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• W2023643206 abstract "Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction. In end-stage renal failure (ESRF) symptomatic hemodialysis-related hypotension may prevent effective provision of renal replacement therapy. Endogenous inhibitors of nitric oxide synthase accumulate in ESRF and are cleared by dialysis. We, therefore, hypothesised that removal of these inhibitors by hemodialysis would increase endothelial nitric oxide generation and promote venodilation. In vivo responses of norepinephrine preconstricted dorsal hand veins to locally active doses of acetylcholine (an activator of nitric oxide synthase) and glyceryl trinitrate (GTN; a nitric oxide donor) were examined in patients undergoing maintenance hemodialysis for ESRF and in healthy age- and sex-matched controls. Patient studies were undertaken before and after dialysis. Studies before dialysis were repeated with co-infusion of either L-arginine or its inactive enantiomer D-arginine. Venodilation in response to acetylcholine was impaired before, and corrected by, dialysis whereas venodilation to GTN was similar before and after dialysis. Venodilation in response to acetylcholine before dialysis was restored by co-infusion of L- but not D-arginine. Therefore, patients with ESRF undergoing hemodialysis have impaired acetylcholine-mediated venodilation consistent with the accumulation in ESRF of functionally important inhibitors of nitric oxide synthase that are cleared by dialysis. Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction. In end-stage renal failure (ESRF) symptomatic hemodialysis-related hypotension may prevent effective provision of renal replacement therapy. Endogenous inhibitors of nitric oxide synthase accumulate in ESRF and are cleared by dialysis. We, therefore, hypothesised that removal of these inhibitors by hemodialysis would increase endothelial nitric oxide generation and promote venodilation. In vivo responses of norepinephrine preconstricted dorsal hand veins to locally active doses of acetylcholine (an activator of nitric oxide synthase) and glyceryl trinitrate (GTN; a nitric oxide donor) were examined in patients undergoing maintenance hemodialysis for ESRF and in healthy age- and sex-matched controls. Patient studies were undertaken before and after dialysis. Studies before dialysis were repeated with co-infusion of either L-arginine or its inactive enantiomer D-arginine. Venodilation in response to acetylcholine was impaired before, and corrected by, dialysis whereas venodilation to GTN was similar before and after dialysis. Venodilation in response to acetylcholine before dialysis was restored by co-infusion of L- but not D-arginine. Therefore, patients with ESRF undergoing hemodialysis have impaired acetylcholine-mediated venodilation consistent with the accumulation in ESRF of functionally important inhibitors of nitric oxide synthase that are cleared by dialysis. Symptomatic hypotension occurs in more than 25% of hemodialysis sessions, and may substantially restrict the amount of fluid that can be removed1.Wehle B. Asaba H. Castenfors J. Furst P. Gunnarsson B. Shaldon S. Bergström J. Hemodynamic changes during sequential ultrafiltration and dialysis.Kidney Int. 1979; 15: 411-418Abstract Full Text PDF PubMed Scopus (79) Google Scholar. Frequently occurring dialysis-associated hypotension impedes regular and efficient renal replacement therapy. Many mechanisms have been proposed as the cause of this clinical problem, all of which invoke an inappropriate physiological response to hypovolemia2.Chaignon M. Chen W. Tarazi R.C. Nakamoto S. Bravo E. Blood pressure response to hemodialysis.Hypertension. 