table 1). Among these are increased activity of the sympathetic nervous system (SNS), increased endothelin (ET) production, decreased availability of endothelium-derived vasodilators/endothelial dysfunction, structural changes of the arteries, renal ischemia, and sleep apnea. In addition, pharmacological interventions aimed at treating the primary renal disease or some of its consequences, such as the use of cyclosporine, steroids, calcium with vitamin D, sympathomimetic agents, erythropoietin, and non-steroidal anti-inflammatory agents, may contribute to sustaining or aggravating hypertension in CKD patients.Table 1Factors implicated in the pathogenesis of hypertension in kidney diseaseTraditional factors Sodium retention and volume excess Activation of the renin–angiotensin systemLess recognized factors Activation of the sympathetic nervous system Renal ischemia Sleep apnea Deficit of endothelium-derived vasodepressor substances Increased endothelin production Reduced central dopaminergic tone Reduced baroreceptor sensitivity/abnormal vagal function Aldosterone Oxidative stress Structural changes of the arteries Obesity/metabolic syndrome Leptin Increased plasma [beta]-endorphin Increased [beta]-lipotropin SerotoninIatrogenic factors Erythropoietin Cyclosporine Steroids Divalent ions and vitamin D Sympathomimetic agents NSAIDSNSAID=non-steroidal anti-inflammatory agents. Open table in a new tab NSAID=non-steroidal anti-inflammatory agents. This review will not address well-established mechanisms, such as sodium retention and activation of the renin–angiotensin system, both of which have been extensively reviewed.1.Campese V.M. Tanacescu A. Hypertension in dialysis patients.in: Henrich W.L. Principles and Practice of Dialysis. Lippincott Williams & Wilkins, Philadelphia2004: 227-256Google Scholar The review will also not address the role of obesity and the metabolic syndrome in hypertension and renal disease, which would require a separate extensive discussion. We will instead emphasize the importance of less established mechanisms, with the belief that therapeutic interventions aimed at those alternative mechanisms may represent the key for adequate BP control in many CKD patients. Increased SNS activity has been demonstrated in diverse experimental models,2.Campese V.M. Kogosov E. Koss M. Renal afferent denervation prevents the progression of renal disease in the renal ablation model of chronic renal failure in the rat.Am J Kidney Dis. 1995; 26: 861-865Abstract Full Text PDF PubMed Scopus (148) Google Scholar, 3.Ye S. Nosrati S. Campese V.M. Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF).J Clin Invest. 1997; 99: 540-548Crossref PubMed Scopus (105) Google Scholar as well as in patients with renal disease.4.Converse Jr, R.L. Jacobsen T.N. Toto R.D. et al.Sympathetic overactivity in patients with chronic renal failure.N Engl J Med. 1992; 327: 1912-1918Crossref PubMed Scopus (965) Google Scholar Animal studies have shown that the kidney is not only an elaborate filtering device but also a sensory organ, richly innervated with sensory and afferent nerves. Thus, in addition to being the target of the SNS activity, the kidney can also be the origin and modulator of this activity. There are two main functional types of renal sensory afferent nerve fibers: (a) hard and sensitive fibers, which increase their firing in response to changes in renal perfusion and intrarenal pressure and (b) chemosensitive fibers, which are stimulated by ischemic metabolites or uremic toxins.5.Katholi R.E. Renal nerves and hypertension: an update.Fed Proc. 1985; 44: 2846-2850PubMed Google Scholar The activation of these fibers may establish connections with integrative nuclei of the SNS in the central nervous system.6.Faber J.E. Brody M.J. Afferent renal nerve-dependent hypertension following acute renal artery stenosis in the conscious rat.Circ Res. 1985; 57: 676-688Crossref PubMed Scopus (78) Google Scholar, 7.Calaresu F.R. Ciriello J. Renal afferent nerves affect discharge rate of medullary and hypothalamic single units in the cat.J Auton Nerv Syst. 1981; 3: 311-320Abstract Full Text PDF PubMed Scopus (118) Google Scholar In experimental animals, stimulation of these afferent nerves by either ischemic metabolites such as adenosine, or by uremic toxins such as urea, evokes reflex increases in SNS activity and BP.5.Katholi R.E. Renal nerves and