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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
Received June 25, 2004; accepted October 18, 2004.
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Abstract |
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; Mearin et al., 1986; Jebbink et al., 1994a; Samsom et al., 1995). In nauseated diabetics, myoelectric abnormalities including tachygastria and bradygastria are prominent and relate to the degree of glycemic control (Jebbink et al., 1994b). Investigators have utilized hyperglycemic clamping in healthy volunteers to assess the role of blood glucose as a pathogenic factor in diabetic gastropathy. Functional abnormalities evoked by acute hyperglycemia are similar to those observed in diabetic patients (Barnett and Owyang, 1988; Fraser et al., 1991; Schvarcz et al., 1997). With respect to myoelectric activity, acute hyperglycemia induces gastric slow-wave tachyarrhythmic activity in normal subjects above plasma glucose levels of 230 mg/dl (Hasler et al., 1995b).
Nitrergic innervation plays important roles in modulating gastric motor activity. Nitric oxide (NO) release is proposed to mediate meal-evoked reflexes including fundic receptive relaxation and accommodation (Desai et al., 1991; Takahashi and Owyang, 1995). Gastric dysrhythmias occurring in diabetes and elicited by acute hyperglycemia in healthy volunteers are blunted by eating, suggesting that some meal-related mechanical or neurohumoral factor has myoelectric rhythm-stabilizing effects (Mathur et al., 2001; Defrancisco et al., 2002). Impaired nitrergic function underlies motor abnormalities in animal models of diabetic gastropathy which are correctable by treatments that enhance NO action (Takahashi et al., 1997; Watkins et al., 2000). It is unknown whether measures to enhance the release or action of NO stabilize myoelectric rhythm in human models of diabetic gastropathy.
We designed studies to test the hypothesis that gastric myoelectric rhythm disturbances occurring during acute hyperglycemia in healthy humans are a consequence of reversible reductions in NO activity. We employed electrogastrography (EGG) to compare gastric myoelectric activity during euglycemia and during hyperglycemic clamping to plasma glucose levels of 250 mg/dl. Studies were repeated under separate conditions in which NO activity was increased either after oral administration of extended release nitroglycerin (a NO donor) or sildenafil (Viagra, Pfizer Laboratories, New York, NY) (a selective inhibitor of cyclic GMP-specific phosphodiesterase type 5). To determine whether effects of nitrergic stimulation are generalized or specific for hyperglycemia, the effects of nitroglycerin and sildenafil on gastric dysrhythmias associated with experimental motion sickness evoked by exposure to a rotatory stimulus were tested. Through these investigations, we hoped to gain insight into the role of impaired nitrergic function in a model of diabetic gastropathy and to determine whether these defects are specific for this model or generalized for other conditions with disturbed gastric myoelectric activity.
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Materials and Methods |
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Electrogastrography Methodology. EGG was performed according to a modification of previously described methods (Stern et al., 1987b). After gentle skin abrasion to enhance electrical conduction, six Ag-AgCl electrodes (Accutac diaphoretic electrocardiograph electrodes; New Dimensions in Medicine, Dayton, OH) were affixed to the abdomen. The first electrode was placed in the midclavicular line below the left costal margin. The third electrode was placed midway between the xiphoid and umbilicus. The second electrode was placed equidistant between the first and third electrodes. Three reference electrodes were affixed in the right upper quadrant below the right costal margin. Electrodes were connected via direct nystagmus couplers (model 9859; SensorMedic Corp., Anaheim, CA) to a chart recorder for continuous display of the slow wave activity. Time constants were set at 10 s and high-frequency cutoffs at 0.3 Hz to minimize interference from nongastric signals. Respirations were monitored by a belt pneumograph connected to an indirect blood pressure coupler (model 9863B; SensorMedic Corp.) on the chart recorder, and any signals exhibiting artifact clearly resulting from body movement or exaggerated respiration activity, such as with a deep sigh or cough, were excluded from analysis. Data were also recorded on a personal computer (4DX2-66V, Gateway 2000; Gateway, North Sioux City, ND) via an analog-to-digital converter (DAS-16; Metrabyte Corp., Taunton, MA). Signals were digitized at 4 Hz and filtered above 15 cycles/min (cpm) and below 0.5 cpm to remove high- and low-frequency noise. After completion of each recording, the three channels were analyzed visually to determine which lead provided the signal most free of noise. The recording from this lead was then subjected to quantitative computer analysis. All tracings were analyzed in blinded fashion so that the investigator did not know either the volunteer or the test conditions being studied.