1981; 3: 333-339Crossref PubMed Scopus (29) Google Scholar,3.Daugirdas J.T. Dialysis hypotension: A hemodynamic analysis.Kidney Int. 1991; 39: 233-246Abstract Full Text PDF PubMed Scopus (298) Google Scholar. Abnormalities of the responses of both resistance and capacitance vessels to hypovolemia have been demonstrated during hemodialysis. Forearm venous capacitance has been shown to increase during acetate and bicarbonate dialysis4.Bradley J.R. Evans D.B. Gore S.M. Cowley A.J. Is dialysis hypotension caused by an abnormality of venous tone?.Brit Med J. 1988; 296: 1634-1637Crossref PubMed Scopus (22) Google Scholar,5.Kooman J.P. Gladziwa U. Bocker G. VAN BORTEL L.M.A.B. VAN HOOFF J.P. Leunissen K.M.L. Role of the venous system in hemodynamics during ultrafiltration and bicarbonate dialysis.Kidney Int. 1992; 42: 718-726Abstract Full Text PDF PubMed Scopus (80) Google Scholar. Inappropriately small reflex increases in peripheral vascular resistance to hypovolemia have also been demonstrated during hemodialysis, but not during fluid removal by ultrafiltration alone1.Wehle B. Asaba H. Castenfors J. Furst P. Gunnarsson B. Shaldon S. Bergström J. Hemodynamic changes during sequential ultrafiltration and dialysis.Kidney Int. 1979; 15: 411-418Abstract Full Text PDF PubMed Scopus (79) Google Scholar,6.BRADLEY J.R. EVANS D.B. COWLEY A.J. Comparison of vascular tone during combined haemodialysis with ultrafiltration and during ultrafiltration followed by haemodialysis: A possible mechanism for dialysis hypotension.Brit Med J. 1990; 300: 1312Crossref PubMed Scopus (12) Google Scholar. These studies are consistent with the hypothesis that an alteration of venous and arterial responses to hypovolemia is due to clearance, by dialysis, of a circulating vasoconstrictor agent. Vascular endothelial cells generate a potent and labile vasodilator substance, nitric oxide7.Furchgott R.F. Zawadzki J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature (Lond). 1980; 288: 373-376https://doi.org/10.1038/288373a0Crossref PubMed Scopus (9605) Google Scholar, 8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar, 9.VALLANCE P. Patton S. Bhagat K. Macallister R. Radomski M. MONCADA S. Malinski T. Direct measurement of nitric oxide in human beings.Lancet. 1995; 346: 153-154https://doi.org/10.1016/S0140-6736(95)91211-8Crossref PubMed Scopus (155) Google Scholar, through the action of a constitutive nitric oxide synthase enzyme acting on its stereospecific substrate, L-arginine10.Sakuma I. Stuehr D.J. Gross S.S. Nathan C. Levi R. Identification of arginine as a precursor of endothelium-derived relaxing factor.Proc Natl Acad Sci USA. 1988; 85: 8664-8667Crossref PubMed Scopus (370) Google Scholar,11.Palmer R.M.J. Rees D.D. Ashton D.S. Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation.Biochem Biophys Res Commun. 1988; 153: 1251-1256Crossref PubMed Scopus (1082) Google Scholar. In end-stage renal failure there is accumulation of methylguanidine12.Orita Y. Ando A. Tsubakihara Y. Mikami H. Kikuchi T. Nakata K. Tissue and blood concentration of methylguanidine in rats and patients with chronic renal failure.Nephron. 1981; 27: 35-39Crossref PubMed Google Scholar, and of other naturally occurring methylated analogs of L-arginine, such as NG, NG, dimethyl-arginine otherwise known as asymmetrical dimethyl arginine (ADMA) and NG, L-monomethyl arginine (L-NMMA)13.Cantoni G.L. Biological methylation: Selected aspects.Annu Rev Biochem. 1975; 44: 435-451Crossref PubMed Scopus (384) Google Scholar,14.Vallance P. Leone A. Calver A. COLLIER J. MONCADA S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575https://doi.org/10.1016/0140-6736(92)90865-ZAbstract PubMed Scopus (1880) Google Scholar. Methylguanidine15.Sorrentino R. SORRENTINO L. Pinto A. Effect of some products of protein catabolism on the endothelium-dependent and -independent relaxation of rabbit thoracic aorta rings.J Pharmacol Exp Ther. 1993; 266: 626-633PubMed Google Scholar,16.Sorrentino R. PINTO A. Effect of methylguanidine on rat blood pressure: Role of endothelial nitric oxide synthase.Br J Pharmacol. 1995; 115: 510-514Crossref PubMed Scopus (15) Google Scholar, ADMA17.CALVER A. Collier J. LEONE A. Moncada S. VALLANCE P. Effect of local intra-arterial asymmetric dimethylarginine (ADMA) on the forearm arteriolar bed of healthy volunteers.J Hum Hypertens. 