Gastric distension attenuates the hypotensive effect of intraduodenal glucose in healthy older subjects

Transcription

1 Am J Physiol Regul Integr Comp Physiol 295: R472 R477, First published May 21, 2008; doi: /ajpregu Gastric distension attenuates the hypotensive effect of intraduodenal glucose in healthy older subjects Diana Gentilcore, 1 James H. Meyer, 1 Christopher K. Rayner, 1 Michael Horowitz, 1 and Karen L. Jones 1 1 University of Adelaide, Discipline of Medicine, Royal Adelaide Hospital, South Australia, Australia Submitted 13 February 2008; accepted in final form 21 May 2008 Gentilcore D, Meyer JH, Rayner CK, Horowitz M, Jones KL. Gastric distension attenuates the hypotensive effect of intraduodenal glucose in healthy older subjects. Am J Physiol Regul Integr Comp Physiol 295: R472 R477, First published May 21, 2008; doi: /ajpregu Postprandial hypotension occurs frequently, and current management is suboptimal. Recent studies suggest that the magnitude of the fall in postprandial blood pressure (BP) may be attenuated by gastric distension. The aim of this study was to determine the effect of gastric distension on the hypotensive response to intraduodenal (ID) glucose. Eight healthy subjects (5 males, 3 females, aged years) received an ID infusion of either 1) 50 g glucose in 300 ml saline (ID glucose) over 60 min (t 0 60 min), 2) 50 g glucose in 300 ml saline over 60 min and intragastric (4) infusion of 500 ml water between t 7 10 min (IG water and ID glucose), or 3) ID saline (0.9%) infusion over 60 min and IG infusion of 500 ml water (IG water and ID saline) all followed by ID saline infusion for another 60 min (t min) on three separate days. BP and heart rate (HR) were measured. Gastric emptying (GE) of the IG water was quantified by two-dimensional ultrasonography. Between t 0 60 min, systolic and diastolic BP was greater (P 0.05 for both) with IG water and ID saline compared with IG water and ID glucose, and less (P 0.05 for both) with ID glucose compared with IG water and ID glucose. These effects were evident at relatively low IG volumes ( 300 ml). GE was faster with IG water and ID saline when compared with IG water and ID glucose. We conclude that, in healthy older subjects, IG administration of water markedly attenuates the hypotensive response to ID glucose, presumably as a result of gastric distension. blood pressure; heart rate; gastric emptying; two-dimensional ultrasound; elderly POSTPRANDIAL HYPOTENSION, defined as a decrease in systolic blood pressure 20 mmhg, occurring within 2 h of the end of a meal (18, 19, 27, 28), is now recognized as an important clinical problem, as it can lead to syncope and falls (19) and in some cases, stroke and angina (1, 19, 39). Those at greatest risk include the elderly and patients with autonomic dysfunction, and most often the latter, secondary to diabetes (18, 19, 27, 28). The mechanisms responsible for postprandial hypotension are unclear, but impaired regulation of splanchnic blood flow, the release of gastrointestinal hormones, and sympathetic nerve activity appear important (18, 19, 27, 28). The magnitude of the postprandial fall in blood pressure is dependent on meal composition; carbohydrates like glucose, have a highly suppressive effect on blood pressure (1, 34). In contrast to oral glucose, intravenous glucose has little, if any, effect on blood pressure (19), indicating that postprandial hypotension is, at least in the broadest sense, triggered by gastrointestinal mechanisms. It is now apparent that the hypotensive response to a meal is modulated by gastric distension (4, 22, 24, 25, 38) and the interaction of nutrients with the small intestine; of the latter, glucose has been the most widely studied (21, 23, 31, 36). The rate of glucose delivery from the stomach to the small intestine has been shown to be a major determinant of the hypotensive response to enterally administered glucose (21, 23, 31, 36). For example, in healthy older subjects, when glucose is infused intraduodenally at a rate of 3 kcal/min, the magnitude of the maximum fall in systolic blood pressure (mean 24 mmhg), is substantially greater compared with