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Superior mesenteric artery dilatation alone does not account for glucose-induced hypotension in human sympathetic denervation
Journal of the Autonomic Nervous System 75 Ž1999. 184–191
Superior mesenteric artery dilatation alone does not account for glucose-induced hypotension in human sympathetic denervation Sharmini Puvi-Rajasingham a,b, Jeffery Kimber a,b, Laura P. Watson Christopher J. Mathias a,b,) a
a,b
,
NeuroÕascular Medicine Unit, DiÕision of Neuroscience and Psychological Medicine, Imperial College School of Medicine at St. Mary’s, London, UK b Autonomic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, and UniÕersity Department of Clinical Neurology, Institute of Neurology, UniÕersity College London, London, UK Received 10 April 1998; revised 24 June 1998; accepted 25 September 1998
Abstract Haemodynamic and hormonal effects of two oral isovolaemic, isoosmotic solutions of 0.5 grkg and 1.0 grkg glucose were studied in 10 humans with sympathetic denervation due to primary autonomic failure ŽAF.. Measurements were made supine for 60 min, and also after 5 min 45 head-up tilt, before and 60 min after glucose. There was a similar fall in blood pressure ŽBP. after each dose, after 0.5 grkg from 160 " 12r87" 6 to 143 " 13r76" 6 mm Hg, P - 0.05 and after 1.0 grkg from 160 " 13r90" 6 to 136 " 9r76 " 5 mm Hg, P - 0.05. Heart rate, cardiac index and forearm muscle blood flow did not change after either dose. After 0.5 grkg, superior mesenteric artery blood flow was unchanged but rose significantly after 1.0 grkg, from 243 Ž169–395. to 722 Ž227–982. mlrmin, P - 0.05, 15 min after ingestion. BP fell further on tilt 60 min after each dose, but there was no difference between doses. Plasma glucose was higher after 1.0 grkg but plasma insulin was similar after each dose. Thus, in AF with sympathetic denervation there was no dose-related effect of glucose on supine or postural hypotension. Supine hypotension after glucose was not attributable solely to increased splanchnic blood flow; other factors, including dilatation in other vascular beds may have contributed. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Autonomic failure; Catecholamines; Glucose; Hypotension; Sympathetic denervation
1. Introduction In subjects with sympathetic denervation due to primary autonomic failure ŽAF., carbohydrate administered as glucose lowers blood pressure ŽBP.; this effect of glucose on BP has been attributed in part to actions of insulin and other vasoactive peptides ŽRaimbach et al., 1989.. All previous studies demonstrating hypotension following oral glucose in AF have employed 1.0 grkg doses ŽMathias et al., 1989a; Hirayama et al., 1993. and there is no data in these subjects on the cardiovascular Žsystemic and regional, especially splanchnic., biochemical or hormonal responses to lower doses of glucose, despite the fact that a
lower intake of carbohydrate is recommended as a therapeutic measure in the management of postprandial hypotension in primary AF ŽMathias and Bannister, 1992a.. The aim of the study, therefore, was to determine whether a smaller dose of glucose would result in a reduced blood pressure fall and if so, whether this was associated with decreased insulin release, or reduced SMA vasodilatation. As food is a major factor exacerbating postural hypotension, we also studied the effect of different glucose loads on the cardiovascular responses to head-up tilt before and 60 min after ingestion.
2. Subjects and methods )
Corresponding author. Neurovascular Medicine Unit ŽPickering Unit., Imperial College School of Medicine at St. Mary’s, Praed St., London W21NY, UK. Tel.: q44-171-886-1468; fax: q44-171-886-1540; e-mail: [email protected]
2.1. Subjects Ten subjects with chronic primary autonomic failure ŽAF, mean age 58, range 40–76, mean weight 68 kg, range
0165-1838r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 1 8 3 8 Ž 9 8 . 0 0 1 5 8 - 1
S. PuÕi-Rajasingham et al.r Journal of the Autonomic NerÕous System 75 (1999) 184–191
52–78 kg. were studied. Six had pure autonomic failure ŽPAF., with no other neurological deficits and four had the multiple system atrophy ŽMSA; synonymous with the Shy–Drager syndrome., in which autonomic failure is accompanied by parkinsonian andror cerebellar features. All had postural hypotension Žsystolic fall of BP ) 20 mm Hg. due to clearly defined sympathetic failure; the diagnosis was confirmed by a series of physiological and biochemical tests ŽMathias and Bannister, 1992b.. All had abnormal responses to the Valsalva manoeuvre and impaired or absent responses to a series of pressor tests Žmental arithmetic, cutaneous cold and isometric exercise.. In all subjects sinus arrhythmia was reduced and there was an abnormal thermoregulatory response to a 18C temperature rise. All had impaired plasma noradrenaline responses to head-up tilt. None had evidence of secondary autonomic failure, as is associated, for example, with diabetes mellitus. Medication consisted of low dose fludrocortisone Ž50– 100 mg. which was withdrawn 2 days prior to the first study day. For a combination of clinical, ethical and practical reasons, including hospitalisation of subjects and withdrawal of medication, two doses of glucose, 0.5 and 1.0 grkg, were chosen. The latter was chosen as it is similar to an oral glucose tolerance test and had previously been used in such subjects ŽRaimbach et al., 1989; Mathias et al., 1989a.; 0.5 grkg was chosen because it was half of the previously used dose and likely to show a clear difference. The study was approved by the Ethics Committees of St. Mary’s Hospital and the National Hospital for Neurology and Neurosurgery. 2.2. Protocol The studies were randomised and single-blind. Subjects were studied on two separate occasions after an overnight fast at 0930 h in a temperature-controlled room Ž22 " 18C.. After 30 min of supine rest basal measurements were taken and blood was collected for measurement of glucose, insulin, epinephrine and norepinephrine. Subjects were then tilted head up to 458 for 5 min, after which they were returned to the horizontal position. Following the return of BP to pre-tilt levels Žapproximately 20 min., subjects were randomised to receive either a glucose load of 1.0 grkg in 250 ml water, or an isoosmotic, isovolaemic 0.5 grkg solution of glucose to which 0.83 grkg of the inert carbohydrate xylose was added. It was essential to match the glucose loads for volume and tonicity in order to specifically determine load-related metabolic differences as volume may affect gastric emptying rate and osmolarity is a determinant of splanchnic responses ŽProctor, 1985.. Solutions were ingested through a straw over 5 min while supine. BP and heart rate were recorded every 2.5 min and other measurements were repeated, including blood samples collected before Ž0. and 15, 30, 45 and 60 min after each glucose load. After 60 min, subjects were
185
again tilted 458 head-up for 5 min and a final set of haemodynamic measurements were made.
2.3. Methods BP and HR were recorded with an automated sphygmomanometer ŽSentron, Bard Biomedical, USA. which was calibrated against a mercury sphygmomanometer. Mean arterial pressure ŽMAP. was calculated as the diastolic pressure plus one-third of the pulse pressure. Stroke distance ŽSD. was derived from the integral of peak velocity profile of ascending aortic blood flow, measured by continuous wave Doppler ultrasound ŽExerdop, Quinton Instrument, Parkway, Bothell, WA, USA.. The transducer was placed in the suprasternal notch with adequate coupling fluid and positioned to aim the beam towards the anticipated location of the aortic root. The major source of error in Doppler measurements of stroke distance is underestimation of aortic velocity because the transducer has not been aimed to produce the optimum Doppler angle. Care was taken to ensure the highest systolic velocity integrals were obtained. These was associated with characteristic high-pitched, crisp, clear sounds during systole with a rapid onset, falling to a minimum during cessation of flow in diastole. The maximum Doppler frequency shift in the signal corresponding to the maximum velocity of the blood from the ascending aorta, occurring at any moment, was recorded during 20 complete and consecutive cardiac cycles and stroke distance was calculated from continuous integration of each systolic velocity integral. Relative cardiac output Žcardiac index, CI. could then be determined from the product of stroke distance and heart rate. A mean value of 20 complete and consecutive cardiac cycles were used for each observation. Changes in CI using this method are reproducible Žc.v. 9% compared to 8.5% for thermodilution. ŽHuntsman et al., 1983.. Total systemic vascular resistance ŽSVR. was calculated by dividing MAP by CI. Forearm muscle blood flow ŽFBF. was calculated using strain gauge plethysmography during venous occlusion and with the hand circulation excluded, from plethysmographic slopes, using a previously described formula ŽWhitney, 1953.. Superior mesenteric artery blood flow ŽSMABF. was measured using real-time, pulsed Doppler flowmetry ŽAcuson 128 Computed Sonography System, Acuson, CA, USA; 3.5 MHz sector transducer.. Diameter of the superior mesenteric artery ŽSMA. and time averaged velocity ŽTAV. were measured in real time using a high resolution enlarging system after a satisfactory visualisation of the artery using a longitudinal epigastric scan and placing the sample volume within the lumen of the artery near its origin from the aorta. A characteristic SMA signal was obtained which could be clearly distinguished from those of neighbouring vessels, namely the aorta and coeliac artery. The real-time amplitude-weighted frequencies dis-
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played on the Doppler screen were then converted by the computer software to TAV using the Doppler formula: Fd s
2 Fo Õcos u c
where Fd s Doppler frequency shift, Fo s incident frequency, Õ s flow velocity, c s speed of sound in tissue and u s angle of insonation Žangle between the Doppler beam and longitudinal axis of the blood flow, kept - 408.. A mean of at least three TAV’s obtained from three Doppler displays of at least three cardiac cycles was taken at each time point. SMABF was then calculated from the time–average velocity ŽTAV. and the average diameter of the SMA using the formula: flow Žmlrmin. s 1 = radius 2 = TAV = 60. Only the fasting diameter of the vessel was used in volume flow calculations due to the small size of SMA arteries Ž- 0.8 cm., and the questionable ability of duplex scanning to detect minimal changes in vessel diameter. The reproducibility of this technique has been described previously ŽChaudhuri et al., 1991.. SMA vascular resistance ŽSMAVR. and forearm vascular resistance ŽFVR. were calculated by dividing MAP by the flow. Venous blood obtained from a cannula inserted into a forearm vein was collected and placed in different tubes for measurement of various substances; tubes containing lithium heparin were used for plasma insulin and the same tubes with added EGTA and glutathione Ž9.5 mg EGTA and 6.0 mg reduced glutathione in 0.1 ml of water to prevent oxidation. for measurement of norepinephrine and epinephrine. Tubes containing fluoride oxalate were used to collect samples for measurement of plasma glucose. Blood was immediately centrifuged and the plasma stored at y208C until assayed. Insulin was measured by radioimmunoassay ŽBloom and Long, 1982; interassay and intraassay coefficients of variation Žc.v..: insulin interassay c.v. 4.9%, intraassay c.v. 3.8%., and norepinephrine ŽNE. and epinephrine ŽE. by high performance liquid chromatography with an electrochemical detector ŽMay et al., 1991; NE: interassay c.v. 4.60%, intraassay c.v. 3.12%; E: interassay c.v. 5.06%, intraassay c.v.% 4.60%. Glucose was measured using colorimetry and the glucose oxidase method Žinterassay and intraassay c.v.- 5%..