Hyperglycemia Study Protocol. Each volunteer underwent electrogastrographic studies under four separate test conditions in random order on 4 separate days separated by at least 72 h: two EGG studies under euglycemic conditions (1 study day with nitroglycerin and the second study day with sildenafil) and two EGG studies using hyperglycemic clamping (1 study day with nitroglycerin and the second study day with sildenafil). Prior to each of the 4 study days, subjects fasted for 8 h and abstained from caffeine, alcohol, and tobacco for at least 12 h. An initial 1-h baseline fasting EGG recording was performed. Then, intravenous perfusion of 0.9% saline or 20% dextrose was begun, and EGG recording proceeded for another hour. Subjects then took either one 9-mg extended release tablet of nitroglycerin (Schwarz Pharma, Mequon, WI) or one 100-mg tablet of sildenafil (Pfizer Laboratories), and an additional 2 h of EGG recordings were performed during which time saline or dextrose infusions were continued. Extended release nitroglycerin exhibits an onset of action of 20 to 45 min, a peak response at 90 min, and a duration of effect of 3 to 8 h. Sildenafil reaches maximal plasma concentrations at 30 to 120 min after ingestion (mean 80 min) and has a mean terminal half-life of 3 to 5 h. The sildenafil dose used in this study was the maximum employed for clinical treatment of erectile dysfunction. In additional control studies, hyperglycemic clamping with concurrent EGG was performed in selected volunteers for 3 h after 1 h of baseline recording without nitroglycerin or sildenafil administration to exclude the possibility that gastric myoelectric rhythm stabilizes and dysrhythmias resolve with continued dextrose infusion.
Hyperglycemic clamping was performed according to previously described methods (DeFronzo et al., 1979). Intravenous catheters were inserted into antecubital veins in each arm. For euglycemic studies, one line was used for intravenous infusion of normal saline and the second for obtaining blood glucose samples at 30-min intervals. For hyperglycemic clamping studies, one venous line was used for infusion of 20% dextrose and one for monitoring blood glucose levels. After a 15-min priming dose of 20% dextrose, the maintenance infusion rates were adjusted as needed by monitoring plasma glucose levels at 5-min intervals throughout the study to maintain the blood glucose concentration level at 250 mg/dl. Patency of the lines was maintained with periodic infusions of heparin flush-lock solution (100 USP units/ml). Plasma glucose level was determined using a portable glucose analyzer (One Touch II; LifeScan Inc., Milpitas, CA). Using these methods, plasma glucose levels were maintained within ±10% of the desired concentrations.
Power spectral analysis was performed on digitized EGG signals across the frequency range from 1 to 9 cpm on 256-s segments of recording with a 76% overlap using commercially available software (MatLab; The Mathworks, Inc., Natick, MA). From this analysis, the dominant frequency was measured for each recording segment. The percentages of recording time in which the dominant frequency was in the bradygastric (
1 and <2 cpm), normal (2 and 
4 cpm), and tachygastric (>4 and 9 cpm) frequency ranges were assessed. The power of the dominant frequency for each recording segment was calculated. The mean power of the dominant frequency for each hour of recording was expressed as a fraction of the mean dominant power of the initial 1-h baseline recording. EGG analysis was performed on data from the initial hour before initiation of hyperglycemia, from the final 30 min of the first hour of hyperglycemia before administration of nitroglycerin or sildenafil, and for the final hour of recording beginning 1 h after nitroglycerin or sildenafil administration. Data from the first 30 min of hyperglycemia are not included, as this was a transition period before stable plasma glucose levels of 250 mg/dl were achieved. Similarly, data from the first hour after nitroglycerin or sildenafil were not analyzed because drug absorption was not yet maximal during this period.