hypertension: an update.Fed Proc. 1985; 44: 2846-2850PubMed Google Scholar Chronic stimulation of these afferent nerves may lead to SNS overactivity and hypertension. This suggests that ischemic injury to the kidneys, owing to macro- or microvascular disease, may cause hypertension through the activation of these chemosensitive fibers. Our studies on 5/6 nephrectomized (NPX) rats have provided the most convincing evidence for a role of the SNS in the pathogenesis of hypertension associated with kidney disease. The turnover rate8.Bigazzi R. Kogosov E. Campese V.M. Altered norepinephrine turnover in the brain of rats with chronic renal failure.J Am Soc Nephrol. 1994; 4: 1901-1907PubMed Google Scholar and the secretion of norepinephrine (NE)9.Ye S. Ozgur B. Campese V.M. Renal afferent impulses, the posterior hypothalamus, and hypertension in rats with chronic renal failure.Kidney Int. 1997; 51: 722-727Abstract Full Text PDF PubMed Scopus (167) Google Scholar from the posterior hypothalamic nuclei were greater in NPX than in control rats. Bilateral dorsal rhizotomy at the level T-10 to L-3 prevented the increase in BP and NE turnover in the posterior hypothalamic nuclei. These studies led us to postulate that increased renal sensory impulses generating in the affected kidney and then transmitted to the central nervous system activate brain regions involved in the noradrenergic control of BP resulting in hypertension. This concept is supported by studies in human subjects with end-stage renal disease (ESRD). Converse et al.4.Converse Jr, R.L. Jacobsen T.N. Toto R.D. et al.Sympathetic overactivity in patients with chronic renal failure.N Engl J Med. 1992; 327: 1912-1918Crossref PubMed Scopus (965) Google Scholar observed increased muscle sympathetic nerve activity (MSNA) and peripheral vascular resistance in hypertensive patients with ESRD. Bilateral NPX patients, on the other hand, manifested lower MSNA, BP, and peripheral vascular resistance compared to patients with native kidneys. In all, these findings support the notion that increased afferent nervous input from the kidney to the central nervous system may play an important role in the pathogenesis of hypertension in CKD and ESRD patients. In our laboratory, we have developed a model of neurogenic hypertension caused by renal injury without measurable alterations in kidney function. In this model, the injection of 50 μl of phenol in the lower pole of one kidney causes an immediate and persistent elevation of BP and SNS activity in the rat; renal denervation prevents these effects.9.Ye S. Ozgur B. Campese V.M. Renal afferent impulses, the posterior hypothalamus, and hypertension in rats with chronic renal failure.Kidney Int. 1997; 51: 722-727Abstract Full Text PDF PubMed Scopus (167) Google Scholar The studies in the 5/6 NPX rat model, ESRD patients and the ‘phenol–renal injury model’ have clearly demonstrated that renal injury may activate renal afferent pathways and result in SNS activation and hypertension (Figure 1). Locally released angiotensin II appears to mediate central activation of SNS activity, as specific angiotensin II AT-1 receptor antagonists abrogate SNS activation caused by renal injury in the rat.10.Ye S. Zhong H. Duong V.N. Campese V.M. Losartan reduces central and peripheral sympathetic nerve activity in a rat model of neurogenic hypertension.Hypertension. 2002; 39: 1101-1106Crossref PubMed Scopus (87) Google Scholar One important primary event leading to increased SNS activity is probably renal ischemia. In patients with renovascular hypertension, Miyajima et al.11.Miyajima E. Yamada Y. Yoshida Y. et al.Muscle sympathetic nerve activity in renovascular hypertension and primary aldosteronism.Hypertension. 1991; 17: 1057-1062Crossref PubMed Google Scholar demonstrated increased levels of MSNA compared to patients with essential hypertension. Restoration of renal perfusion with renal angioplasty reduced MSNA and BP in these patients. Ligtenberg et al.12.Ligtenberg G. Blankestijn P.J. Oey P.L. et al.Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure.N Engl J Med. 1999; 340: 1321-1328Crossref PubMed Scopus (375) Google Scholar observed an increase in MSNA in patients with CKD and renin-dependent hypertension, when compared with controls, and Klein et al.13.Klein I.H. Ligtenberg G. Oey P.L. et al.Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension.J Am Soc Nephrol. 