3. Results 3.1. Supine measurements 3.1.1. Blood pressure and heart rate Basal levels of systolic and diastolic BP ŽSBP and DBP. were similar on both study days Ž160 " 12 vs. 160 " 13 mm Hg SBP and 87 " 6 vs. 90 " 6 mm Hg DBP., indicating supine hypertension which may occur in AF due to alpha-adrenoreceptor supersensitivity, impaired baroreflex activity, iatrogenic effects or an increase in central blood volume due to translocation of blood from the periphery ŽBannister and Mathias, 1992.. BP fell after both doses of glucose and reached levels significantly lower than baseline values after ingestion of each glucose load ŽFig. 1.. There was no significant difference in the fall in BP occurring after each dose; however 15 min after 0.5 grkg, BP had fallen maximally from 160 " 12 to 143 " 13 mm Hg SBP Ž11%, P - 0.05. and 87 " 6 to 76 " 6 mm Hg DBP Ž12%, P - 0.05. and had fallen similarly 15 min after 1.0 grkg, but then fell further from 160 " 13 to 136 " 9 mm Hg systolic Ž13%, P - 0.05.
2.4. Statistics Paired t-tests and two-way ANOVAs with corrections for multiple measures ŽMinitab data analysis software, Minitab 1989. were used to calculate the significance of changes after glucose ingestion and differences between doses. Statistical significance was accepted at P - 0.05. Data were presented as means " SEM at each time point, except for SMA blood flow and SMA vascular resistance for which results were not normally distributed and have been presented as medians and interquartile ranges; this data was analysed using Wilcoxon signed rank and Mann–Whitney U-tests.
Fig. 1. Change in systolic and diastolic pressures before Ž0. and at 15-min intervals after 0.5 grkg Žunfilled circles. and 1.0 grkg Žfilled circles. oral glucose. Values are means"SEM. Changes from baseline analysed using paired t-tests. ) P - 0.05, )) P - 0.01, ))) P - 0.0005.
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Table 1 Forearm blood flow ŽFBF., calculated forearm vascular resistance ŽFVR., stroke distance ŽSD., cardiac index ŽCI. and calculated systemic vascular resistance ŽSVR. before Ž0. and 15, 30, 45 and 60 min after ingestion of 0.5 grkg and 1.0 grkg doses of glucose 0
15
30
45
60
FBF 0.5 grkg 1.0 grkg
5.5 " 0.8 5.5 " 0.7
4.1 " 0.8 6.0 " 1.2
4.3 " 0.4 6.3 " 1.4
5.6 " 1.5 5.1 " 0.7
4.6 " 0.7 5.2 " 0.6
FVR 0.5 grkg 1.0 grkg
20.1 " 2.0 20.5 " 1.0
23.9 " 2.7 16.8 " 2.2
23.3 " 1.4 15.4 " 2.3
17.9 " 3.2 18.8 " 1.9
22.3 " 2.7 19.0 " 1.9
SD 0.5 grkg 1.0 grkg
10.5 " 1.6 8.6 " 0.9
9.0 " 2.1 8.6 " 1.8
9.9 " 2.2 9.1 " 1.4
10.0 " 2.1 8.6 " 1.4
11.0 " 2.1 7.7 " 1.5
CI 0.5 grkg 1.0 grkg
756 " 45 657 " 42
684 " 55 683 " 31
762 " 51 748 " 56
750 " 43 714 " 49
814 " 58 607 " 38
SVR 0.5 grkg 1.0 grkg
0.15 " 0.02 0.17 " 0.02
0.15 " 0.02 0.15 " 0.02
0.13 " 0.02 0.13 " 0.01 )
0.13 " 0.01 ) 0.13 " 0.02 )
0.13 " 0.02 0.16 " 0.02
Values are means" SEM. Significance of changes from baseline: ) P - 0.05.
and from 90 " 6 to 76 " 5 mm Hg DBP Ž13%, P - 0.01. 45 min post-ingestion. DBP was not significantly below baseline levels at 60 min after ingestion of 0.5 grkg but was still low after 1.0 grkg ŽFig. 1.; the reduction in BP was not significantly different between doses. On both occasions, the fall in BP was accompanied by a non-significant increase in heart rate, after 0.5 grkg from 72 " 4 to 76 " 4 beatsrmin at 15 min, 77 " 4 beatsrmin at 30 min, 75 " 4 beatsrmin at 45 min and 74 " 4 beatsrmin at 60 min, and after 1.0 grkg from 76 " 4 to 79 " 4 beatsrmin at 15 min, 82 " 5 beatsrmin at 30 min, 83 " 4 beatsrmin at 45 min and 79 " 4 at 60 min Ž1.0 grkg.. 3.1.2. Stroke Õolume and CI Absolute measurements of stroke volume and cardiac output depend on aortic diameter which was not measured; resting values of SD and CI have therefore not been compared on the 2 study days. There were no changes in SD or CI after either dose of glucose ŽTable 1.. 3.1.3. Forearm blood flow and forearm Õascular resistance Baseline FBF was similar on both study days Ž5.5 " 0.8 vs. 5.5 " 0.7 mlrmin 100 gy1 .. There were no significant changes in FBF and FVR after either dose of glucose ŽTable 1.. 3.1.4. SMA blood flow and SMA Õascular resistance As SMA blood flow data was not normally distributed, it has been presented in this section as medians and interquartile ranges but in graph format as mean " SEM of the percentage change from basal values ŽFig. 2.. Basal
Fig. 2. Percentage change in superior mesenteric artery ŽSMA. blood flow Ža. and SMA vascular resistance Žb. before Ž0. and at 15-min intervals after 0.5 grkg Žunfilled circles. and 1.0 grkg Žfilled circles. oral glucose. Values are means"SEM. Comparison between doses by Mann–Whitney U-test. ) P - 0.05, )) P - 0.01.
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values of SMABF were similar on both days; 201 Ž164– 257. mlrmin before 0.5 grkg and 243 Ž169–395. mlrmin before 1.0 grkg. After 0.5 grkg, SMABF rose to a maximal value of 353 Ž201–517. mlrmin, 30 min after ingestion, but this was not significant ŽFig. 2.. After 0.5 grkg SMAVR fell at 15 min by 23% and at 30 min by 20%, n.s. After 1.0 grkg SMABF rose, reaching a peak of 722 Ž227–982. mlrmin, P - 0.05, 15 min after ingestion; SMABF was also elevated at 30 min Ž692 Ž383–830. mlrmin, P - 0.05. at 45 min Ž656 Ž280–758. mlrmin. and at 60 min Ž418 Ž197–600. mlrmin.. There was a corresponding but more gradual fall in SMAVR, which fell maximally by 47%, P - 0.05, 30 min after ingestion ŽFig. 2.. 3.1.5. Systemic Õascular resistance Calculated SVR fell after both doses of glucose; after 0.5 grkg from 0.15 " 0.02 to 0.13 " 0.01, Ž14%., P - 0.05 and after 1.0 grkg from 0.17 " 0.02 to 0.13 " 0.01 Ž20%., P - 0.05. There was no difference in the extent of the fall between the doses. The lowest SVR value Ž0.13 " 0.01. was recorded 45 min after 1.0 grkg glucose, coincided with the greatest fall in MAP Ž13%. and occurred after lowest SMAVR values.