Circular Vection Study Protocol. Circular vection was performed on each volunteer using previously described methods on three separate occasions separated by at least 1 week (one control study, one study after oral nitroglycerin, and one study after oral sildenafil) (Stern et al., 1987a). Prior to each study day, subjects fasted for 8 h and abstained from caffeine, alcohol, and tobacco for at least 12 h. Volunteers were seated vertically in the center of a drum (76-cm diameter, 92 cm in height) with the use of a chin rest to maintain head position. The drum interior was painted with alternating black and white 3.8-cm vertical stripes and was illuminated by a stationary light above the volunteer. After an initial 15-min basal EGG recording period, clockwise drum rotation was begun at 60°/s and continued for 15 min or until the level of symptomatology precluded further stimulation. Subjects were instructed to report if they experienced severe nausea with impending vomiting. If severe nausea was reported, drum rotation was immediately discontinued. Times to maximal EGG rhythm disruption from the onset of circular vection were recorded. For nitroglycerin studies, basal EGG recording was begun 90 min after ingestion of one 9-mg extended release tablet of nitroglycerin (Schwarz Pharma). For sildenafil studies, basal EGG recording was begun 90 min after ingestion of one 100-mg sildenafil tablet (Pfizer Laboratories).
Power spectral analysis was performed on digitized EGG signals from the circular vection studies across the frequency range from 1 to 9 cpm on 128-s segments of recording with a 76% overlap using commercially available software (Fourier Perspective III; Alligator Technologies, Fountain Valley, CA). As with the hyperglycemia studies, the frequency range 2 and 4 cpm was defined to represent normal, whereas the frequency range >4 and 9 cpm represented tachygastria, and the range 1 and <2 cpm represented bradygastria. The summed signal powers in the bradygastric, normal, and tachygastric frequency ranges were quantified as a percentage of a total signal power from 1 to 9 cpm. This signal analysis protocol has been specifically employed for circular vection studies because dysrhythmias may develop quickly in association with severe nausea that necessitates cessation of drum rotation (Hasler et al., 1995a). In such instances, it is not possible to calculate the percent recording times with dominant frequencies in normal rhythm, bradygastria, and tachygastria due to the brief nature of the recordings. The effects of circular vection on the summed power of the dominant frequency band were expressed as a fraction of the power of the dominant frequency band prior to initiation of drum rotation.
Statistical Analysis. All results are expressed as means ± S.E.M. Longitudinal regression analysis of repeated measures was performed to compare EGG parameters in the hyperglycemic clamping studies including percentages of recording time in the different frequency ranges and powers of the dominant frequencies. For circular vection studies, paired two-tailed Student's t testing was performed to compare percentages of signal power in different frequency ranges before and during vection within each given test condition. One-way analysis of variance with Student-Newman-Keuls post testing compared latencies to maximal dysrhythmias and changes in power in the normal and tachygastric frequency ranges between the different test conditions before and during vection. A P value of <0.05 was defined as statistically significant.
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Results |
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Effects of Nitroglycerin on EGG Parameters. Hyperglycemic clamping studies. Sample EGG tracings and spectral analyses from a hyperglycemic clamping study before and after nitroglycerin are shown in Fig. 1. During the initial baseline recording, the raw signal exhibits a regular sinusoidal morphology with a period of 20 s. Frequency analysis shows a regular 3-cpm peak throughout the recording. Hyperglycemia elicited a chaotic low-amplitude wave form with more rapid cycling. Spectral analysis of this signal showed a dominant frequency of nearly 8 cpm. After nitroglycerin administration, the raw signal showed normalization to a sinusoidal wave form with a period of 20 s and a dominant frequency of 3 cpm on frequency analysis.
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The effects of hyperglycemic clamping on EGG rhythm and power before and after nitroglycerin were compared for all volunteers. Hyperglycemia to 250 mg/dl significantly decreased the percentage of recording time in normal rhythm from 84 ± 4 to 69 ± 7% (P < 0.05) and increased the percentage of recording time in tachygastria from 7 ± 3 to 23 ± 7% (P < 0.01) (Fig. 2, A and B). There were no significant effects of hyperglycemia on bradygastric activity. Hyperglycemia also significantly reduced powers of the dominant frequency to 0.33 ± 0.22 of baseline values (P < 0.05) (Fig. 2C). Although hyperglycemia was ongoing, nitroglycerin reversed the decrease in the percentage of recording time in normal rhythm (83 ± 5%) (P < 0.05) and the increase in tachygastria (11 ± 5%) (P < 0.01) (Fig. 2, A and B). The mean latency for nitroglycerin action to reverse tachygastric activity was 61 ± 5 min. Similarly, nitroglycerin significantly reversed the blunting effects of hyperglycemia on power of the dominant frequency to 0.84 ± 0.30 of control values (P < 0.05 compared with hyperglycemia alone) (Fig. 2C).