2001; 12: 2427-2433PubMed Google Scholar observed increased MSNA in hypertensive but not in normotensive patients with polycystic kidney disease regardless of kidney function. One potential mechanism for cyclosporine-induced hypertension is through activation of renal afferent pathways, which result in the activation of efferent sympathetic nerves and decreases fractional excretion of sodium.14.Zhang W. Li J.L. Hosaka M. et al.Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings.Proc Natl Acad Sci USA. 2000; 97: 9765-9770Crossref PubMed Scopus (67) Google Scholar Other mechanisms potentially responsible for the increase in SNS activity in uremic patients include reduced central dopaminergic tone,15.Kuchel O.G. Shigetomi S. Dopaminergic abnormalities in hypertension associated with moderate renal insufficiency.Hypertension. 1994; 23: I240-245Crossref PubMed Google Scholar reduced baroreceptors sensitivity,16.Pickering T.G. Gribbin B. Oliver D.O. Baroreflex sensitivity in patients on long-term haemodialysis.Clin Sci. 1972; 42: 10PCrossref PubMed Google Scholar abnormal vagal function,17.Zucchelli P. Catizone L. Esposti E.D. et al.Influence of ultrafiltration on plasma renin activity and adrenergic system.Nephron. 1978; 21: 317-324Crossref PubMed Scopus (39) Google Scholar increased plasma β-endorphin and β-lipotropin,18.Elias A.N. Vaziri N.D. Plasma catecholamines in chronic renal disease.Int J Artif Organs. 1985; 8: 243-244PubMed Google Scholar and increased serum leptin levels.19.Wolf G. Chen S. Han D.C. Ziyadeh F.N. Leptin and renal disease.Am J Kidney Dis. 2002; 39: 1-11Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar The increased activity of the SNS does not only contribute to hypertension but it may also contribute to the progression of kidney disease and cardiovascular mortality in ESRD patients. Amann et al.20.Amann K. Rump L.C. Simonaviciene A. et al.Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nephrectomized rats.J Am Soc Nephrol. 2000; 11: 1469-1478PubMed Google Scholar observed that proteinuria and the development of glomerulosclerosis were significantly attenuated by sympatholytic drug in subtotally NPX rats. Zoccali et al.21.Zoccali C. Mallamaci F. Parlongo S. et al.Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease.Circulation. 2002; 105: 1354-1359Crossref PubMed Scopus (438) Google Scholar have shown a correlation between blood levels of NE and cardiovascular mortality in ESRD patients. For the reasons exposed above, antiadrenergic drugs should be an important component of hypertension management in CKD patients. Of note, angiotensin-converting enzyme inhibitors and angiotensin receptor blockades partially reduce SNS activity, by interfering with effects of angiotensin II on SNS transmission both at peripheral and central sites. Sleep apnea is common among CKD patients and it may contribute to abnormal circadian BP variability, hypertension and cardiovascular disease.22.Zoccali C. Benedetto F.A. Tripepi G. et al.Nocturnal hypoxemia, night-day arterial pressure changes and left ventricular geometry in dialysis patients.Kidney Int. 1998; 53: 1078-1084Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Normally, BP tends to be the highest during the morning, gradually decreases during the course of the day and reaches the lowest levels at night. Approximately 10–25% of patients with essential hypertension does not display the normal nocturnal dipping of BP and are called ‘non-dippers’, as opposed to those with a normal circadian rhythm who are called ‘dippers’. Among CKD patients,23.Farmer C.K. Goldsmith D.J. Cox J. et al.An investigation of the effect of advancing uraemia, renal replacement therapy and renal transplantation on blood pressure diurnal variability.Nephrol Dial Transplant. 1997; 12: 2301-2307Crossref PubMed Scopus (155) Google Scholar and those on maintenance hemodialysis,24.Peixoto A.J. White W.B. Ambulatory blood pressure monitoring in chronic renal disease: technical aspects and clinical relevance.Curr Opin Nephrol Hypertens. 