3.2. Responses to head-up tilt During head-up tilt prior to each dose, MAP fell significantly; 111 " 8 to 86 " 9 mm Hg, P - 0.0005 Ž0.5 grkg. and 113 " 8 to 91 " 11 mm Hg, P - 0.0005 Ž1.0 grkg.. After glucose, MAP fell to even lower levels on tilt; after 0.5 grkg from 103 " 6 to 74 " 8 mm Hg and after 1.0 grkg from 99 " 5 to 77 " 10 mm Hg, but the BP fall was similar with each dose and BP fell to similar levels. HR increased during tilt both before and after glucose and there was no difference in HR response between doses ŽTable 2.. After 1.0 grkg, CI fell during tilt but not significantly ŽTable 2.. After both doses, calculated SVR fell non-significantly during tilt both before and after each dose ŽTable 2.. FBF fell during tilt, but non-significantly, before and after 0.5 grkg and before and after 1.0 grkg. FVR was unchanged during tilt both before and after each dose ŽTable 2.. SMABF fell non-significantly on tilt before
3.1.6. Plasma glucose and insulin leÕels Basal plasma glucose levels were similar on both study days Ž5.7 " 0.8 vs. 5.5 " 0.4 mmolrl.. After 1.0 grkg, plasma glucose levels were higher at 15 min Ž7.6 " 0.7 vs. 6.8 " 0.8 mmolrl. at 30 Ž8.8 " 0.8 vs. 7.6 " 0.8, P - 0.05. at 45 Ž10.0 " 0.5 vs. 8.0 " 0.9 mmolrl. and at 60 min Ž10.5 " 0.5 vs. 7.9 " 0.7, P - 0.03.. Basal plasma insulin levels were similar on both occasions Žbefore 0.5 grkg 5.5 " 1.5, before 1.0 grkg, 5.1 " 1.3 units.. After each dose, levels rose and peaked at 60 min Ž24.4 " 6.7 units Ž0.5 grkg. vs. 23.7 " 6.2 Ž1.0 grkg... Despite the clear differences in plasma glucose, there was a similar pattern of insulin response after each dose ŽFig. 3.. 3.1.7. Plasma norepinephrine and epinephrine Resting venous plasma norepinephrine concentrations were similar on the 2 study days Ž224 " 49 and 235 " 92 pgrml before 0.5 grkg and 1.0 grkg, respectively.. Venous plasma norepinephrine levels remained unchanged after each dose of glucose, Žat 15 min, 219 " 94 vs. 227 " 59; 30 min, 236 " 96 vs. 235 " 64; 45 min, 214 " 98 vs. 251 " 74; and 60 min, 190 " 62 vs. 197 " 50 pgrml for 0.5 grkg and 1.0 grkg doses of glucose, respectively.. Venous plasma epinephrine did not change following either dose of glucose; at baseline, 44 " 17 Ž0.5 grkg. and 30 " 12 Ž1.0 grkg.; 15 min, 42 " 14 vs. 21 " 4; 30 min, 35 " 7 vs. 18 " 3; 45 min, 34 " 9 vs. 28 " 10; and 60 min, 43 " 14 vs. 27 " 8 pgrml for 0.5 grkg and 1.0 grkg doses of glucose, respectively.
Fig. 3. Levels of plasma glucose and insulin before Ž0. and at 15-min intervals after 0.5 grkg Žunfilled circles. and 1.0 grkg Žfilled circles. oral glucose. Values are means"SEM. Significant differences between doses by ANOVA, ) P - 0.05.
S. PuÕi-Rajasingham et al.r Journal of the Autonomic NerÕous System 75 (1999) 184–191 Table 2 Systolic and diastolic pressure ŽSBP and DBP., heart rate ŽHR., cardiac index ŽCI., calculated systemic vascular resistance ŽSVR., forearm blood flow ŽFBF., calculated forearm vascular resistance ŽFVR., SMA blood flow ŽSMABF. and SMA vascular resistance ŽSMAVR. while supine and during head-up tilt before and after ingestion of either 0.5 grkg or 1.0 grkg doses of glucose Before glucose
After glucose
Supine
Tilted
Supine
Tilted
SBP 0.5 grkg 1.0 grkg
160"12 160"13
122"15))) 129"16)))
147"9 142"7
101"12))) 105"15))
DBP 0.5 grkg 1.0 grkg
87"6 90"6
68"7))) 72"9))
81"5 77"4
60"7))) 72"9))
in sympathetically denervated subjects. The BP fall was not accompanied by significant rises in HR, CI or FVR, indicating impaired sympathetic compensatory mechanisms. SVR fell after both doses, following a similar time course to the BP response. SMABF did not change significantly after 0.5 grkg but rose rapidly after 1.0 grkg accompanied by a fall in SMAVR, indicating that mechanisms other than splanchnic vasodilatation may be contributing to the reduction in systemic BP following glucose ingestion in AF. 4.1. Haemodynamic mechanisms
HR 0.5 grkg 1.0 grkg
70"4 76"4
75"7 81"6
73"4 79"6
85"10 85"7
CI 0.5 grkg 1.0 grkg
756"45 657"42
715"32 632"28
814"58 607"38
798"39 599"41
0.12"0.01 0.14"0.03
0.13"0.02 0.16"0.02
0.09"0.01 0.13"0.01
5.5"0.8 5.5"0.6
4.7"0.6 4.4"0.5
4.6"0.7 5.2"0.5
3.9"0.4 4.2"0.7
FVR 0.5 grkg 20.1"2.0 1.0 grkg 20.5"1.0
18.3"1.8 20.7"1.4
22.3"2.7 19.0"3.9
18.9"1.9 18.3"2.6
SMABF 0.5 grkg 261 Ž206–326. 1.0 grkg 243 Ž169–395.
201 Ž164–257. 159 Ž108–265.
231 Ž205–320. 418 Ž197–600.
227 Ž209–339. 461 Ž383–512.
SMAVR 0.5 grkg 0.43 Ž0.33–0.63. 1.0 grkg 0.53 Ž0.28–0.80.
0.51 Ž0.33–0.73. 0.59 Ž0.39–0.77.
0.46 Ž0.29–0.54. 0.25 Ž0.18–0.59.
0.32 Ž0.27–0.39. 0.19 Ž0.15–0.21.
SVR 0.5 grkg 0.15"0.02 1.0 grkg 0.17"0.02 FBF 0.5 grkg 1.0 grkg
189
Values are means"SEM except for SMABF and SMAVR, presented as medians and interquartile ranges. Significance of changes from baseline by ANOVA, )) P - 0.01, ))) P - 0.0005.
0.5 grkg; 261 Ž206–326. to 201 Ž164–257. mlrmin and before 1.0 grkg; 243 Ž169–395. to 159 Ž108–265.. SMABF did not change on tilt after 0.5 grkg but tended to rise after 1.0 grkg. All changes in SMABF and SMAVR on tilt were non-significant ŽTable 2..
4. Discussion In this study, two different isoosmotic, isovolaemic doses of glucose caused a similar reduction in supine BP
In our study after 1.0 grkg glucose there was a fall in BP which corresponded with the fall in SVR and was preceded by the fall in SMAVR, suggesting that changes in splanchnic blood flow contributed to the fall in BP following this dose. However, BP fell to a similar extent after 0.5 grkg without a similar fall in SMAVR, indicating that other haemodynamic mechanisms need consideration. There was no change in SD or CI after either dose, as in previous studies using 1.0 grkg oral glucose ŽRaimbach et al., 1989.; indicating that a fall in venous return and thus in cardiac preload did not contribute to the reduction in BP. The absence of significant changes in FBF and FVR after each dose suggested that vasodilatation in forearm muscle did not play a major role. However, since measurements were not made in the large leg muscle vascular bed and reductions in leg vascular resistance of approximately 30% have been previously reported in AF following 75 g glucose ŽHirayama et al., 1993., we cannot exclude a skeletal muscle vasodilatatory effect following each dose. Vasodilatation also may have occurred in the renal circulation; glucose infusions causing hyperglycemia in dogs ŽWoods et al., 1987., or raising glucose concentrations within the physiological range in normal subjects ŽAppiani et al., 1990. elevate glomerular filtration rate and renal blood flow. However, even if vasodilatation occurred in vascular territories where measurements were not made, haemodynamic mechanisms alone can not provide a complete explanation for the similar BP reductions observed after each dose. Any vascular effects presumably would have occurred to a greater degree after 1.0 grkg, after which there was the additional effect of vasodilatation in the large splanchnic bed. However, secondary and slower compensatory mechanisms may have been responsible, as discussed later. Similar insulin responses following the two doses of glucose may account for similar BP reductions after each dose, although any effects of insulin are likely to be complicated by insulin resistance in AF ŽMathias et al., 1989a.. Insulin, either as a bolus or as an intravenous infusion, lowers BP in AF ŽMathias et al., 1987; Brown et al., 1989. and thus may contribute to food and glucose-induced hypotension in AF ŽArmstrong and Mathias, 1991..