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Euglycemic studies. Control studies of 0.9% saline infusion were performed. In contrast to hyperglycemic clamping studies, saline infusion had no effect on percentages of recording time in normal rhythm (86 ± 4 versus 83 ± 5%) or tachygastria (2 ± 1 versus 6 ± 3%) (P = N.S.). Similarly, saline had no effect on EGG power (0.80 ± 0.35 of baseline) (P = N.S.). Nitroglycerin did not change percentages of time in normal rhythm (82 ± 6%) or tachygastria (9 ± 4%) (P = N.S.). Nitroglycerin did not significantly affect EGG power during saline infusion studies (0.81 ± 0.40 of baseline levels) (P = N.S.).
Effects of Sildenafil on EGG Parameters. Hyperglycemic clamping studies. Sample EGG tracings and spectral analyses from a hyperglycemic clamping study before and after sildenafil are shown in Fig. 1. As with the nitroglycerin studies, sildenafil converted the chaotic, rapid, low-amplitude wave form to a more regular sinusoidal wave form with a period of 20 s. Spectral analysis confirmed that sildenafil reversed a prolonged tachygastria at a frequency of 4 to 7 cpm to a more normal pattern with a dominant frequency of 3 cpm.
The effects of hyperglycemic clamping on EGG rhythm and power before and after sildenafil were compared for all volunteers. As observed during nitroglycerin studies, hyperglycemia to 250 mg/dl significantly decreased the percentage of recording time in normal rhythm from 87 ± 4to73 ± 5% (P < 0.05) and increased the percentage of recording time in tachygastria from 5 ± 3 to 18 ± 4% (P < 0.01) (Fig. 3, A and B). There were no significant effects of hyperglycemia on bradygastric activity. In the sildenafil studies, hyperglycemia showed a trend to reducing powers of the dominant frequency to 0.58 ± 0.28 of baseline levels (P = 0.06) (Fig. 3C). Although hyperglycemia was ongoing, sildenafil administration reversed the decrease in percentage of recording time in normal rhythm (86 ± 3%) (P < 0.05) and the increase in tachygastria (5 ± 2%) (P < 0.01) (Fig. 3, A and B). The mean latency for sildenafil action to reverse tachygastric activity was 72 ± 8 min. Sildenafil showed a trend to reversal of the blunting effects of hyperglycemia on power of the dominant frequency to 1.14 ± 0.40 of baseline values (P = 0.08 compared with hyperglycemia alone) (Fig. 3C).
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Euglycemic studies. As with the nitroglycerin studies, control experiments of 0.9% saline infusion were performed to exclude significant independent effects of sildenafil on EGG parameters. Saline infusion had no effect on percentages of recording time in normal rhythm (94 ± 2 versus 90 ± 3%) or tachygastria (2 ± 1 versus 5 ± 2%). Similarly, saline had no effect on EGG power (61 ± 44% of baseline) (P = N.S.). Sildenafil did not change percentages of time in normal rhythm (91 ± 3%) or tachygastria (5 ± 2%), but it did show a trend to reducing power of the dominant frequency to 0.32 ± 0.31 of baseline levels (P = 0.08).
Control Hyperglycemic Clamping Studies. To confirm that this stabilization of EGG rhythm by nitroglycerin and sildenafil was not due to intrinsic adaptation to prolonged hyperglycemia, experiments were performed in four healthy volunteers in which hyperglycemia was performed for 3 h without nitroglycerin or sildenafil administration. For each hour of EGG recording, significant increases in tachygastric activity were observed (Fig. 4). There were no differences in the magnitude of tachygastric activity between the second, third, and fourth hours of recording (P = N.S.).
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Circular Vection Studies
Circular vection disrupted EGG rhythm in all 12 volunteers. Representative responses to circular vection without and after nitroglycerin and sildenafil are shown in Fig. 5. Prior to initiation of drum rotation, the raw signal exhibits a regular wave form at a frequency of 3 cpm. Soon after initiation of circular vection, EGG rhythmicity deteriorated and was replaced with intense high-frequency EGG signal oscillations. In contrast to the hyperglycemia studies, nitroglycerin and sildenafil pretreatment had no effect on EGG dysrhythmias in this individual.