2002; 11: 507-516Crossref PubMed Scopus (29) Google Scholar the prevalence of non-dippers is 74–82%. Sometimes, in these patients, BP during the night can be greater than that measured during the day (nocturnal hypertension). The phenomena of non-dipping and nocturnal hypertension have been associated with greater risk of cardiac concentric hypertrophy, and cardiovascular events in ESRD patients.25.Amar J. Vernier I. Rossignol E. et al.Nocturnal blood pressure and 24-hour pulse pressure are potent indicators of mortality in hemodialysis patients.Kidney Int. 2000; 57: 2485-2491Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar Several mechanisms may be responsible for the phenomena of non-dipping in patients with CKD including extracellular volume expansion, uremic neuropathy, and restless leg syndrome. However, sleep disordered breathing also seems to play an important role. Oxygen desaturation, triggered by sleep apnea, occurs in 21–47% of ESRD patients, and it may contribute to raising BP through the activation of chemoreceptors connected with the SNS. Removal of excessive volume with dialysis26.Hanly P.J. Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis.N Engl J Med. 2001; 344: 102-107Crossref PubMed Scopus (448) Google Scholar or treatment with nasal continuous positive pressure may improve nocturnal oxygen desaturation, and reduce SNS activity and BP in these patients.27.Pressman M.R. Benz R.L. Schleifer C.R. Peterson D.D. Sleep disordered breathing in ESRD: acute beneficial effects of treatment with nasal continuous positive airway pressure.Kidney Int. 1993; 43: 1134-1139Abstract Full Text PDF PubMed Scopus (90) Google Scholar The role of the endothelium in vascular and renal physiology and pathology is well recognized. A number of investigators have speculated that an altered balance between endothelium-derived relaxing factors and endothelium-derived constricting factors may play a role in hypertension associated with kidney disease.28.Shultz P.J. An emerging role for endothelin in renal disease.J Lab Clin Med. 1992; 119: 448-449PubMed Google Scholar The role of ET in CKD-related hypertension has been the focus of active research and controversy. Two distinct complementary DNAs of ET receptors have been identified. The ET-A receptor is predominately expressed on vascular smooth muscle cells, where its action mediates vasoconstriction. The ET-B receptor is predominately found on endothelial cells, where its action promotes vasodilation via the release of nitric oxide (NO) and prostacyclin.29.Gray G.A. Webb D.J. The endothelin system and its potential as a therapeutic target in cardiovascular disease.Pharmacol Ther. 1996; 72: 109-148Crossref PubMed Scopus (137) Google Scholar ET-1's affinity for the ET-A receptor is the greatest (ET-1>ET-2>ET-3), likely related to its almost irreversible binding to the receptor lasting greater than 2 h. ET-B receptors have equal affinity for all three isoforms. ETs have a variety of actions, some of which are related to the maintenance of vascular tone. The role of ET in the regulation of vascular tone has been studied in animal and human models through the use of selective receptor antagonists.30.Haynes W.G. Ferro C.J. O’Kane K.P. et al.Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans.Circulation. 1996; 93: 1860-1870Crossref PubMed Scopus (284) Google Scholar ET-A blockade results in vasodilatation, probably as a result of an increase in NO generation. By contrast, blockade of ET-B receptors results in vasoconstriction, indicating that there is a balance between the two receptor actions.31.Verhaar M.C. Strachan F.E. Newby D.E. et al.Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade.Circulation. 1998; 97: 752-756Crossref PubMed Scopus (396) Google Scholar In addition to its contractile actions on vascular smooth muscle, ET can also modulate SNS activity.32.Hoang D. Macarthur H. Gardner A. Westfall T.C. Endothelin-induced modulation of neuropeptide Y and norepinephrine release from the rat mesenteric bed.Am J Physiol Heart Circ Physiol. 2002; 283: H1523-1530Crossref PubMed Scopus (24) Google Scholar Some controversy exists whether ET secretion exerts a primary role in hypertension or whether it is the result of vascular injury caused by the shear stress or by vasoconstrictors. Cytokines, thrombin, vasoactive hormones such as epinephrine, vasopressin and angiotensin II, and oxidative stress stimulate ET release from endothelial cells, suggesting a secondary role. Interestingly, angiotensin II's stimulation of ET-1 release has been shown to be mediated by oxidative stress. Ortiz et al.33.Ortiz M.C. Manriquez M.C. Romero J.C. Juncos L.A. Antioxidants block angiotensin II-induced increases in blood pressure and endothelin.Hypertension. 