infusion at a rate of 1 kcal/min (mean 9 mmhg) (31). Even healthy young subjects exhibit a fall in blood pressure in response to intraduodenal glucose at 3 kcal/min, although the magnitude of this decrease is less than in healthy elderly (41). Studies conducted by both ourselves (22) and others (4, 24, 25, 35, 38, 40) indicate that gastric distension has the capacity to attenuate the postprandial fall in blood pressure. In healthy young and older subjects, an increase in intragastric pressure induced by a gastric balloon linked to a barostat device increases systolic blood pressure and muscle sympathetic nerve activity in a pressure-dependent fashion the so-called gastrovascular reflex (35, 40). Intragastric volume was not measured in those experiments. In patients with postprandial hypotension associated with autonomic neuropathy, Shannon et al. (38) observed that 480 ml of water, drunk immediately before a 414-calorie meal (52% of calories as carbohydrate), prevented a postprandial fall in blood pressure for 40 min, after which systolic blood pressure fell below baseline. Subsequently, Deguchi et al. (5) reported similar effects in patients with multiple-system atrophy, who consumed 350 ml of water before a standardized breakfast the beneficial effect of the drink on blood pressure was sustained for 30 min. Ingestion of water has also been shown to increase blood pressure in the fasted state (25). A limitation of all these studies (35, 38, 40) was that changes in intragastric volumes during gastric emptying after meals were not quantified. Hence, there is no information as to the minimum intragastric volume needed to modulate blood pressure in the fasted state or eliminate the hypotensive response to a meal. The primary aim of this study was to determine in healthy older subjects whether a volume of 500 ml water has the capacity to counteract the maximum hypotensive effect of glucose infused into the duodenum at 3 kcal/min and to determine the minimum intragastric volume required to elicit a blood pressure response in the fasting state. Address for reprint requests and other correspondence: K. L. Jones, Univ. of Adelaide, Discipline of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia ( karen.jones@adelaide.edu.au). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. R /08 $8.00 Copyright 2008 the American Physiological Society

2 R473 MATERIALS AND METHODS Subjects Eight healthy older subjects, (five male and three female) with a median age of 71 years (range: years) and body mass index (BMI) of 24.1 kg/m 2 (range: kg/m 2 ), recruited by advertisement, were studied. All subjects were nonsmokers. None had a history of gastrointestinal disease or surgery, diabetes, significant respiratory, renal, hepatic or cardiac disease, chronic alcohol abuse or epilepsy, or was taking medication known to influence blood pressure or gastrointestinal function. Protocol The protocol was approved by the Human Research Ethics Committee of the Royal Adelaide Hospital, and each subject provided written, informed consent prior to their involvement. All experiments were carried out in accordance with the Declaration of Helsinki. Each subject was studied on three occasions, each separated by a minimum of 7 days, in single-blind, randomized order. On each day, the subject attended the University of Adelaide, Discipline of Medicine, Royal Adelaide Hospital, at 0830 following a fast (10.5 h for solids; 8.5 h for liquids) (9 11). At that time, a silicone-rubber catheter (external diameter 4 mm) (Dentsleeve International, Mui Scientific, Ontario, Canada), was introduced into the stomach via an anesthetized nostril (10, 31). The assembly included an infusion channel (internal diameter 1 mm) and was positioned so that the infusion port was located 10 cm distal to the pylorus (i.e., in the duodenum), as well as two other channels that were positioned in the antrum (2.5 cm proximal to the pylorus) and duodenum (2.5 cm distal to the pylorus), respectively, and were perfused with 0.9% saline. The correct positioning of the catheter was maintained by continuous measurement of the transmucosal potential difference