1993; 7: 193-194PubMed Google Scholar and L-NMMA8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar,18.Vallance P. Leone A. Calver A. COLLIER J. MONCADA S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man.Lancet. 1989; ii: 997-1000https://doi.org/10.1016/S0140-6736(89)91013-1Abstract Scopus (1370) Google Scholar are competitive inhibitors of nitric oxide synthase. In addition, ADMA is cleared by hemodialysis14.Vallance P. Leone A. Calver A. COLLIER J. MONCADA S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575https://doi.org/10.1016/0140-6736(92)90865-ZAbstract PubMed Scopus (1880) Google Scholar,19.Arese M. Strasly M. Ruva C. Costamagna C. Ghigo D. MACALLISTER R. Verzetti G. Tetta C. Bosia A. Bussolino F. Regulation of nitric oxide synthesis in uraemia.Nephrol Dial Transplant. 1995; 10: 1386-1397PubMed Google Scholar and causes vasoconstriction in ex vivo studies at similar concentrations to those found in some patients with end-stage renal failure20.Macallister R.J. Whitley G.S.T.J. VALLANCE P. Effect of guanidino and uraemic toxins on nitric oxide pathways.Kidney Int. 1994; 45: 737-742Abstract Full Text PDF PubMed Scopus (147) Google Scholar. ADMA also causes local vasoconstriction when infused into healthy subjects14.Vallance P. Leone A. Calver A. COLLIER J. MONCADA S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575https://doi.org/10.1016/0140-6736(92)90865-ZAbstract PubMed Scopus (1880) Google Scholar,17.CALVER A. Collier J. LEONE A. Moncada S. VALLANCE P. Effect of local intra-arterial asymmetric dimethylarginine (ADMA) on the forearm arteriolar bed of healthy volunteers.J Hum Hypertens. 1993; 7: 193-194PubMed Google Scholar. Furthermore, these nitric oxide synthase inhibitors may act synergistically14.Vallance P. Leone A. Calver A. COLLIER J. MONCADA S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.Lancet. 1992; 339: 572-575https://doi.org/10.1016/0140-6736(92)90865-ZAbstract PubMed Scopus (1880) Google Scholar,19.Arese M. Strasly M. Ruva C. Costamagna C. Ghigo D. MACALLISTER R. Verzetti G. Tetta C. Bosia A. Bussolino F. Regulation of nitric oxide synthesis in uraemia.Nephrol Dial Transplant. 1995; 10: 1386-1397PubMed Google Scholar. We tested the hypotheses that: (i) end-stage renal failure is associated with endothelial dysfunction; (ii) endothelial dysfunction is due to the presence of a dialysable substance and so would be improved by dialysis; and (iii) such endothelial dysfunction, being caused by inhibitors of nitric oxide synthase, would be reversed by L- but not D-arginine. Dialysis related hypotension appears to be predominantly mediated by changes within the capacitance system5.Kooman J.P. Gladziwa U. Bocker G. VAN BORTEL L.M.A.B. VAN HOOFF J.P. Leunissen K.M.L. Role of the venous system in hemodynamics during ultrafiltration and bicarbonate dialysis.Kidney Int. 1992; 42: 718-726Abstract Full Text PDF PubMed Scopus (80) Google Scholar,21.KOOMAN J.P. VAN HOOFF J.P. LEUNISSEN K.M.L. The venous system and dialysis-associated hypotension.Contrib Nephrol. 1994; 106: 99-105Crossref PubMed Google Scholar. In addition, cutaneous limb veins are under sympathetic venomotor control22.Zelis R. Mason D.T. Comparison of the reflex activity of skin and muscle veins in the human forearm.J Clin Invest. 1969; 48: 1870-1877Crossref PubMed Scopus (38) Google Scholar, indicating that the responses in hand veins should reflect responses found in those vessels that control venous capacitance and cardiac preload23.Haynes W.G. Hand M.F. Johnstone H.A. Padfield P.L. Webb D.J. Direct and sympathetically mediated venoconstriction in essential hypertension: Enhanced responses to endothelin-1.J Clin Invest. 1994; 94: 1359-1364Crossref PubMed Google Scholar,24.WEBB D.J. The pharmacology of human blood vessels in vivo.J Vasc Res. 1995; 32: 2-15Crossref PubMed Scopus (71) Google Scholar. Furthermore, investigation of hand veins avoids the confounding effects associated with vascular hypertrophy and other structural changes that may occur in the resistance vessels of patients with hypertension23.Haynes W.G. Hand M.F. Johnstone H.A. Padfield P.L. Webb D.J. Direct and sympathetically mediated venoconstriction in essential hypertension: Enhanced responses to endothelin-1.J Clin Invest. 