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Insulin may exert dilatatory effects on skeletal muscle ŽKearney et al., 1996.; as discussed earlier, although we did not record significant changes in the forearm, we cannot exclude the possibility that vasodilatation may have occurred in other skeletal muscle beds. Insulin is unlikely to have reduced plasma volume and increased haematocrit ŽGundersen and Christensen, 1977. as these effects do not occur in sympathectomised subjects ŽMacKay et al., 1978; Frier et al., 1983., possibly because the effect is mediated by catecholamines ŽCohn, 1966.. Although glucose itself can lower BP in AF when administered as a hypertonic solution intravenously, ŽMathias et al., 1987., i.v. infusion causing higher plasma glucose levels than those after 1.0 grkg oral glucose does not cause a comparable fall in BP ŽMathias and Bannister, 1992a., making a systemic vascular effect of glucose unlikely. However, a direct effect on the splanchnic bed after the 1.0 grkg dose is likely; an increase in tissue oxygen demand in the small intestine after carbohydrate causes a decrease in tissue oxygen tension ŽShepherd, 1979; Gallavan and Chou, 1985. and an increase in concentration of vasodilator metabolites in the interstitial fluid, leading to an increase in local blood flow ŽSit et al., 1980.. The mechanisms discussed above do not indicate why the BP fall was not larger after 1.0 grkg, especially when there were marked differences in the splanchnic region. This raises the possibility that slower compensatory humoral mechanisms, limiting the fall in BP, may have played a role after the larger dose. For example, renin is released in normals and in some AF subjects after ingestion of a mixed liquid meal ŽMathias et al., 1989b. and following 1.0 grkg oral glucose ŽMathias et al., 1989a.. Although it is not known if renin levels were higher after 1.0 grkg than 0.5 grkg in our study, it is recognised that even small elevations in renin may raise BP since AF subjects have an increased pressor sensitivity to angiotensin II ŽDavies et al., 1979.. Furthermore, the splanchnic vascular bed is highly sensitive to the effects of angiotensin II; this may account for the waning SMA vasodilatatory effects after 1.0 grkg seen at 60 min ŽFig. 2.. Haemodynamic and hormonal effects of xylose are unlikely to have accounted for part of the BP fall after 0.5 grkg; in previous studies, larger Ž0.83 grkg. doses of xylose Žas compared to our 0.42 grkg. caused a modest Ž15%. reduction in MAP compared to the greater Ž30%. fall after 1.0 grkg glucose in AF subjects ŽMathias et al., 1989a.. Xylose loads of 76 g caused only small Ž5 mU. increases in plasma insulin in normal subjects ŽBerne et al., 1989. and plasma insulin was unchanged after 63 g xylose in normals ŽTse et al., 1983. and after 1.0 grkg doses in normals and AF subjects ŽMathias et al., 1989a.. The dose of 20–30 g xylose in our study therefore, is unlikely to have influenced insulin levels. A reduction in plasma volume due to translocation of fluid into the intestinal lumen is also improbable as stroke volume did not
change in our study and haematocrit increased only by 3–4% after higher doses of xylose in AF Ž40–66 g. ŽMathias et al., 1989a.. Furthermore, studies currently in progress using a similar dose of xylose in AF have shown no fall in BP. 4.2. Responses to head-up tilt Postural hypotension in AF is exacerbated by food ingestion ŽMathias, 1995. and it was anticipated that the 0.5 grkg dose would have a smaller effect on both supine and tilted BP, as is presumed in clinical practice. However, our findings indicate no relationship between these doses of glucose and the BP fall with head-up tilt and indicate that postprandial postural hypotension is more likely to be determined by the level of supine BP. 4.3. Physiological and clinical implications The BP-lowering properties of carbohydrate have been documented in AF ŽMathias et al., 1989a. and other groups of subjects, including the elderly ŽJansen et al., 1995.. However, our investigation indicates that there is no simple relationship between the dose of glucose, its effects on BP, on the splanchnic vasculature and on postural hypotension post-glucose. Our results suggest that the splanchnic circulation alone is not responsible for the fall in BP and that other effects, including vasodilatation in other regions Žsuch as the skeletal muscle or renal vasculature. could be additive in lowering BP after 0.5rkg. In addition, the role of non-sympathetically mediated compensatory humoral mechanisms such the renin–angiotensin system need to be considered. Finally, although our studies were based on single and not multiple administrations, the results indicate that advice to reduce the intake of carbohydrate within the range used, may not be as clinically successful as has been presumed, since neither supine postprandial hypotension nor the fall in BP on standing was diminished after 0.5 compared to 1.0 grkg glucose. Acknowledgements We thank the Pacific Basin Education Foundation and the Newby Trust for supporting these studies. References Appiani, A.C., Assael, B.M., Tirelli, A.S., Cavanna, G., Marra, G., 1990. Sodium excretion and hyperfiltration during glucose infusion in man. Am. J. Nephrol. 10, 103–108. Armstrong, E., Mathias, C.J., 1991. The effects of the somatostatin analogue Octreotide on postural hypotension before and after food ingestion in primary autonomic failure. Clin. Auton. Res. 1, 135–140. Bannister, R., Mathias, C.J., 1992. Management of postural hypotension. In: Bannister, R., Mathias, C.J. ŽEds.., Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 3rd edn. Oxford University Press, Oxford, 623–645.
S. PuÕi-Rajasingham et al.r Journal of the Autonomic NerÕous System 75 (1999) 184–191 Berne, C., Fagius, J., Niklasson, F., 1989. Sympathetic response to oral carbohydrate administration: evidence from microelectrode recordings. J. Clin. Invest. 84, 1403–1409. Bloom, S.R., Long, R.G., 1982. Radioimmunoassay of Gut Regulatory Peptides. W.B. Saunders, London. Brown, R.T., Polinsky, R.J., Baucom, C.E., 1989. Euglycaemic insulininduced hypotension in autonomic failure. Clin. Neuropharmacol. 12, 227–231. Chaudhuri, K.R., Thomaides, T., Hernandez, P., Mathias, C.J., 1991. Noninvasive quantification of superior mesenteric artery blood flow during sympathoneural activation in normal subjects. Clin. Auton. Res. 1, 37–42. Cohn, J.N., 1966. Relationship of plasma volume changes to resistance and capacitance vessel effects of sympathomimetic amines and angiotensin in man. Clin. Sci. 30, 267–278. Davies, B., Bannister, R., Sever, P., Wilcox, C.S., 1979. The pressor actions of noradrenaline, angiotensin II and saralasin in chronic autonomic failure treated with fludrocortisone. Br. J. Clin. Pharmacol. 10, 223–229. Frier, B.M., Corrall, R.J.M., Davidson, N.M., Webber, R.G., Dewar, A., French, E.B., 1983. Peripheral blood cell changes in response to acute hypoglycaemia in man. Eur. J. Clin. Invest. 13, 33–39. Gallavan, R.H.J., Chou, C.C., 1985. Possible mechanisms for the initiation and maintenance of postprandial hyperaemia. Am. J. Physiol. 249, G301–G308. Gundersen, H.J.G., Christensen, N.J., 1977. Intravenous insulin causing loss of intravascular water and albumin and increased adrenergic activity in diabetics. Diabetes 26, 551–557. Hirayama, M., Watanabe, H., Koike, Y. et al., 1993. Postprandial hypotension: hemodynamic differences between multiple system atrophy and peripheral autonomic neuropathy. J. Auton. Nerv. Syst. 43, 1–6. Huntsman, L., Stewart, D., Barnes, S., Franklin, S., Colocousis, J., Hessel, E., 1983. Non-invasive Doppler determination of cardiac output in man. Circulation 67, 593–602. Jansen, R.W., Connelly, C.M., Kelly-Gagnon, M.M., Parker, J.A., Lipsitz, L.A., 1995. Postprandial hypotension in elderly patients with unexplained syncope. Arch. Int. Med. 155, 945–952. Kearney, M.T., Stubbs, T.A., Evans, A.E., Cowley, A.J., Macdonald, I.A., 1996. Insulin mediated skeletal muscle vasodilation: a mechanism for postprandial hypotension. Clin. Auton. Res. 6, 51. MacKay, J.D., Hayakawa, H., Watkins, P.J., 1978. Cardiovascular effects of insulin: plasma volume changes in diabetics. Diabetologia 15, 453–457.