between the antral ( 40 mv) and the duodenal (0 mv), channel (13). For this purpose, an intravenous cannula filled with sterile saline was placed subcutaneously in the left forearm and used as a reference electrode (13). A smaller-diameter ( 0.2 mm internal) silicone tube was attached to the catheter with its outlet located 10 cm proximal to the pylorus, to allow intragastric (4) infusion. The tip of the catheter passed into the duodenum by peristalsis, which took between 40 and 205 min. An automated blood pressure cuff was placed around the left arm (10, 31). Once intubated, the subject initially rested in the recumbent position. Approximately 30 min after the tube was positioned correctly (at t 0 min), the subject was seated in a chair and received either 1) an intraduodenal (ID) infusion of 50 g of glucose dissolved in 300 ml 0.9% saline (ID glucose group) at a rate of 5 ml/min (3.3 kcal/min) between t 0 60 min, 2) an identical ID infusion between t 0 60 min, and an intragastric (IG) infusion of 500 ml water between t 7 10 min (IG water and ID glucose group), or 3) an ID saline (0.9%) infusion at 5 ml/min between t 0 60 min and an IG infusion of 500 ml water between t 7 10 min (IG water and ID saline group). On all three days, normal saline was infused intraduodenally at 5 ml/min between t min (31). The osmotic pressure of the intraduodenal glucose solution was 22.4 atmospheres. Intraduodenal infusions were performed using a volumetric infusion pump (Imed Gemini PC-1; San Diego, CA). For the intragastric infusions, water was pressurized (170 kpa) with oxygen and delivered at a rate of 166 ml/min. Gastric emptying of the water was measured using ultrasound (17); in the ID glucose group (between t min), sham ultrasonography measurements were performed to ensure that the subject remained blinded to the study conditions. At t 120 min, the catheter was removed, the subject was given a light meal and then allowed to leave the laboratory. On one day, cardiovascular autonomic nerve function was evaluated immediately after the completion of the study (7, 33). Measurements Blood pressure and heart rate. Blood pressure (systolic and diastolic) and heart rate were measured using an automated oscillometric blood pressure monitor (DINAMAP ProCare 100, GE Medical Systems, Milwaukee, WI) at t 9, 6, and 3 min before commencement of the intraduodenal infusions and then every 3 min between t min (10, 31). Baseline blood pressure and heart rate, that is, t 0 min, were calculated as the mean of measurements taken at t 9, 6, and 3 min. Postprandial hypotension was defined as a fall in systolic blood pressure of 20 mmhg that was sustained for at least 30 min (19). Gastric emptying. Antral area was measured by real-time twodimensional ultrasonography using a Logiq 9 ultrasonography system (GE Healthcare Technologies, Sydney, Australia). The subject was scanned using a 3.5C broad-spectrum MHz convex transducer (20) before (t 2 min) the commencement of the intraduodenal infusion, at t 15 min, i.e., 5 min after the completion of the intragastric infusion and then every 15 min until t 120 min. With the subject seated, the transducer was positioned vertically, in the region of the umbilicus, to visualize the antrum in cross section with the superior mesenteric vein and the abdominal aorta as landmarks (17). Antral area (cm 2 ) was measured using manually operated onscreen calipers. The circumference of the antrum was outlined and the area recorded during the fasting state (t 2 min) was subtracted from subsequent measurements. At all time points, gastric emptying was expressed as retention (%) [AA(t) AA( 2)]/[AA(max) AA( 2)] 100, where AA(t) antral area measured at a specific time point, AA( 2) antral area at t 2 min and AA(max) maximum antral area (17). The 50% emptying time (T50) was also determined, as previously described (12). This method has been well validated to calculate total intragastric volumes (17). Autonomic function. Autonomic nerve function was assessed using standardized cardiovascular reflex tests (7, 33). Parasympathetic function was evaluated by the variation (R-R interval) of the heart rate during deep