2001; 38: 655-659Crossref PubMed Google Scholar infused angiotensin II chronically causing hypertension in rats, all of which were blocked by both an antioxidant and ET receptor blockade. ET may also exert effects on renal tubular sodium handling. The predominant receptor in the kidney is the ET-B receptor,34.Davenport A.P. Morton A.J. Brown M.J. Localization of endothelin-1 (ET-1), ET-2, and ET-3, mouse VIC, and sarafotoxin S6b binding sites in mammalian heart and kidney.J Cardiovasc Pharmacol. 1991; 17: S152-S155Crossref PubMed Scopus (26) Google Scholar and its activation results in natriuresis. ET-B receptor antagonists exacerbate hypertension in high salt diet-fed rats, although ET-A blockade reverses the hypertension to normal.35.Pollock D.M. Pollock J.S. Evidence for endothelin involvement in the response to high salt.Am J Physiol Renal Physiol. 2001; 281: F144-F150PubMed Google Scholar It has also been shown that ET-B receptor-deficient rats develop salt-sensitive hypertension.36.Gariepy C.E. Ohuchi T. Williams S.C. et al.Salt-sensitive hypertension in endothelin-B receptor-deficient rats.J Clin Invest. 2000; 105: 925-933Crossref PubMed Scopus (254) Google Scholar Increased plasma ET-1 levels have been shown in patients with essential hypertension by some investigators37.Saito Y. Nakao K. Mukoyama M. Imura H. Increased plasma endothelin level in patients with essential hypertension.N Engl J Med. 1990; 322: 205Crossref PubMed Scopus (405) Google Scholar but not by others.38.Schiffrin E.L. Thibault G. Plasma endothelin in human essential hypertension.Am J Hypertens. 1991; 4: 303-308Crossref PubMed Scopus (201) Google Scholar The systemic levels may not be as important given that ET is released on the basolateral surface and exerts its effect in a paracrine and autocrine manner on nearby endothelial and smooth muscle cells. Hypertensive patients with CKD39.Koyama H. Tabata T. Nishzawa Y. et al.Plasma endothelin levels in patients with uraemia.Lancet. 1989; 1: 991-992Abstract PubMed Scopus (308) Google Scholar and ESRD40.Suzuki N. Matsumoto H. Miyauchi T. et al.Endothelin-3 concentrations in human plasma: the increased concentrations in patients undergoing haemodialysis.Biochem Biophys Res Commun. 1990; 169: 809-815Crossref PubMed Scopus (46) Google Scholar display higher plasma levels of ET-1 and ET-3 than normotensive subjects. It is unclear whether this is the result of the uremic state or the exposure of blood to an extracorporeal circuit during hemodialysis. ET receptor antagonists have been shown to significantly reduce BP in patients with essential hypertension41.Krum H. Viskoper R.J. Lacourciere Y. et al.The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators.N Engl J Med. 1998; 338: 784-790Crossref PubMed Scopus (508) Google Scholar and to reduce blood pressure and proteinuria in CKD patients.42.Goddard J. Eckhart C. Johnston N.R. et al.Endothelin A receptor antagonism and angiotensin-converting enzyme inhibition are synergistic via an endothelin B receptor-mediated and nitric oxide-dependent mechanism.J Am Soc Nephrol. 2004; 15: 2601-2610Crossref PubMed Scopus (39) Google Scholar The place of ET-1 antagonists in the management of hypertension in CKD and ESRD patients remains to be further explored. Endothelial cells cause vasodilatation in response to increases in flow, shear stress and agonists through the release of several mediators, which include prostaglandin I2, endothelium-derived hyperpolarizing factor and NO. The formation of NO by NO synthase (NOS) in the vascular endothelium from the amino-acid L-arginine has opened up a new area of biological research. Several forms of NOS have been identified; endothelial NOS regulates endothelial function and vascular tone, whereas the neuronal isoform of NOS (nNOS) modulates SNS activity. Impaired endothelium-dependent vasodilation has been observed in CKD and ESRD patients.43.Thambyrajah J. Landray M.J. McGlynn F.J. et al.Abnormalities of endothelial function in patients with predialysis renal failure.Heart. 2000; 83: 205-209Crossref PubMed Scopus (171) Google Scholar, 44.Passauer J. Bussemaker E. Range U. et al.Evidence in vivo showing increase of baseline nitric oxide generation and impairment of endothelium-dependent vasodilation in normotensive patients on chronic hemodialysis.J Am Soc Nephrol. 