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EGG responses to circular vection without and after nitroglycerin were compared in all volunteers. In control studies, circular vection evoked maximal dysrhythmic activity with a latency of 355 ± 57 s (Fig. 6). Drum rotation evoked maximal decreases in percentages of signal power in the normal frequency range from 64 ± 8 to 32 ± 6% (P < 0.01) and increases in tachygastric activity from 16 ± 4 to 56 ± 5% (P < 0.01) (Fig. 7, A and B). Power of the dominant frequency slightly increased during circular vection to 1.57 ± 0.44 of baseline (P = N.S.) in contrast to the effects of hyperglycemia (Fig. 7C). After nitroglycerin, latencies to maximal dysrhythmic activity after initiation of drum rotation were similar to control studies (402 ± 68 s, P = N.S.) (Fig. 6). Circular vection after nitroglycerin elicited maximal decreases in normal rhythm from 62 ± 6to27 ± 3% (P < 0.01) and increases in tachygastria from 11 ± 2 to 52 ± 4% (P < 0.01) (Fig. 7, A and B). Similarly, circular vection after sildenafil evoked maximal decreases in normal rhythm from 70 ± 9to42 ± 5% (P < 0.01) and increases in tachygastria from 11 ± 3 to 48 ± 7% (P < 0.01) with latencies of 330 ± 76 s (Fig. 6; Fig. 7, A and B). When differences in power distribution in each of the frequency ranges before and during circular vection were compared, these effects were not different from control studies (P = N.S.). Likewise, nitroglycerin and sildenafil did not affect the increase in power of the dominant frequency in response to circular vection compared with control studies (P = N.S.) (Fig. 7C).
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Discussion |
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). The gastric slow wave regulates the direction of propagation and the maximal frequency of phasic contractions in the distal stomach, thus abnormal slow wave patterns are postulated to underlie many gastric dysmotility syndromes (Stern et al., 1987b). Slow wave activity is measured using EGG, the findings of which show close correlations with recordings from serosal electrodes (Chen et al., 1994). Rhythm disturbances such as tachygastria and bradygastria are observed in up to 75% of patients with diabetic gastroparesis (Koch et al., 1989; Rothstein et al., 1993; Jebbink et al., 1994a). These dysrhythmias have been reported to improve, but not resolve, with eating suggestive of mediation by meal-related mechanical or neurochemical factors (Mathur et al., 2001). An additional abnormality, a reduced EGG signal amplitude after meal ingestion, correlates with delayed gastric emptying of solids (Chen et al., 1996).
In diabetic patients, the magnitude of gastric myoelectric rhythm disruption correlates with the degree of glycemic control. During hyperglycemia, dysrhythmias are observed 41% of the time, whereas clamping of the plasma glucose to the euglycemic range decreases rhythm disruption to 6% of the recording (Jebbink et al., 1994b). These findings support the postulate that plasma glucose is an important cofactor in the regulation of gastric function and the clinical manifestations of diabetic gastropathy. Indeed, the effects of hyperglycemic clamping in healthy volunteers mimic those observed in patients with diabetes including slowing of solid gastric emptying, inhibition of antral motor function, and induction of increased pyloric motility (Barnett and Owyang, 1988; Fraser et al., 1991; Schvarcz et al., 1997). Increases in gastric tachyarrhythmic activity in healthy volunteers were evoked by hyperglycemic clamping to plasma glucose levels of 230 mg/dl in prior studies from our laboratory (Hasler et al., 1995b). We further showed that these dysrhythmias could be prevented by pretreatment with the prostaglandin synthesis inhibitor indomethacin, suggesting that hyperglycemia-induced myoelectric disturbances are mediated by endogenous prostaglandins (Hasler et al., 1995b). As observed in diabetic patients, we also have noted greater degrees of hyperglycemia-evoked dysrhythmic activity during fasting than after ingestion of a mixed meal (Defrancisco et al., 2002).