breathing and the response to standing (30:15 ratio). Sympathetic function was assessed by the fall in systolic blood pressure in response to standing. Each of the test results was scored according to age-adjusted predefined criteria as 0 normal, 1 borderline, and 2 abnormal for a total maximum score of 6. A score 3 was considered to indicate autonomic dysfunction (7, 33). Statistical Analysis Data were evaluated using mixed-model repeated-measures twoway ANOVA, with treatment and time as within-subject factors. Systolic and diastolic blood pressure and heart rate were analyzed as changes from baseline. Data were analyzed separately from t 0 60 min and t min to evaluate the effects of treatment and time on the effects of intraduodenal glucose. Gastric emptying was analyzed as absolute values. One-way ANOVA was used to analyze the effects of time on systolic and diastolic blood pressure, heart rate, and gastric emptying. The maximum fall in blood pressure was defined as the greatest mean change from baseline in each subject at any given time point for each treatment. In all analyses, post hoc comparisons of adjusted means were performed using Student s t-tests. All analyses were performed using Statview (ver. 5.0; Abacus Concepts, Berkeley, CA) and SuperANOVA (ver. 1.11, Abacus Concepts). Data are shown as the change from baseline and mean values SE. A P value 0.05 was considered significant in all analyses. RESULTS The studies were well tolerated, and there were no untoward events. The median score for autonomic nerve dysfunction was 0.88 (range: 0 3). One of the eight subjects had definite autonomic dysfunction. While no subject experienced post-

3 R474 prandial hypotension (i.e., a fall in systolic blood pressure 20 mmhg sustained for at least 30 min), in five of them, the magnitude of the fall in systolic blood pressure was 20 mmhg at one or more time points. In one subject, gastric emptying data could not be obtained because of technical difficulties relating to the ultrasonography measurements; hence, the subject was excluded from the gastric emptying analysis. Baseline Blood Pressure and Heart Rate There was no significant difference in baseline blood pressure or heart rate between the 3 days (IG water and ID saline vs. ID glucose vs. IG water and ID glucose): systolic blood pressure ( mmhg vs mmhg vs mmhg); diastolic blood pressure ( mmhg vs mmhg vs mmhg) and heart rate ( bpm vs bpm vs bpm). Systolic and diastolic blood pressures. Between t 0 60 min, there was a rise in systolic (P 0.01), and a trend for a rise in diastolic (P 0.09), blood pressure during IG water and ID saline (Fig. 1, A and B). In contrast, there was a fall in systolic (P 0.05) (maximum fall: mmhg at t min) and diastolic (P ) blood pressure with ID glucose and no change in systolic (P 0.98) or diastolic (P 0.17) blood pressure during IG water and ID glucose. There were significant treatment time effects for systolic (P 0.001) and diastolic (P ) blood pressure between t 0 60 min, so that systolic and diastolic blood pressure were greater (P 0.05 for both) during IG water and ID saline when compared with IG water and ID glucose, and less (P 0.05 for both), during ID glucose when compared with IG water and ID glucose. Between t min, systolic blood pressure was higher (P 0.05) after IG water and ID saline when compared with IG water and ID glucose. However, there was no difference (P 0.70) in systolic blood pressure after ID glucose compared with IG water and ID glucose. There was also a rise (P 0.01) in diastolic blood pressure after ID glucose, but not following IG water and ID glucose (P 0.48) or IG water and ID saline (P 0.97) and a trend (P 0.09) for a difference in diastolic blood pressure between the three study days. Heart rate. Between t 0 60 min, there was no effect of IG water and ID saline on heart rate (Fig. 1C; P 0.23). In contrast, there was a progressive rise in heart rate (P for all) during ID glucose with, or without, IG water. There was a significant treatment time effect (P ) for heart rate between t 0 60 min. Heart rate was higher (P 0.05) with IG water and ID glucose when compared with IG water