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Mathias, C.J., 1995. Orthostatic hypotension: causes, mechanisms and influencing factors. Neurology 45, s6–s10. Mathias, C.J., Bannister, R., 1992a. Postcibal hypotension in autonomic disorders. In: Bannister, R., Mathias, C.J. ŽEds.., Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 3rd edn. Oxford University Press, Oxford, 489–508. Mathias, C.J., Bannister, R., 1992b. Investigation of autonomic disorders. In: Bannister, R., Mathias, C. ŽEds.., Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 3rd edn. Oxford University Press, Oxford, 255–290. Mathias, C.J., da Costa, D.F., Fosbraey, P., Christensen, N.J., Bannister, R., 1987. Hypotensive and sedative effects of insulin in autonomic failure. B.M.J. ŽClinical Research. 295, 161–163. Mathias, C.J., da Costa, D.F., Macintosh, C.M., et al., 1989a. Differential blood pressure and hormonal effects after glucose and xylose ingestion in chronic autonomic failure. Clin. Sci. 77, 85–92. Mathias, C.J., da Costa, D.F., Fosbraey, P. et al., 1989b. Cardiovascular, biochemical and hormonal changes during food-induced hypotension in chronic autonomic failure. J. Neurol. Sci. 94, 255–269. May, C., Ham, I., Heslop, K., Stone, F., Mathias, C.J., 1991. Intravenous morphine causes hypotension, hypoglycaemia and increases sympathoadrenal activity in the conscious rabbit. Clin. Sci. 75, 71–77. Proctor, K.G., 1985. Contribution of hyperosmolality to glucose-induced intestinal hyperaemia. Am. J. Physiol. 248, G521–G525. Raimbach, S.J., Cortelli, P., Kooner, J.S., Bannister, R., Bloom, S.R., Mathias, C.J., 1989. Prevention of glucose-induced hypotension by the somatostatin analogue Octreotide ŽSMS 201–995. in chronic autonomic failure: Haemodynamic and hormonal changes. Clin. Sci. 77, 623–628. Shepherd, A.P., 1979. Intestinal capillary blood flow during metabolic hyperaemia. Am. J. Physiol. 237, E548–E554. Sit, S.P., Nyhof, P., Gallavan, R., Chou, C.C., 1980. Mechanisms of glucose-induced hyperaemia in the jejunum. Proc. Soc. Exp. Biol. Med. 163, 273–277. Tse, T., Clutter, W.E., Shah, S.D., Miller, J.P., Cryer, P.E., 1983. Neuroendocrine responses to glucose ingestion in man. J. Clin. Invest. 72, 270–277. Whitney, R., 1953. The measurement of volume changes in human limbs. J. Physiol. 121, 1–27. Woods, L.L., Mizelle, H.L., Hall, J.E., 1987. Control of renal haemodynamics in hyperglycaemia: possible role of tubuloglomerular feedback. Am. J. Physiol. 252, F65–F73.
Superior mesenteric artery dilatation alone does not account for glucose-induced hypotension in human sympathetic denervation Sharmini Puvi-Rajasingham a,b, Jeffery Kimber a,b, Laura P. Watson Christopher J. Mathias a,b,) a
a,b
,
NeuroÕascular Medicine Unit, DiÕision of Neuroscience and Psychological Medicine, Imperial College School of Medicine at St. Mary’s, London, UK b Autonomic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, and UniÕersity Department of Clinical Neurology, Institute of Neurology, UniÕersity College London, London, UK Received 10 April 1998; revised 24 June 1998; accepted 25 September 1998
Abstract Haemodynamic and hormonal effects of two oral isovolaemic, isoosmotic solutions of 0.5 grkg and 1.0 grkg glucose were studied in 10 humans with sympathetic denervation due to primary autonomic failure ŽAF.. Measurements were made supine for 60 min, and also after 5 min 45 head-up tilt, before and 60 min after glucose. There was a similar fall in blood pressure ŽBP. after each dose, after 0.5 grkg from 160 " 12r87" 6 to 143 " 13r76" 6 mm Hg, P - 0.05 and after 1.0 grkg from 160 " 13r90" 6 to 136 " 9r76 " 5 mm Hg, P - 0.05. Heart rate, cardiac index and forearm muscle blood flow did not change after either dose. After 0.5 grkg, superior mesenteric artery blood flow was unchanged but rose significantly after 1.0 grkg, from 243 Ž169–395. to 722 Ž227–982. mlrmin, P - 0.05, 15 min after ingestion. BP fell further on tilt 60 min after each dose, but there was no difference between doses. Plasma glucose was higher after 1.0 grkg but plasma insulin was similar after each dose. Thus, in AF with sympathetic denervation there was no dose-related effect of glucose on supine or postural hypotension. Supine hypotension after glucose was not attributable solely to increased splanchnic blood flow; other factors, including dilatation in other vascular beds may have contributed. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Autonomic failure; Catecholamines; Glucose; Hypotension; Sympathetic denervation
1. Introduction In subjects with sympathetic denervation due to primary autonomic failure ŽAF., carbohydrate administered as glucose lowers blood pressure ŽBP.; this effect of glucose on BP has been attributed in part to actions of insulin and other vasoactive peptides ŽRaimbach et al., 1989.. All previous studies demonstrating hypotension following oral glucose in AF have employed 1.0 grkg doses ŽMathias et al., 1989a; Hirayama et al., 1993. and there is no data in these subjects on the cardiovascular Žsystemic and regional, especially splanchnic., biochemical or hormonal responses to lower doses of glucose, despite the fact that a
lower intake of carbohydrate is recommended as a therapeutic measure in the management of postprandial hypotension in primary AF ŽMathias and Bannister, 1992a.. The aim of the study, therefore, was to determine whether a smaller dose of glucose would result in a reduced blood pressure fall and if so, whether this was associated with decreased insulin release, or reduced SMA vasodilatation. As food is a major factor exacerbating postural hypotension, we also studied the effect of different glucose loads on the cardiovascular responses to head-up tilt before and 60 min after ingestion.
2. Subjects and methods )
Corresponding author. Neurovascular Medicine Unit ŽPickering Unit., Imperial College School of Medicine at St. Mary’s, Praed St., London W21NY, UK. Tel.: q44-171-886-1468; fax: q44-171-886-1540; e-mail: [email protected]
2.1. Subjects Ten subjects with chronic primary autonomic failure ŽAF, mean age 58, range 40–76, mean weight 68 kg, range
0165-1838r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 1 8 3 8 Ž 9 8 . 0 0 1 5 8 - 1
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52–78 kg. were studied. Six had pure autonomic failure ŽPAF., with no other neurological deficits and four had the multiple system atrophy ŽMSA; synonymous with the Shy–Drager syndrome., in which autonomic failure is accompanied by parkinsonian andror cerebellar features. All had postural hypotension Žsystolic fall of BP ) 20 mm Hg. due to clearly defined sympathetic failure; the diagnosis was confirmed by a series of physiological and biochemical tests ŽMathias and Bannister, 1992b.. All had abnormal responses to the Valsalva manoeuvre and impaired or absent responses to a series of pressor tests Žmental arithmetic, cutaneous cold and isometric exercise.. In all subjects sinus arrhythmia was reduced and there was an abnormal thermoregulatory response to a 18C temperature rise. All had impaired plasma noradrenaline responses to head-up tilt. None had evidence of secondary autonomic failure, as is associated, for example, with diabetes mellitus. Medication consisted of low dose fludrocortisone Ž50– 100 mg. which was withdrawn 2 days prior to the first study day. For a combination of clinical, ethical and practical reasons, including hospitalisation of subjects and withdrawal of medication, two doses of glucose, 0.5 and 1.0 grkg, were chosen. The latter was chosen as it is similar to an oral glucose tolerance test and had previously been used in such subjects ŽRaimbach et al., 1989; Mathias et al., 1989a.; 0.5 grkg was chosen because it was half of the previously used dose and likely to show a clear difference. The study was approved by the Ethics Committees of St. Mary’s Hospital and the National Hospital for Neurology and Neurosurgery. 2.2. Protocol The studies were randomised and single-blind. Subjects were studied on two separate occasions after an overnight fast at 0930 h in a temperature-controlled room Ž22 " 18C.. After 30 min of supine rest basal measurements were taken and blood was collected for measurement of glucose, insulin, epinephrine and norepinephrine. Subjects were then tilted head up to 458 for 5 min, after which they were returned to the horizontal position. Following the return of BP to pre-tilt levels Žapproximately 20 min., subjects were randomised to receive either a glucose load of 1.0 grkg in 250 ml water, or an isoosmotic, isovolaemic 0.5 grkg solution of glucose to which 0.83 grkg of the inert carbohydrate xylose was added. It was essential to match the glucose loads for volume and tonicity in order to specifically determine load-related metabolic differences as volume may affect gastric emptying rate and osmolarity is a determinant of splanchnic responses ŽProctor, 1985.. Solutions were ingested through a straw over 5 min while supine. BP and heart rate were recorded every 2.5 min and other measurements were repeated, including blood samples collected before Ž0. and 15, 30, 45 and 60 min after each glucose load. After 60 min, subjects were
185
again tilted 458 head-up for 5 min and a final set of haemodynamic measurements were made.