2000; 11: 1726-1734PubMed Google Scholar In 5/6 NPX rats, Vaziri et al.45.Vaziri N.D. Ni Z. Wang X.Q. et al.Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH.Am J Physiol. 1998; 274: F642-F649PubMed Google Scholar observed downregulation of endothelial and inducible NOS, and suggested that this may contribute to the BP elevation. Chronic inhibition of NO synthesis by NG-nitro--L-arginine methyl ester (L-NAME) has been used as a model of arterial hypertension in animals. Administration of nitro-L-arginine to rats causes systemic hypertension, marked renal vasoconstriction and hypoperfusion, as well as a fall in glomerular filtration rate.46.Chen P.Y. Sanders P.W. -arginine abrogates salt-sensitive hypertension in Dahl/Rapp rats.J Clin Invest. 1991; 88: 1559-1567Crossref PubMed Scopus (409) Google Scholar Sakuma et al.47.Sakuma I. Togashi H. Yoshioka M. et al.NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone?.Circ Res. 1992; 70: 607-611Crossref PubMed Scopus (386) Google Scholar have also shown that the increase in renal SNS activity and in BP after administration of NG-methyl-L-arginine (NOS inhibitor) to male Wistar rats could be reduced by spinal C1–C2 transection, implying that NO may play a role in the central regulation of SNS tone. nNOS is present in a specific area of the brain involved in the modulation of the noradrenergic control of BP48.Anderstam B. Katzarski K. Bergstrom J. Serum levels of NGNG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients.J Am Soc Nephrol. 1997; 8: 1437-1442PubMed Google Scholar, 49.Vallance P. Leone A. Calver A. et al.Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575Abstract PubMed Scopus (1880) Google Scholar and is an important component of transduction pathways that tonically inhibit SNS activity.3.Ye S. Nosrati S. Campese V.M. Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF).J Clin Invest. 1997; 99: 540-548Crossref PubMed Scopus (105) Google Scholar A decrease in central nNOS may result in greater SNS activity and BP. However, in Sprague–Dawley 5/6 NPX rats, we observed that nNOS mRNA gene expression and NO2/NO3 content were increased in several brain nuclei involved in the noradrenergic control of BP. L-NAME increased BP and NE turnover rate in those brain nuclei. These studies suggest that the increase in central SNS activity in chronic renal failure rats may be partially mitigated by increased expression of nNOS mRNA in the brain.3.Ye S. Nosrati S. Campese V.M. Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF).J Clin Invest. 1997; 99: 540-548Crossref PubMed Scopus (105) Google Scholar Some evidence also indicates that NO may modulate peripheral sympathetic neurotransmission.50.Kolo L.L. Westfall T.C. Macarthur H. Nitric oxide decreases the biological activity of norepinephrine resulting in altered vascular tone in the rat mesenteric arterial bed.Am J Physiol Heart Circ Physiol. 2004; 286: H296-H303Crossref PubMed Scopus (67) Google Scholar Vallance et al.49.Vallance P. Leone A. Calver A. et al.Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575Abstract PubMed Scopus (1880) Google Scholar have shown both in vitro and in vivo that NO synthesis can be inhibited by an endogenous compound, NGNG-dimethylarginine (asymmetrical dimethylarginine). ESRD patients on chronic hemodialysis display significantly higher plasma levels of asymmetrical dimethylarginine and significantly lower plasma arginine-to-dimethylarginine ratio, suggesting asymmetrical dimethylarginine may contribute to hypertension in these patients.48.Anderstam B. Katzarski K. Bergstrom J. Serum levels of NGNG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients.J Am Soc Nephrol. 1997; 8: 1437-1442PubMed Google Scholar In CKD patients, asymmetrical dimethylarginine levels correlated with severity of atherosclerosis,51.Kielstein J.T. Boger R.H. Bode-Boger S.M. et al.Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease.J Am Soc Nephrol. 1999; 10: 594-600PubMed Google Scholar cardiovascular events and mortality.52.Zoccali C. Bode-Boger S. Mallamaci F. et al.Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.Lancet. 2001; 358: 2113-2117Abstract Full Text Full Text PDF PubMed Scopu" @default.
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• W1980809339 title "Hypertension in renal parenchymal disease: Why is it so resistant to treatment?" @default.
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