and ID saline, with no difference between the ID glucose and IG water and ID glucose groups. Between t min, there was no change (P 0.23) in heart rate, during IG water and ID saline and a progressive fall (P for both) with ID glucose both with, and without, IG water. There was a significant treatment time effect (P 0.05); heart rate was greater (P 0.05) following IG water and ID glucose when compared with IG water and ID saline. Gastric Emptying Gastric emptying of water following IG water and ID saline approximated a monoexponential pattern, so that emptying of Fig. 1. Change in systolic blood pressure (A), diastolic blood pressure (B), and heart rate (C), from baseline in response to intraduodenal infusion of glucose alone [intraduodenal (ID) glucose] ( ), intraduodenal glucose infusion followed by intragastric infusion of water [intragastric (IG) water and ID glucose] (F), and intraduodenal saline infusion followed by intragastric infusion of water (IG water and ID saline) (E). Data are expressed as means SE (n 8). Treatment time effect: *P 0.05 IG water and ID saline compared with IG water and ID glucose; ^P 0.05 ID glucose compared with IG water and ID glucose. water was rapid from instillation to t 45 min and then reached a plateau so that by t min only 100 ml of water remained in the stomach (Fig. 2). Following IG water and ID glucose, there was no statistically significant emptying of water until t 75 min (P 0.04), and intragastric volumes remained stable after that time. Gastric emptying was much faster (P 0.01) during IG water and ID saline when compared with IG water and ID glucose. Similarly, the T50 was less during IG water and ID saline ( min) compared with IG water and ID glucose ( min; P 0.006). At t 120 min, the intragastric retention of water was ml after IG water and ID glucose and ml after IG water and ID saline. DISCUSSION We have demonstrated that gastric distension produced by intragastric instillation of water, prevents the falls in systolic

4 Fig. 2. Gastric emptying of 500 ml water measured by two-dimensional ultrasound in seven healthy older subjects after ID glucose (IG water and ID glucose) ( ) and ID saline (IG water and ID saline) (E). Data are expressed as means SE (n 7). Treatment effect: P and diastolic blood pressures induced by intraduodenal glucose infusion at a rate of 3 kcal/min in healthy older subjects and established that these effects are evident at relatively low intragastric volumes of 300 ml. While none of our subjects had postprandial hypotension, the magnitude of the fall in systolic blood pressure induced by intraduodenal glucose was substantial (maximum mmhg), consistent with previous studies (10, 31, 32). Hence, our observations, which establish that the hypotensive response to small intestinal nutrients is attenuated by nonnutrient gastric distension, have substantial implications for the management of postprandial hypotension. Our previous studies have established that there is a direct relationship between the magnitude of the fall in systolic blood pressure and the rise in heart rate with the rate of gastric emptying of glucose drinks (23) and the exposure of glucose to the small intestinal mucosa (21, 32, 36) and that the response to small intestinal glucose is load, rather than concentration, dependent (10). In healthy subjects, gastric emptying of glucose solutions approximates an overall rate of kcal/min, after an initial emptying phase that may be somewhat faster (14, 16), as a result of inhibitory feedback arising from the small intestine (15, 26). This formed the basis for the use of a 3 kcal/min infusion in the current study, which can be considered to be a maximum stimulus. Gastric distension has the capacity to influence blood pressure (4, 22, 24, 25, 35, 38, 40). While there is no doubt that rapid ingestion of water has the ability to attenuate the hypotensive response to a meal (4, 5, 22, 24, 25, 38, 42, 43), the volume required for this effect is uncertain. In our recent study of healthy older subjects (22), the fall in blood pressure was less when glucose drinks of the same concentration (12.5%) were ingested at a higher volume (600 ml vs. 200 ml), but from this study, we cannot predict whether blood pressure would have decreased to a greater extent with the 200-ml drinks, had there been no intragastric volume, while glucose was entering the small intestine. This is, however, supported by observations that 1) oral glucose (75 g in 350 ml water), which emptied from the stomach at kcal/min decreases blood pressure significantly in healthy older, but not young subjects (23) and 2) intraduodenal glucose at 3 kcal/min decreases blood pressure in healthy young, as well as older subjects, albeit to a lesser extent (41). In the current study, gastric emptying of water was predictably much slower during intraduodenal glucose infusion, so that the intragastric volume remained at around 300 ml throughout the entire 60-min glucose perfusion, as a result of small intestinal feedback stimulated by the presence of glucose (2). Given that during this period, the 300 ml of intragastric volume significantly elevated blood pressure to baseline to levels much above those observed when glucose was perfused in the absence of intragastric water, it is clear that as little as 300 ml of intragastric water suffices to correct the hypotensive effects of high loads of intraduodenal glucose. By contrast, emptying of intragastric water commenced immediately during intraduodenal saline infusion so that only 100 ml remained by min. During this period of rapid decay of intragastric volume, systolic blood pressure remained elevated by 6 8 mmhg over baseline. Although we found no effect of volume in the range of ml on blood pressure, van Orshoven et al. (40) reported that proximal gastric balloon stepwise distension using a barostat device increased blood pressure (mean 12 mmhg) in healthy older subjects (40). It remains to be determined whether these effects are dependent on the region of the stomach distended (22). Furthermore, Shannon et al. (38) reported that a 480-ml drink of water elevated blood pressure for up to 40 min after a meal but did not observe or relate intragastric volume to the time course of the hypotensive effects of the drink. The mechanisms mediating the blood pressure responses to acute ingestion of water and small intestinal glucose/gastric distension remain unclear. It has been suggested that the increase in blood pressure induced by water ingestion may reflect resetting of the baroreflex (35), diminished compliance of the splanchnic arteries (40), reflex sympathetic activation (24), the hypoosmotic properties of water (3), and individual fluid balance (30). Plasma noradrenaline levels have been reported to be increased after water ingestion in normal healthy young (37) and elderly (24) subjects, despite a pressor effect evident only in the older group. The release of vasoactive peptides, including insulin (18), neurotensin (28), vasoactive intestinal polypeptide (29), CGRP (6), and glucagon-like peptide-1 (GLP-1) (9) by enteral glucose may potentially modulate blood pressure. It has been reported that the magnitude of the increase in muscle sympathetic nerve activity (MSNA) induced by intraduodenal glucose infusion is comparable in healthy young and older subjects (41), while the response to gastric distension is attenuated in the elderly (40). Hence, the blunted response to oral glucose in the elderly (8) is likely to reflect an impaired gastrovascular reflex. Perspectives and Significance R475 Our observations establish that, in healthy older subjects, intragastric administration of water markedly attenuates the hypotensive response to intraduodenal glucose infusion, presumably as a result of gastric distension, and suggest that low volumes of water ( 300 ml and, possibly 100 ml) would prove effective. While further studies are required to formally evaluate the effects of volumes of water 500 ml and the effects of chronic gastric distension, our observations add to the rationale for patients with postprandial hypotension to drink water before eating.