1994; 94: 1359-1364Crossref PubMed Google Scholar. Therefore, we chose to examine endothelial function in dorsal hand veins. These studies have the advantage of using locally active doses of drugs and do not require systemic doses which may obscure any direct vascular action by direct effects on other organs, such as the heart and kidney, or activate reflex mechanisms due to changes in blood pressure. We used the muscarinic agonist, acetylcholine, as an endothelium dependent venodilator8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar, 9.VALLANCE P. Patton S. Bhagat K. Macallister R. Radomski M. MONCADA S. Malinski T. Direct measurement of nitric oxide in human beings.Lancet. 1995; 346: 153-154https://doi.org/10.1016/S0140-6736(95)91211-8Crossref PubMed Scopus (155) Google Scholar, 25.Collier J. Vallance P. Biphasic response to acetylcholine in human vessels in vivo: The role of the endothelium.Clin Sci. 1990; 78: 101-104Crossref PubMed Scopus (32) Google Scholar and glyceryl trinitrate (GTN), as an endothelium independent venodilator8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar. Studies were performed in patients with end-stage renal failure undergoing hemodialysis and healthy age- and sex-matched control subjects. In order to eliminate potential confounding factors that may influence the interpretation of the vascular responses to acetylcholine, we also measured plasma concentrations of arginine, the substrate for nitric oxide synthase; cholesterol, which may influence endothelial responsiveness to acetylcholine; and cholinesterase, which by degrading acetylcholine may influence the observed vascular responsiveness, both before and after dialysis. Twelve consecutive patients with established end-stage renal failure Table 1 were recruited for the study. All patients had been maintained on renal replacement therapy three times weekly for at least three months, at the Western General Hospital or Royal Infirmary, Edinburgh. Patients were excluded if they had a diagnosis of diabetes mellitus, had commenced on human recombinant erythropoietin within the preceding three months, or were taking alpha receptor antagonists or nitrovasodilators.Table 1Patient characteristics All patients continued with their regular dialysis prescription administered using Fresenius A 2008 C dialysis machines with cuprophan (Alwall GFE 11 or 18; Gambro Ltd, Sidcup, UK) or cellulose-acetate membranes (180 MCA; Althin Ltd, Cambridge, UK) Table 1. All patients were dialyzed against bicarbonate. Two patients Table 1 were taking antihypertensive medication (nifedipine and metoprolol) and their doses were not changed during the study. Diet was high in calories but limited to a daily intake of 1 g/kg body wt protein, 80 to 100 mmol sodium and 1 mmol/kg body wt potassium, with a daily fluid restriction of 500 ml plus a volume equal to urine output in the previous 24 hours. Eight age- and sex-matched control subjects were also recruited. All studies were conducted with the approval of the Lothian Research Ethics Committee and all subjects gave their written informed consent to participate. All subjects avoided caffeine-containing drinks or cigarettes on the day of each study, and were fasted for at least three hours before each study. Locally, but not systemically, active doses of norepinephrine (3 to 192 pmol/min; Sterling-Winthrop, Guildford, UK)23.Haynes W.G. Hand M.F. Johnstone H.A. Padfield P.L. Webb D.J. Direct and sympathetically mediated venoconstriction in essential hypertension: Enhanced responses to endothelin-1.J Clin Invest. 