NO released by nonadrenergic, noncholinergic inhibitory myenteric neurons is a key inhibitory neurotransmitter in the regulation of gastric motor activity, through production of cyclic GMP (Bult et al., 1990). Defects in NO pathways are postulated to underlie gastric motor dysfunction in animal models of gastroparesis. In animals and healthy volunteers, neuronal NO synthase (nNOS) inhibitors increase fundus tone and blunts fundic relaxation to pharmacologic stimulation and meal ingestion, whereas NO donors such as nitroglycerin evoke fundic relaxation and enhance meal-induced accommodation (Desai et al., 1991; Coulie et al., 1999). In diabetic rats, reduced nNOS activity in gastric and duodenal myenteric plexus is associated with impaired nonadrenergic, noncholinergic relaxation in gastric and duodenal muscle strips (Takahashi et al., 1997; Watkins et al., 2000). Delayed gastric emptying and increases in pyloric tone are observed in diabetic mice in association with relative reductions in pyloric nNOS levels, similar to findings in mice lacking the nNOS gene (Huang et al., 1993). Sildenafil, a selective inhibitor of cyclic GMP-specific phosphodiesterase type 5, reversed many of the functional defects noted in those diabetic mice. This agent enhances the effectiveness of endogenously released NO by preventing breakdown of cyclic GMP generated by nitrergic activation of guanylate cyclase (Corbin and Francis, 1999).
In the present study, we tested whether enhanced nitrergic function reverses gastric myoelectric rhythm disturbances elicited by acute hyperglycemia in healthy volunteers. Two interventions were employed: administration of the NO donor nitroglycerin and administration of the phosphodiesterase inhibitor sildenafil. Each of these agents produced significant reductions in dysrhythmic activity during hyperglycemic clamping to 250 mg/dl and further, partly reversed the decrease in EGG power elicited by hyperglycemic clamping. In contrast, neither treatment affected EGG rhythm during euglycemia, although sildenafil evoked modest reductions in signal power. These findings agree with those of a previous investigation in which NO pathways did not influence gastric pacemaker activity during euglycemia (Hou et al., 2001). Our results are consistent with the hypothesis that hyperglycemia-elicited gastric myoelectric rhythm disruption in healthy humans is mediated by reduced gastric NO activity. These observations also raise the possibility that the observed incomplete myoelectric rhythm stabilization with eating in diabetics and healthy subjects during hyperglycemia may be secondary to meal-evoked NO release. This hypothesis is speculative and should be confirmed in animal models.
The mechanisms by which nitrergic stimulation stabilizes gastric dysrhythmias evoked by hyperglycemia are unknown. In cultured murine intestinal interstitial cells of Cajal, NO donors and cyclic GMP analogs slow pacemaker frequencies (Koh et al., 2000). Responses of muscle strips containing interstitial cells are similar suggesting that NO-activated cyclic GMP-dependent pathways regulate slow wave frequency at the level of the cells that generate pacemaker activity. The relation of the stabilizing effects of nitrergic stimulation on gastric myoelectric activity to the mediation of hyperglycemia-evoked dysrhythmias by endogenous prostaglandins is unexplored. In rats, the delay in gastric emptying evoked by endotoxin may be mediated by nNOS down-regulation and increased prostaglandin synthesis (Calatayud et al., 2002). This model would fit well with observations of our studies investigating nitrergic and prostaglandin pathways in the hyperglycemic induction of myoelectric rhythm disturbances. However, in rat ileum, NO activates cyclooxygenase with production of prostaglandin E2 which then acts synergistically with NO to elicit smooth muscle relaxation (Espanol and Sales, 2003). These divergent findings likely are a function of the different models that were studied. Further studies addressing the coinvolvement of prostaglandin and nitrergic pathways in control of gastric slow wave frequency should be performed.
The effects of nitrergic stimulation on hyperglycemia-evoked gastric myoelectric disruption were contrasted to its actions in experimental motion sickness. Circular vection was chosen because gastric myoelectric rhythm disturbances elicited by this technique are mediated by distinct pathways from those activated by acute hyperglycemia. Specifically, indomethacin does not prevent induction of tachygastria by circular vection indicating the lack of participation by endogenous prostaglandins (Hasler et al., 1995a). Rather, gastric myoelectric rhythm disturbances in motion sickness may be mediated in part by cholinergic pathways and vasopressin release (Kim et al., 1997). In the present investigation, nitroglycerin and sildenafil had no prophylactic effect on circular vection-induced dysrhythmias. The findings of these studies are consistent with mediation of motion sickness-associated slow wave disruptions by NO- and prostaglandin-independent pathways in contrast to the NO- and prostaglandin-dependent mechanisms with acute hyperglycemia.