5 R476 ACKNOWLEDGMENTS Data from this manuscript have been presented in abstract form at Digestive Diseases Week at the 108th Annual Meeting of the American Gastroenterology Association, Washington DC, USA, May 20, 2007 (Gentilcore D, Meyer JH, Horowitz M, Jones KL. Gastroenterology 132: A324, 2007). GRANTS This study was supported by the National Health and Medical Research Council (NHMRC) of Australia. Dr. Gentilcore is supported by a postdoctoral fellowship (PR 07A 3309) from the National Heart Foundation of Australia. Associate Professor Jones salary is funded jointly by Diabetes Australia and the NHMRC of Australia. The purchase of the Logiq 9 ultrasonography system was supported by an Equipment Grant from the NHMRC of Australia, funds from the University of Adelaide, and GE Medical Systems Australia. REFERENCES 1. Aronow WS, Ahn C. Association of postprandial hypotension with incidence of falls, syncope, coronary events, stroke, and total mortality at 29-mo follow-up in 499 older nursing home residents. J Am Geriatr Soc 45: , Brener W, Hendrix TR, McHugh PR. Regulation of the gastric emptying of glucose. Gastroenterology 85: 76 82, Brown CM, Barberini L, Dulloo AG, Montani JP. Cardiovascular responses to water drinking: does osmolality play a role? Am J Physiol Regul Integr Comp Physiol 289: R1687 R1692, Cariga P, Mathias CJ. Haemodynamics of the pressor effect of oral water in human sympathetic denervation due to autonomic failure. Clin Sci (Lond) 101: , Deguchi K, Ikeda K, Sasaki I, Shimamura M, Urai Y, Tsukaguchi M, Touge T, Takeuchi H, Kuriyama S. Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy. J Neurol 254: , Edwards B, Perry 3rd HM, Kaiser FE, Morley JE, Kraenzle D, Stevenson R, Kreutter D. Relationship of age and calcitonin gene-related peptide to postprandial hypotension. Mech Ageing Dev 87: 61 73, Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. Br Med J 285: , Fagius J, Ellerfelt K, Lithell H, Berne C. Increase in muscle nerve sympathetic activity after glucose intake is blunted in the elderly. Clin Auton Res 6: , Gentilcore D, Bryant B, Wishart JM, Morris HA, Horowitz M, Jones KL. Acarbose attenuates the hypotensive response to sucrose and slows gastric emptying in the elderly. Am J Med 118: 1289, Gentilcore D, Doran S, Meyer JH, Horowitz M, Jones KL. Effects of intraduodenal glucose concentration on blood pressure and heart rate in healthy older subjects. Dig Dis Sci 51: , Gentilcore D, Visvanathan R, Russo A, Chaikomin R, Stevens JE, Wishart JM, Tonkin A, Horowitz M, Jones KL. Role of nitric oxide mechanisms in gastric emptying of, and the blood pressure and glycemic responses to, oral glucose in healthy older subjects. Am J Physiol Gastrointest Liver Physiol 288: G1227 G1232, Hausken T, Berstad A. Wide gastric antrum in patients with non-ulcer dyspepsia. Effect of cisapride. Scand J Gastroenterol 27: , Heddle R, Collins PJ, Dent J, Horowitz M, Read NW, Chatterton B, Houghton LA. Motor mechanisms associated with slowing of the gastric emptying of a solid meal by an intraduodenal lipid infusion. J Gastroenterol Hepatol 4: , Horowitz M, Cunningham KM, Wishart JM, Jones KL, Read NW. The effect of short-term dietary supplementation with glucose on gastric emptying of glucose and fructose and oral glucose tolerance in normal subjects. Diabetologia 39: , Horowitz M, Su YC, Rayner CK, Jones KL. Gastroparesis: prevalence, clinical significance and treatment. Can J Gastroenterol 15: , Hunt JN, Smith JL, Jiang CL. Effect of meal volume and energy density on the gastric emptying of carbohydrates. Gastroenterology 89: , Hveem K, Jones KL, Chatterton BE, Horowitz M. Scintigraphic measurement of gastric emptying and ultrasonographic assessment of antral area: relation to appetite. Gut 38: , Jansen R, Hoefnagels W. Hormonal mechanisms of postprandial hypotension. J Am Geriatr Soc 39: , Jansen RW, Lipsitz LA. Postprandial hypotension: epidemiology, pathophysiology, and clinical management. Ann Intern Med 122: , Jones KL, Doran SM, Hveem K, Bartholomeusz FD, Morley JE, Sun WM, Chatterton BE, Horowitz M. Relation between postprandial satiation and antral area in normal subjects. Am J Clin Nutr 66: , Jones KL, MacIntosh C, Su YC, Wells F, Chapman IM, Tonkin A, Horowitz M. Guar gum reduces postprandial hypotension in older people. J Am Geriatr Soc 