1994; 94: 1359-1364Crossref PubMed Google Scholar, acetylcholine (0.1 to 100 nmol/min; IOLAB, Bracknell, UK)8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar, GTN (0.3 to 10 pmol/min; Schwartz Pharma Ltd, Chesham, UK)8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar, L-arginine hydrochloride (100 nmol/min; Stockport Pharmaceuticals, Stepping Hill Hospital, UK)8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar and D-arginine hydrochloride (100 nmol/min; Clinalfa AG, Switzerland)8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar were infused. All drugs were dissolved in saline. Ascorbic acid (Evans Medical, Horsham, UK) at a final concentration of 100 μg/ml was added to the norepinephrine solutions to prevent degradation by oxidation26.COLLIER J.G. Lorge R.E. Robinson B.F. Comparison of the effects of tolmesoxide (RX71107), diazoxide, hydrallazine, prazosin, glyceryl trinitrate and sodium nitroprusside on forearm and dorsal hand veins of man.Br J Clin Pharmacol. 1978; 5: 35-44Crossref PubMed Scopus (91) Google Scholar. A selected dorsal hand vein on the non-fistula arm of the hemodialysis patients, or the non-dominant arm in controls, was cannulated in the direction of flow with a 23 SWG cannula (Abbott, Sligo, Republic of Ireland), without the use of local anesthesia, for the purpose of intravenous infusion of drugs. The total rate of infusion was maintained constant throughout all of the studies at 20 ml/hr. The infused arm was supported above the level of the heart by means of an arm rest. Internal diameter of the dorsal hand vein, distended by inflation of an upper arm cuff to 30 mm Hg, was measured by the technique of Aellig27.Aellig W.H. A new technique for recording compliance of human hand veins.Br J Clin Pharmacol. 1981; 11: 237-243Crossref PubMed Scopus (160) Google Scholar. In brief, a lightweight magnetized rod rested on the summit of the infused vein ∼1 cm downstream from the tip of the infusion cannula. This rod passed through the core of a linear variable differential transformer (LVDT; Lucas Control Systems Products, Slough, UK) supported above the hand by means of a small tripod, the legs of which rested on areas of the dorsum of the hand free of veins. Local changes in vein size resulted in displacement of the rod causing a linear change in the voltage generated by the LVDT and allowed the determination of the internal diameter of the vein. Voltage output from the LVDT was transferred to a Macintosh personal computer file using a MacLab analog-digital converter and Chart software (v. 3.2.8; both from AD Instruments, Castle Hill, NSW, Australia). Arterial pressure was measured using a well-validated semi-automated oscillometric method (Takeda UA 751)28.Wiinberg N. WALTER-LARSON S. Eriksen C. Nielsen P.E. An evaluation of semi-automatic blood pressure manometers against inta-arterial blood pressure.J Ambulatory Monitoring. 1988; 1: 303-309Google Scholar,29.Evans C.E. HAYNES R.B. Goldsmith C.H. Hewson S.A. Home blood pressure-measuring devices: A comparative study of accuracy.J Hypertens. 1989; 7: 133-142Crossref PubMed Scopus (39) Google Scholar in the non-fistula arm of patients with end-stage renal failure and in the non-infused arm of control subjects. Hemoglobin was measured using a Coulter STKS analyzer (Coulter Electronics Ltd, UK). Venous blood to measure hematocrit before and after hemodialysis was collected in an EDTA tube, and subsequently transferred to a capillary tube and centrifuged for five minutes using a Hawksley microcentrifuge, after which the hematocrit was determined using a Hawksley micro-hematocrit reader (Hawksley Ltd, UK). Blood was collected in lithium heparin tubes and centrifuged for 10 minutes at 2500 rpm. Plasma was then stored at -80°C until assayed. Plasma cholinesterase activity was measured using a cholinesterase (BTC) colorimetric analyser kit (Sigma Chemical Co. Ltd. Poole, Dorset, UK) using a COBAS-BIO analyzer30.Dietz A.A. Rubenstein H.M. Lubrana T. Colorimetric determination of serum cholinesterase and its genetic variants by the propionyl-thiocholine-dithiobis (Nitrobenzoic acid) procedure.Clin Chem. 1973; 19: 1309-1313PubMed Google Scholar. Plasma cholesterol concentrations were measured using a Cholesterol CHOD-PAP method enzyme colorimetric test (Boehringer Mannheim) using an Hitachi 747 analyzer31.Siedel J. Hagele E.O. Ziegenhorn J. Wahlefeld A.W. Reagent for the enzymatic determination of serum