2.3. Methods BP and HR were recorded with an automated sphygmomanometer ŽSentron, Bard Biomedical, USA. which was calibrated against a mercury sphygmomanometer. Mean arterial pressure ŽMAP. was calculated as the diastolic pressure plus one-third of the pulse pressure. Stroke distance ŽSD. was derived from the integral of peak velocity profile of ascending aortic blood flow, measured by continuous wave Doppler ultrasound ŽExerdop, Quinton Instrument, Parkway, Bothell, WA, USA.. The transducer was placed in the suprasternal notch with adequate coupling fluid and positioned to aim the beam towards the anticipated location of the aortic root. The major source of error in Doppler measurements of stroke distance is underestimation of aortic velocity because the transducer has not been aimed to produce the optimum Doppler angle. Care was taken to ensure the highest systolic velocity integrals were obtained. These was associated with characteristic high-pitched, crisp, clear sounds during systole with a rapid onset, falling to a minimum during cessation of flow in diastole. The maximum Doppler frequency shift in the signal corresponding to the maximum velocity of the blood from the ascending aorta, occurring at any moment, was recorded during 20 complete and consecutive cardiac cycles and stroke distance was calculated from continuous integration of each systolic velocity integral. Relative cardiac output Žcardiac index, CI. could then be determined from the product of stroke distance and heart rate. A mean value of 20 complete and consecutive cardiac cycles were used for each observation. Changes in CI using this method are reproducible Žc.v. 9% compared to 8.5% for thermodilution. ŽHuntsman et al., 1983.. Total systemic vascular resistance ŽSVR. was calculated by dividing MAP by CI. Forearm muscle blood flow ŽFBF. was calculated using strain gauge plethysmography during venous occlusion and with the hand circulation excluded, from plethysmographic slopes, using a previously described formula ŽWhitney, 1953.. Superior mesenteric artery blood flow ŽSMABF. was measured using real-time, pulsed Doppler flowmetry ŽAcuson 128 Computed Sonography System, Acuson, CA, USA; 3.5 MHz sector transducer.. Diameter of the superior mesenteric artery ŽSMA. and time averaged velocity ŽTAV. were measured in real time using a high resolution enlarging system after a satisfactory visualisation of the artery using a longitudinal epigastric scan and placing the sample volume within the lumen of the artery near its origin from the aorta. A characteristic SMA signal was obtained which could be clearly distinguished from those of neighbouring vessels, namely the aorta and coeliac artery. The real-time amplitude-weighted frequencies dis-
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played on the Doppler screen were then converted by the computer software to TAV using the Doppler formula: Fd s
2 Fo Õcos u c
where Fd s Doppler frequency shift, Fo s incident frequency, Õ s flow velocity, c s speed of sound in tissue and u s angle of insonation Žangle between the Doppler beam and longitudinal axis of the blood flow, kept - 408.. A mean of at least three TAV’s obtained from three Doppler displays of at least three cardiac cycles was taken at each time point. SMABF was then calculated from the time–average velocity ŽTAV. and the average diameter of the SMA using the formula: flow Žmlrmin. s 1 = radius 2 = TAV = 60. Only the fasting diameter of the vessel was used in volume flow calculations due to the small size of SMA arteries Ž- 0.8 cm., and the questionable ability of duplex scanning to detect minimal changes in vessel diameter. The reproducibility of this technique has been described previously ŽChaudhuri et al., 1991.. SMA vascular resistance ŽSMAVR. and forearm vascular resistance ŽFVR. were calculated by dividing MAP by the flow. Venous blood obtained from a cannula inserted into a forearm vein was collected and placed in different tubes for measurement of various substances; tubes containing lithium heparin were used for plasma insulin and the same tubes with added EGTA and glutathione Ž9.5 mg EGTA and 6.0 mg reduced glutathione in 0.1 ml of water to prevent oxidation. for measurement of norepinephrine and epinephrine. Tubes containing fluoride oxalate were used to collect samples for measurement of plasma glucose. Blood was immediately centrifuged and the plasma stored at y208C until assayed. Insulin was measured by radioimmunoassay ŽBloom and Long, 1982; interassay and intraassay coefficients of variation Žc.v..: insulin interassay c.v. 4.9%, intraassay c.v. 3.8%., and norepinephrine ŽNE. and epinephrine ŽE. by high performance liquid chromatography with an electrochemical detector ŽMay et al., 1991; NE: interassay c.v. 4.60%, intraassay c.v. 3.12%; E: interassay c.v. 5.06%, intraassay c.v.% 4.60%. Glucose was measured using colorimetry and the glucose oxidase method Žinterassay and intraassay c.v.- 5%..
3. Results 3.1. Supine measurements 3.1.1. Blood pressure and heart rate Basal levels of systolic and diastolic BP ŽSBP and DBP. were similar on both study days Ž160 " 12 vs. 160 " 13 mm Hg SBP and 87 " 6 vs. 90 " 6 mm Hg DBP., indicating supine hypertension which may occur in AF due to alpha-adrenoreceptor supersensitivity, impaired baroreflex activity, iatrogenic effects or an increase in central blood volume due to translocation of blood from the periphery ŽBannister and Mathias, 1992.. BP fell after both doses of glucose and reached levels significantly lower than baseline values after ingestion of each glucose load ŽFig. 1.. There was no significant difference in the fall in BP occurring after each dose; however 15 min after 0.5 grkg, BP had fallen maximally from 160 " 12 to 143 " 13 mm Hg SBP Ž11%, P - 0.05. and 87 " 6 to 76 " 6 mm Hg DBP Ž12%, P - 0.05. and had fallen similarly 15 min after 1.0 grkg, but then fell further from 160 " 13 to 136 " 9 mm Hg systolic Ž13%, P - 0.05.
2.4. Statistics Paired t-tests and two-way ANOVAs with corrections for multiple measures ŽMinitab data analysis software, Minitab 1989. were used to calculate the significance of changes after glucose ingestion and differences between doses. Statistical significance was accepted at P - 0.05. Data were presented as means " SEM at each time point, except for SMA blood flow and SMA vascular resistance for which results were not normally distributed and have been presented as medians and interquartile ranges; this data was analysed using Wilcoxon signed rank and Mann–Whitney U-tests.
Fig. 1. Change in systolic and diastolic pressures before Ž0. and at 15-min intervals after 0.5 grkg Žunfilled circles. and 1.0 grkg Žfilled circles. oral glucose. Values are means"SEM. Changes from baseline analysed using paired t-tests. ) P - 0.05, )) P - 0.01, ))) P - 0.0005.
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Table 1 Forearm blood flow ŽFBF., calculated forearm vascular resistance ŽFVR., stroke distance ŽSD., cardiac index ŽCI. and calculated systemic vascular resistance ŽSVR. before Ž0. and 15, 30, 45 and 60 min after ingestion of 0.5 grkg and 1.0 grkg doses of glucose 0
15
30
45
60
FBF 0.5 grkg 1.0 grkg
5.5 " 0.8 5.5 " 0.7
4.1 " 0.8 6.0 " 1.2
4.3 " 0.4 6.3 " 1.4
5.6 " 1.5 5.1 " 0.7
4.6 " 0.7 5.2 " 0.6
FVR 0.5 grkg 1.0 grkg
20.1 " 2.0 20.5 " 1.0
23.9 " 2.7 16.8 " 2.2
23.3 " 1.4 15.4 " 2.3
17.9 " 3.2 18.8 " 1.9
22.3 " 2.7 19.0 " 1.9
SD 0.5 grkg 1.0 grkg
10.5 " 1.6 8.6 " 0.9
9.0 " 2.1 8.6 " 1.8
9.9 " 2.2 9.1 " 1.4
10.0 " 2.1 8.6 " 1.4
11.0 " 2.1 7.7 " 1.5
CI 0.5 grkg 1.0 grkg
756 " 45 657 " 42
684 " 55 683 " 31
762 " 51 748 " 56
750 " 43 714 " 49
814 " 58 607 " 38
SVR 0.5 grkg 1.0 grkg
0.15 " 0.02 0.17 " 0.02
0.15 " 0.02 0.15 " 0.02
0.13 " 0.02 0.13 " 0.01 )
0.13 " 0.01 ) 0.13 " 0.02 )
0.13 " 0.02 0.16 " 0.02
Values are means" SEM. Significance of changes from baseline: ) P - 0.05.
and from 90 " 6 to 76 " 5 mm Hg DBP Ž13%, P - 0.01. 45 min post-ingestion. DBP was not significantly below baseline levels at 60 min after ingestion of 0.5 grkg but was still low after 1.0 grkg ŽFig. 1.; the reduction in BP was not significantly different between doses. On both occasions, the fall in BP was accompanied by a non-significant increase in heart rate, after 0.5 grkg from 72 " 4 to 76 " 4 beatsrmin at 15 min, 77 " 4 beatsrmin at 30 min, 75 " 4 beatsrmin at 45 min and 74 " 4 beatsrmin at 60 min, and after 1.0 grkg from 76 " 4 to 79 " 4 beatsrmin at 15 min, 82 " 5 beatsrmin at 30 min, 83 " 4 beatsrmin at 45 min and 79 " 4 at 60 min Ž1.0 grkg.. 3.1.2. Stroke Õolume and CI Absolute measurements of stroke volume and cardiac output depend on aortic diameter which was not measured; resting values of SD and CI have therefore not been compared on the 2 study days. There were no changes in SD or CI after either dose of glucose ŽTable 1.. 3.1.3. Forearm blood flow and forearm Õascular resistance Baseline FBF was similar on both study days Ž5.5 " 0.8 vs. 5.5 " 0.7 mlrmin 100 gy1 .. There were no significant changes in FBF and FVR after either dose of glucose ŽTable 1.. 3.1.4. SMA blood flow and SMA Õascular resistance As SMA blood flow data was not normally distributed, it has been presented in this section as medians and interquartile ranges but in graph format as mean " SEM of the percentage change from basal values ŽFig. 2.. Basal
Fig. 2. Percentage change in superior mesenteric artery ŽSMA. blood flow Ža. and SMA vascular resistance Žb. before Ž0. and at 15-min intervals after 0.5 grkg Žunfilled circles. and 1.0 grkg Žfilled circles. oral glucose. Values are means"SEM. Comparison between doses by Mann–Whitney U-test. ) P - 0.05, )) P - 0.01.