49: , Jones KL, O Donovan D, Russo A, Meyer JH, Stevens JE, Lei Y, Keogh J, Tonkin A, Horowitz M. Effects of drink volume and glucose load on gastric emptying and postprandial blood pressure in healthy older subjects. Am J Physiol Gastrointest Liver Physiol 289: G240 G248, Jones KL, Tonkin A, Horowitz M, Wishart JM, Carney BI, Guha S, Green L. Rate of gastric emptying is a determinant of postprandial hypotension in non-insulin-dependent diabetes mellitus. Clin Sci (Lond) 94: 65 70, Jordan J, Shannon JR, Black BK, Ali Y, Farley M, Costa F, Diedrich A, Robertson RM, Biaggioni I, Robertson D. The pressor response to water drinking in humans : a sympathetic reflex? Circulation 101: , Jordan J, Shannon JR, Grogan E, Biaggioni I, Robertson D. A potent pressor response elicited by drinking water. Lancet 353: 723, Lin HC, Doty JE, Reedy TJ, Meyer JH. Inhibition of gastric emptying by glucose depends on length of intestine exposed to nutrient. Am J Physiol Gastrointest Liver Physiol 256: G404 G411, Mathias C. Postprandial hypotension: Pathophysiological mechanisms and clinical implications in different disorders. Hypertension 18: , Mathias CJ, da Costa DF, Fosbraey P, Bannister R, Wood SM, Bloom SR, Christensen NJ. Cardiovascular, biochemical and hormonal changes during food-induced hypotension in chronic autonomic failure. J Neurol Sci 94: , Mathias CJ, Matthews WB, Spalding JM. Postural changes in plasma renin activity and responses to vasoactive drugs in a case of Shy-Drager syndrome. J Neurol Neurosurg Psychiatry 40: , Mathias CJ, Young TM. Water drinking in the management of orthostatic intolerance due to orthostatic hypotension, vasovagal syncope and the postural tachycardia syndrome. Eur J Neurol 11: , O Donovan D, Feinle C, Tonkin A, Horowitz M, Jones KL. Postprandial hypotension in response to duodenal glucose delivery in healthy older subjects. J Physiol 540: , O Donovan D, Feinle-Bisset C, Chong C, Cameron A, Tonkin A, Wishart J, Horowitz M, Jones KL. Intraduodenal guar attenuates the fall in blood pressure induced by glucose in healthy older adults. J Gerontol A Biol Sci Med Sci 60: , Piha SJ. Cardiovascular autonomic reflex tests: normal responses and age-related reference values. Clin Physiol 11: , Potter J, Heseltine D, Hartley G, Matthews J, MacDonald I, James O. Effects of meal composition on the postprandial blood pressure, catecholamine and insulin changes in elderly subjects. Clin Sci 77: , Rossi P, Andriesse G, Oey P, Wieneke G, Roelofs J, Akkermans L. Stomach distension increases efferent muscle sympathetic nerve activity and blood pressure in healthy humans. J Neurol Sci 161: , Russo A, Stevens JE, Wilson T, Wells F, Tonkin A, Horowitz M, Jones KL. Guar attenuates fall in postprandial blood pressure and slows gastric emptying of oral glucose in type 2 diabetes. Dig Dis Sci 48: , Scott EM, Greenwood JP, Gilbey SG, Stoker JB, Mary DA. Water ingestion increases sympathetic vasoconstrictor discharge in normal human subjects. Clin Sci (Lond) 100: , Shannon JR, Diedrich A, Biaggioni I, Tank J, Robertson RM, Robertson D, Jordan J. Water drinking as a treatment for orthostatic syndromes. Am J Med 112: , Vaitkevicius PV, Esserwein DM, Maynard AK, O Connor FC, Fleg JL. Frequency and importance of postprandial blood pressure reduction in elderly nursing-home patients. Ann Intern Med 115: , van Orshoven NP, Oey PL, van Schelven LJ, Roelofs JM, Jansen PA, Akkermans LM. Effect of gastric distension on cardiovascular parame-

6 R477 ters: gastrovascular reflex is attenuated in the elderly. J Physiol 555: , van Orshoven NP, van Schelven LJ, Akkermans LM, Jansen PA, Horowitz M, Feinle-Bisset C, van Huffelen AC, Oey PL. The effect of intraduodenal glucose on muscle sympathetic nerve activity in healthy young and older subjects. Clin Auton Res 18: 28 35, Young TM, Mathias CJ. Pressor effect of water instilled via a gastrostomy tube in pure autonomic failure. Auton Neurosci 113: 79 81, Young TM, Mathias CJ. The effects of water ingestion on orthostatic hypotension in two groups of chronic autonomic failure: multiple system atrophy and pure autonomic failure. J Neurol Neurosurg Psychiatry 75: , 2004.