cholesterol with improved lipolytic efficiency.Clin Chem. 1983; 29: 1075-1080Crossref PubMed Scopus (860) Google Scholar. Plasma arginine concentrations were measured using automated orthopthaldehyde derivatisation and dialysis by ASTED (Gilson Medical Electronics, Villiers le Bel, France) and then separated from other amino acids using high performance liquid chromatography. Analytical separation was achieved using a tertiary gradient system permitting resolution of the amino acids based on both pKA and hydrophobic interaction with the column (15 cm, 2.5 mm ID, ODS). A fluorimeter (Gilsen Medical Electronics) set at 305 to 395 nm excitation, 430 to 470 emission was used as a detector32.Turnell D.C. Cooper J.D. Rapid assay for aminoacids in serum or urine by pre-column derivatization and reverse-phase liquid chromatography.Clin Chem. 1982; 28: 527-531PubMed Google Scholar. The coefficient of variation for the measurement of arginine was 8.9%. Each study was performed on a separate day and for each subject studies were separated by at least one week. The same hand vein was used when repeated studies were performed in the same subject. Each study that involved patients with end-stage renal failure related to the same dialysis session during the week. In addition, the dialysis time and artificial kidney size and composition were unchanged during the period of study. Also all patients achieved their clinically assessed dry weight by the end of each dialysis session. Not all of the patients underwent all of the protocols, and the details are in Table 1. Subjects rested semi-recumbent in a quiet room which was maintained at a constant temperature of between 23 and 25°C. The dorsal hand vein was cannulated and the LVDT sited. In control subjects a 21 SWG cannula was inserted under local anesthesia (1% lidocaine) into an antecubital vein of the opposite arm for venous blood sampling. Blood pressure and body wt were measured and blood was withdrawn from the ’arterial’ dialysis cannula in the patients with end-stage renal failure both before and after dialysis. In all studies, saline was then infused for 30 minutes to allow the establishment of basal vein size. Vein size was measured at five minutes intervals throughout each study. In the control subjects, venous blood was sampled, and blood pressure was measured, after establishing baseline vein size during the acetylcholine/GTN dose response study. In resting subjects, in a warm environment, superficial hand veins have no tone33.Collier J.G. Nachev C. ROBINSON B.F. Effects of catecholamines and other vasoactive substances on superficial hand veins in man.Clin Sci. 1972; 43: 455-467Crossref PubMed Scopus (54) Google Scholar; to investigate venodilation the vein must first be preconstricted. Therefore, in the first study, after establishing basal vein size norepinephrine was infused at doubling doses (3 to 192 pmol/min, each dose for 10 min) to determine the dose response relationship. This study was performed in all subjects and allowed the calculation of a dose of norepinephrine sufficient to cause ∼60% venoconstriction in subsequent studies. The study was performed > 24 hours after the previous hemodialysis session and <16 hours before the next. Oral aspirin (600 mg) was given 30 minutes before drug infusion to inhibit prostacyclin synthesis8.Vallance P. Collier J. Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo.Cardiovasc Res. 1989; 23: 1053-1057Crossref PubMed Scopus (194) Google Scholar,34.Heavey D.J. Barrow S.E. Hickling N.E. Ritter J.M. Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man.Nature (Lond). 