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values of SMABF were similar on both days; 201 Ž164– 257. mlrmin before 0.5 grkg and 243 Ž169–395. mlrmin before 1.0 grkg. After 0.5 grkg, SMABF rose to a maximal value of 353 Ž201–517. mlrmin, 30 min after ingestion, but this was not significant ŽFig. 2.. After 0.5 grkg SMAVR fell at 15 min by 23% and at 30 min by 20%, n.s. After 1.0 grkg SMABF rose, reaching a peak of 722 Ž227–982. mlrmin, P - 0.05, 15 min after ingestion; SMABF was also elevated at 30 min Ž692 Ž383–830. mlrmin, P - 0.05. at 45 min Ž656 Ž280–758. mlrmin. and at 60 min Ž418 Ž197–600. mlrmin.. There was a corresponding but more gradual fall in SMAVR, which fell maximally by 47%, P - 0.05, 30 min after ingestion ŽFig. 2.. 3.1.5. Systemic Õascular resistance Calculated SVR fell after both doses of glucose; after 0.5 grkg from 0.15 " 0.02 to 0.13 " 0.01, Ž14%., P - 0.05 and after 1.0 grkg from 0.17 " 0.02 to 0.13 " 0.01 Ž20%., P - 0.05. There was no difference in the extent of the fall between the doses. The lowest SVR value Ž0.13 " 0.01. was recorded 45 min after 1.0 grkg glucose, coincided with the greatest fall in MAP Ž13%. and occurred after lowest SMAVR values.
3.2. Responses to head-up tilt During head-up tilt prior to each dose, MAP fell significantly; 111 " 8 to 86 " 9 mm Hg, P - 0.0005 Ž0.5 grkg. and 113 " 8 to 91 " 11 mm Hg, P - 0.0005 Ž1.0 grkg.. After glucose, MAP fell to even lower levels on tilt; after 0.5 grkg from 103 " 6 to 74 " 8 mm Hg and after 1.0 grkg from 99 " 5 to 77 " 10 mm Hg, but the BP fall was similar with each dose and BP fell to similar levels. HR increased during tilt both before and after glucose and there was no difference in HR response between doses ŽTable 2.. After 1.0 grkg, CI fell during tilt but not significantly ŽTable 2.. After both doses, calculated SVR fell non-significantly during tilt both before and after each dose ŽTable 2.. FBF fell during tilt, but non-significantly, before and after 0.5 grkg and before and after 1.0 grkg. FVR was unchanged during tilt both before and after each dose ŽTable 2.. SMABF fell non-significantly on tilt before
3.1.6. Plasma glucose and insulin leÕels Basal plasma glucose levels were similar on both study days Ž5.7 " 0.8 vs. 5.5 " 0.4 mmolrl.. After 1.0 grkg, plasma glucose levels were higher at 15 min Ž7.6 " 0.7 vs. 6.8 " 0.8 mmolrl. at 30 Ž8.8 " 0.8 vs. 7.6 " 0.8, P - 0.05. at 45 Ž10.0 " 0.5 vs. 8.0 " 0.9 mmolrl. and at 60 min Ž10.5 " 0.5 vs. 7.9 " 0.7, P - 0.03.. Basal plasma insulin levels were similar on both occasions Žbefore 0.5 grkg 5.5 " 1.5, before 1.0 grkg, 5.1 " 1.3 units.. After each dose, levels rose and peaked at 60 min Ž24.4 " 6.7 units Ž0.5 grkg. vs. 23.7 " 6.2 Ž1.0 grkg... Despite the clear differences in plasma glucose, there was a similar pattern of insulin response after each dose ŽFig. 3.. 3.1.7. Plasma norepinephrine and epinephrine Resting venous plasma norepinephrine concentrations were similar on the 2 study days Ž224 " 49 and 235 " 92 pgrml before 0.5 grkg and 1.0 grkg, respectively.. Venous plasma norepinephrine levels remained unchanged after each dose of glucose, Žat 15 min, 219 " 94 vs. 227 " 59; 30 min, 236 " 96 vs. 235 " 64; 45 min, 214 " 98 vs. 251 " 74; and 60 min, 190 " 62 vs. 197 " 50 pgrml for 0.5 grkg and 1.0 grkg doses of glucose, respectively.. Venous plasma epinephrine did not change following either dose of glucose; at baseline, 44 " 17 Ž0.5 grkg. and 30 " 12 Ž1.0 grkg.; 15 min, 42 " 14 vs. 21 " 4; 30 min, 35 " 7 vs. 18 " 3; 45 min, 34 " 9 vs. 28 " 10; and 60 min, 43 " 14 vs. 27 " 8 pgrml for 0.5 grkg and 1.0 grkg doses of glucose, respectively.
Fig. 3. Levels of plasma glucose and insulin before Ž0. and at 15-min intervals after 0.5 grkg Žunfilled circles. and 1.0 grkg Žfilled circles. oral glucose. Values are means"SEM. Significant differences between doses by ANOVA, ) P - 0.05.
S. PuÕi-Rajasingham et al.r Journal of the Autonomic NerÕous System 75 (1999) 184–191 Table 2 Systolic and diastolic pressure ŽSBP and DBP., heart rate ŽHR., cardiac index ŽCI., calculated systemic vascular resistance ŽSVR., forearm blood flow ŽFBF., calculated forearm vascular resistance ŽFVR., SMA blood flow ŽSMABF. and SMA vascular resistance ŽSMAVR. while supine and during head-up tilt before and after ingestion of either 0.5 grkg or 1.0 grkg doses of glucose Before glucose
After glucose
Supine
Tilted
Supine
Tilted
SBP 0.5 grkg 1.0 grkg
160"12 160"13
122"15))) 129"16)))
147"9 142"7
101"12))) 105"15))
DBP 0.5 grkg 1.0 grkg
87"6 90"6
68"7))) 72"9))
81"5 77"4
60"7))) 72"9))
in sympathetically denervated subjects. The BP fall was not accompanied by significant rises in HR, CI or FVR, indicating impaired sympathetic compensatory mechanisms. SVR fell after both doses, following a similar time course to the BP response. SMABF did not change significantly after 0.5 grkg but rose rapidly after 1.0 grkg accompanied by a fall in SMAVR, indicating that mechanisms other than splanchnic vasodilatation may be contributing to the reduction in systemic BP following glucose ingestion in AF. 4.1. Haemodynamic mechanisms
HR 0.5 grkg 1.0 grkg
70"4 76"4
75"7 81"6
73"4 79"6
85"10 85"7
CI 0.5 grkg 1.0 grkg
756"45 657"42
715"32 632"28
814"58 607"38
798"39 599"41
0.12"0.01 0.14"0.03
0.13"0.02 0.16"0.02
0.09"0.01 0.13"0.01
5.5"0.8 5.5"0.6
4.7"0.6 4.4"0.5
4.6"0.7 5.2"0.5
3.9"0.4 4.2"0.7
FVR 0.5 grkg 20.1"2.0 1.0 grkg 20.5"1.0
18.3"1.8 20.7"1.4
22.3"2.7 19.0"3.9
18.9"1.9 18.3"2.6
SMABF 0.5 grkg 261 Ž206–326. 1.0 grkg 243 Ž169–395.
201 Ž164–257. 159 Ž108–265.
231 Ž205–320. 418 Ž197–600.
227 Ž209–339. 461 Ž383–512.
SMAVR 0.5 grkg 0.43 Ž0.33–0.63. 1.0 grkg 0.53 Ž0.28–0.80.
0.51 Ž0.33–0.73. 0.59 Ž0.39–0.77.
0.46 Ž0.29–0.54. 0.25 Ž0.18–0.59.
0.32 Ž0.27–0.39. 0.19 Ž0.15–0.21.
SVR 0.5 grkg 0.15"0.02 1.0 grkg 0.17"0.02 FBF 0.5 grkg 1.0 grkg
189
Values are means"SEM except for SMABF and SMAVR, presented as medians and interquartile ranges. Significance of changes from baseline by ANOVA, )) P - 0.01, ))) P - 0.0005.
0.5 grkg; 261 Ž206–326. to 201 Ž164–257. mlrmin and before 1.0 grkg; 243 Ž169–395. to 159 Ž108–265.. SMABF did not change on tilt after 0.5 grkg but tended to rise after 1.0 grkg. All changes in SMABF and SMAVR on tilt were non-significant ŽTable 2..
4. Discussion In this study, two different isoosmotic, isovolaemic doses of glucose caused a similar reduction in supine BP
In our study after 1.0 grkg glucose there was a fall in BP which corresponded with the fall in SVR and was preceded by the fall in SMAVR, suggesting that changes in splanchnic blood flow contributed to the fall in BP following this dose. However, BP fell to a similar extent after 0.5 grkg without a similar fall in SMAVR, indicating that other haemodynamic mechanisms need consideration. There was no change in SD or CI after either dose, as in previous studies using 1.0 grkg oral glucose ŽRaimbach et al., 1989.; indicating that a fall in venous return and thus in cardiac preload did not contribute to the reduction in BP. The absence of significant changes in FBF and FVR after each dose suggested that vasodilatation in forearm muscle did not play a major role. However, since measurements were not made in the large leg muscle vascular bed and reductions in leg vascular resistance of approximately 30% have been previously reported in AF following 75 g glucose ŽHirayama et al., 1993., we cannot exclude a skeletal muscle vasodilatatory effect following each dose. Vasodilatation also may have occurred in the renal circulation; glucose infusions causing hyperglycemia in dogs ŽWoods et al., 1987., or raising glucose concentrations within the physiological range in normal subjects ŽAppiani et al., 1990. elevate glomerular filtration rate and renal blood flow. However, even if vasodilatation occurred in vascular territories where measurements were not made, haemodynamic mechanisms alone can not provide a complete explanation for the similar BP reductions observed after each dose. Any vascular effects presumably would have occurred to a greater degree after 1.0 grkg, after which there was the additional effect of vasodilatation in the large splanchnic bed. However, secondary and slower compensatory mechanisms may have been responsible, as discussed later. Similar insulin responses following the two doses of glucose may account for similar BP reductions after each dose, although any effects of insulin are likely to be complicated by insulin resistance in AF ŽMathias et al., 1989a.. Insulin, either as a bolus or as an intravenous infusion, lowers BP in AF ŽMathias et al., 1987; Brown et al., 1989. and thus may contribute to food and glucose-induced hypotension in AF ŽArmstrong and Mathias, 1991..