1985; 318: 186-188Crossref PubMed Google Scholar. After saline infusion, norepinephrine was infused sufficient to cause ∼60% venoconstriction. Acetylcholine was co-infused at increasing doses (0.1, 1, 10 and 100 nmol/min; each dose for 10 min) followed by saline for at least 10 minutes to allow the vein to return to its preconstricted state. Glyceryl trinitrate (GTN; 0.3, 1, 3 and 10 pmol/min; each dose for 10 min) was then infused. This protocol was identical to that used when responses were assessed pre-dialysis except the study took place 45 to 60 minutes after completion of hemodialysis. The pre-dialysis protocol was again followed except that, after establishing basal vein size and before starting the norepinephrine infusion, either L-arginine or D-arginine were co-infused at 100 nmol/min and continued throughout the studies. After undergoing a norepinephrine dose response study, healthy control subjects underwent a three phase single-blind randomized study. Responses to acetylcholine and GTN were assessed as in the pre-hemodialysis study and, on separate days at least one week apart, these were repeated with co-infusion of L-arginine and D-arginine. For both patients and control subjects, the order of administration of acetylcholine and GTN was randomized. However, once determined, this order was maintained for each subject though subsequent phases of the study. The order of pre- and post-dialysis studies and the L- or D-arginine studies were also randomized. Basal vein diameter was calculated by taking the mean of the last four measurements during saline infusion, and is expressed in millimeters. Venoconstriction to norepinephrine is expressed as % constriction [100 × (resting vein size - vein size with norepinephrine)/resting vein size]. Responses to acetylcholine and GTN are expressed as % reversal of constriction [100 × (vein size when agent is infused - vein size with norepinephrine)/(resting vein size - vein size with norepinephrine)]. Change in plasma volume during hemodialysis was calculated according to the following formula: Δ plasma volume = (100/100-Hctbefore)×(100[Hctbefore- Hctafter]/Hctafter)35.VAN BEAUMONT W. Evaluation of hemoconcentration from hematocrit measurements.J Appl Physiol. 1972; 32: 712-713https://doi.org/10.1038/318186a0Crossref PubMed Scopus (104) Google Scholar. Changes in blood pressure, hematocrit, plasma volume and body wt with each dialysis session were analyzed in all subjects. However, because the pre- and post-dialysis vein studies took place on different days, the relationship between the changes in response to acetylcholine and % changes in blood pressure, hematocrit, plasma volume, arginine and body wt across dialysis the blood pressure, hematocrit, arginine and body wt values used data obtained on the relevant study day. The dose response data are presented as the area under the curve, expressed as the mean ±SEM, and examined using Student's paired or unpaired t-test as appropriate. Blood pressure, basal vein size, hematological and biochemical data are expressed as the mean ±SEM, and were analyzed using Student's paired or unpaired t-test as appropriate. The relationships between the % change of blood pressure and the % change in hematocrit, plasma volume and plasma concentrations of arginine across dialysis were analyzed using simple regression analysis. All statistical analysis was performed using the STATVIEW 512+™ software (Brain-power Inc., Calabasas, CA, USA) for the Apple Macintosh microcomputer. Values of P≤ 0.05 were considered statistically significant. All 12 hemodialysis patients (8 men, 4 women; aged 45 ± 5; range 26 to 65 years) and the 8 control subjects (6 men, 2 women; age 44 ± 6; 26 to 69 years) underwent the dose response study. There was no difference in the responsiveness to norepinephrine between the hemodialysis patients and control subjects (P = 0.96; Figure 1). Basal vein sizes did not differ between studies Table 2a. Venoconstriction in response to norepinephrine before the acetylcholine and GTN infusions was also similar Table 2a, although the pre-constriction before GTN in the L-arginine study was sig" @default.
• W2023643206 created "2016-06-24" @default.
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• W2023643206 date "1998-04-01" @default.
• W2023643206 modified "2023-10-16" @default.
• W2023643206 title "Hemodialysis and L-arginine, but not D-arginine, correct renal failure-associated endothelial dysfunction" @default.
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