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Insulin may exert dilatatory effects on skeletal muscle ŽKearney et al., 1996.; as discussed earlier, although we did not record significant changes in the forearm, we cannot exclude the possibility that vasodilatation may have occurred in other skeletal muscle beds. Insulin is unlikely to have reduced plasma volume and increased haematocrit ŽGundersen and Christensen, 1977. as these effects do not occur in sympathectomised subjects ŽMacKay et al., 1978; Frier et al., 1983., possibly because the effect is mediated by catecholamines ŽCohn, 1966.. Although glucose itself can lower BP in AF when administered as a hypertonic solution intravenously, ŽMathias et al., 1987., i.v. infusion causing higher plasma glucose levels than those after 1.0 grkg oral glucose does not cause a comparable fall in BP ŽMathias and Bannister, 1992a., making a systemic vascular effect of glucose unlikely. However, a direct effect on the splanchnic bed after the 1.0 grkg dose is likely; an increase in tissue oxygen demand in the small intestine after carbohydrate causes a decrease in tissue oxygen tension ŽShepherd, 1979; Gallavan and Chou, 1985. and an increase in concentration of vasodilator metabolites in the interstitial fluid, leading to an increase in local blood flow ŽSit et al., 1980.. The mechanisms discussed above do not indicate why the BP fall was not larger after 1.0 grkg, especially when there were marked differences in the splanchnic region. This raises the possibility that slower compensatory humoral mechanisms, limiting the fall in BP, may have played a role after the larger dose. For example, renin is released in normals and in some AF subjects after ingestion of a mixed liquid meal ŽMathias et al., 1989b. and following 1.0 grkg oral glucose ŽMathias et al., 1989a.. Although it is not known if renin levels were higher after 1.0 grkg than 0.5 grkg in our study, it is recognised that even small elevations in renin may raise BP since AF subjects have an increased pressor sensitivity to angiotensin II ŽDavies et al., 1979.. Furthermore, the splanchnic vascular bed is highly sensitive to the effects of angiotensin II; this may account for the waning SMA vasodilatatory effects after 1.0 grkg seen at 60 min ŽFig. 2.. Haemodynamic and hormonal effects of xylose are unlikely to have accounted for part of the BP fall after 0.5 grkg; in previous studies, larger Ž0.83 grkg. doses of xylose Žas compared to our 0.42 grkg. caused a modest Ž15%. reduction in MAP compared to the greater Ž30%. fall after 1.0 grkg glucose in AF subjects ŽMathias et al., 1989a.. Xylose loads of 76 g caused only small Ž5 mU. increases in plasma insulin in normal subjects ŽBerne et al., 1989. and plasma insulin was unchanged after 63 g xylose in normals ŽTse et al., 1983. and after 1.0 grkg doses in normals and AF subjects ŽMathias et al., 1989a.. The dose of 20–30 g xylose in our study therefore, is unlikely to have influenced insulin levels. A reduction in plasma volume due to translocation of fluid into the intestinal lumen is also improbable as stroke volume did not
change in our study and haematocrit increased only by 3–4% after higher doses of xylose in AF Ž40–66 g. ŽMathias et al., 1989a.. Furthermore, studies currently in progress using a similar dose of xylose in AF have shown no fall in BP. 4.2. Responses to head-up tilt Postural hypotension in AF is exacerbated by food ingestion ŽMathias, 1995. and it was anticipated that the 0.5 grkg dose would have a smaller effect on both supine and tilted BP, as is presumed in clinical practice. However, our findings indicate no relationship between these doses of glucose and the BP fall with head-up tilt and indicate that postprandial postural hypotension is more likely to be determined by the level of supine BP. 4.3. Physiological and clinical implications The BP-lowering properties of carbohydrate have been documented in AF ŽMathias et al., 1989a. and other groups of subjects, including the elderly ŽJansen et al., 1995.. However, our investigation indicates that there is no simple relationship between the dose of glucose, its effects on BP, on the splanchnic vasculature and on postural hypotension post-glucose. Our results suggest that the splanchnic circulation alone is not responsible for the fall in BP and that other effects, including vasodilatation in other regions Žsuch as the skeletal muscle or renal vasculature. could be additive in lowering BP after 0.5rkg. In addition, the role of non-sympathetically mediated compensatory humoral mechanisms such the renin–angiotensin system need to be considered. Finally, although our studies were based on single and not multiple administrations, the results indicate that advice to reduce the intake of carbohydrate within the range used, may not be as clinically successful as has been presumed, since neither supine postprandial hypotension nor the fall in BP on standing was diminished after 0.5 compared to 1.0 grkg glucose. Acknowledgements We thank the Pacific Basin Education Foundation and the Newby Trust for supporting these studies. References Appiani, A.C., Assael, B.M., Tirelli, A.S., Cavanna, G., Marra, G., 1990. Sodium excretion and hyperfiltration during glucose infusion in man. Am. J. Nephrol. 10, 103–108. Armstrong, E., Mathias, C.J., 1991. The effects of the somatostatin analogue Octreotide on postural hypotension before and after food ingestion in primary autonomic failure. Clin. Auton. Res. 1, 135–140. Bannister, R., Mathias, C.J., 1992. Management of postural hypotension. In: Bannister, R., Mathias, C.J. ŽEds.., Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, 3rd edn. Oxford University Press, Oxford, 623–645.
S. PuÕi-Rajasingham et al.r Journal of the Autonomic NerÕous System 75 (1999) 184–191 Berne, C., Fagius, J., Niklasson, F., 1989. Sympathetic response to oral carbohydrate administration: evidence from microelectrode recordings. J. Clin. Invest. 84, 1403–1409. Bloom, S.R., Long, R.G., 1982. Radioimmunoassay of Gut Regulatory Peptides. W.B. Saunders, London. Brown, R.T., Polinsky, R.J., Baucom, C.E., 1989. Euglycaemic insulininduced hypotension in autonomic failure. Clin. Neuropharmacol. 12, 227–231. Chaudhuri, K.R., Thomaides, T., Hernandez, P., Mathias, C.J., 1991. Noninvasive quantification of superior mesenteric artery blood flow during sympathoneural activation in normal subjects. Clin. Auton. Res. 1, 37–42. Cohn, J.N., 1966. Relationship of plasma volume changes to resistance and capacitance vessel effects of sympathomimetic amines and angiotensin in man. Clin. Sci. 30, 267–278. Davies, B., Bannister, R., Sever, P., Wilcox, C.S., 1979. The pressor actions of noradrenaline, angiotensin II and saralasin in chronic autonomic failure treated with fludrocortisone. Br. J. Clin. Pharmacol. 10, 223–229. Frier, B.M., Corrall, R.J.M., Davidson, N.M., Webber, R.G., Dewar, A., French, E.B., 1983. Peripheral blood cell changes in response to acute hypoglycaemia in man. Eur. J. Clin. Invest. 13, 33–39. Gallavan, R.H.J., Chou, C.C., 1985. Possible mechanisms for the initiation and maintenance of postprandial hyperaemia. Am. J. Physiol. 249, G301–G308. Gundersen, H.J.G., Christensen, N.J., 1977. Intravenous insulin causing loss of intravascular water and albumin and increased adrenergic activity in diabetics. Diabetes 26, 551–557. Hirayama, M., Watanabe, H., Koike, Y. et al., 1993. Postprandial hypotension: hemodynamic differences between multiple system atrophy and peripheral autonomic neuropathy. J. Auton. Nerv. Syst. 43, 1–6. Huntsman, L., Stewart, D., Barnes, S., Franklin, S., Colocousis, J., Hessel, E., 1983. Non-invasive Doppler determination of cardiac output in man. Circulation 67, 593–602. Jansen, R.W., Connelly, C.M., Kelly-Gagnon, M.M., Parker, J.A., Lipsitz, L.A., 1995. Postprandial hypotension in elderly patients with unexplained syncope. Arch. Int. Med. 155, 945–952. Kearney, M.T., Stubbs, T.A., Evans, A.E., Cowley, A.J., Macdonald, I.A., 1996. Insulin mediated skeletal muscle vasodilation: a mechanism for postprandial hypotension. Clin. Auton. Res. 6, 51. MacKay, J.D., Hayakawa, H., Watkins, P.J., 1978. Cardiovascular effects of insulin: plasma volume changes in diabetics. Diabetologia 15, 453–457.
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