This investigation has potential clinical implications for patients with diabetic gastropathy. Until now, nitroglycerin has been investigated primarily for its fundic relaxant properties. In this capacity, the drug has shown benefits in small studies of patients with functional dyspepsia (Gilja et al., 1997). The current study suggests NO donors and other agents that increase NO activity may have other actions which may be useful in diabetics with nausea and vomiting and associated gastric myoelectric dysrhythmias; however, it is uncertain if the findings of the present study can be extended to diabetic patients. Indeed, the use of nitrergic agents that inhibit motor function might conceptually be expected to worsen delays in gastric emptying. However, if symptoms stem from slow wave disruptions rather than delays in emptying, such treatments might prove to be beneficial. Further studies will define any clinical utility of nitroglycerin or sildenafil in diabetic gastropathy and other dyspeptic disorders.
Some issues can be raised about the findings of the present investigation. First, it can be questioned whether the EGG abnormalities seen reflect changes in gastric myoelectrical activity versus electrical signals from other organs. We have performed preliminary studies employing endoscopically directed mucosal recordings of gastric slow wave frequency which demonstrate that there are specific disruptive effects of hyperglycemia on electrical activity in the stomach (Coleski et al., 2004). We also addressed the question of whether the improvements seen with nitroglycerin and sildenafil resulted from adaptation to the dysrhythmic effects of hyperglycemia. Control studies were performed which showed persistence of slow wave rhythm disruption for the full 3 h of hyperglycemic clamping, making this less likely. One could question if the selective benefits of nitrergic stimulation with hyperglycemic clamping stems from enrollment of different subjects in the two phases of the study. However, 10 individuals participated in both hyperglycemic clamping and circular vection studies making this possibility unlikely. Additionally, no placebo arm was included in this investigation. However, subjects did not perceive the onset of dysrhythmias and did not observe real-time recordings of dysrhythmic activity. Additionally, subjects showed impressive responses to drugs with one stimulus (hyperglycemia) but not the other (vection). Thus, we do not believe the responses observed are placebo effects. Finally, it is uncertain if the antidysrhythmic effects of nitroglycerin and sildenafil are accompanied by reductions in nausea and vomiting. Hyperglycemia in healthy volunteers elicits postprandial fullness and early satiety but little nausea (Hasler et al., 1995b; Defrancisco et al., 2002). Possible explanations include: 1) the dysrhythmias are only one cofactor for symptom development, 2) hyperglycemia has concurrent effects on gastric perception which blunt any nausea-inducing effects of the dysrhythmias, or 3) the dysrhythmias are markers of gastric motor dysfunction and do not cause symptoms by themselves. Further studies should address this issue.
Another concern relates to the benefits observed with sildenafil administration. Animal studies have localized the type 5 phosphodiesterase to pyloric tissues in the proximal gut (Kotera et al., 1998). It is uncertain if the antidysrhythmic effects of sildenafil in the current model might be a consequence of selective action on the most distal gastric regions, or if the drug has more generalized actions on the human stomach. In humans, sildenafil decreases lower esophageal sphincter tone in patients with achalasia, nutcracker esophagus, and hypertensive lower esophageal sphincter indicating effects in regions other than the pylorus showing species-related differences in the actions of the drug (Bortolotti et al., 2000; Eherer et al., 2002). It also is not defined if the myoelectric rhythm stabilizing effects of the two agents used in this study might be secondary to NO-mediated fundic relaxation. In preliminary studies, we reported increases in EGG power with fundic distention suggesting that distal gastric myoelectric activity may be modulated by more proximal stimulation (Koshy et al., 1996). These and other areas are worthy of future investigation.
In conclusion, nitroglycerin, a NO donor, and sildenafil, a selective inhibitor of cyclic GMP-specific phosphodiesterase type 5, reverse the dysrhythmic effects of hyperglycemic clamping to plasma glucose levels of 250 mg/dl on gastric myoelectric activity in healthy humans. These agents also blunt the effects of hyperglycemia on electrogastrographic power. In contrast, nitroglycerin and sildenafil administration have no effect on gastric dysrhythmias associated with experimental motion sickness. These findings are consistent with selectively impaired nitrergic function in this acute model of diabetic gastropathy but do not suggest generalized nitrergic defects in all dysrhythmic conditions. They further raise the possibility that therapies directed at enhancing NO action may be beneficial in this troubling condition.
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Footnotes |
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ABBREVIATIONS: NO, nitric oxide; EGG, electrogastrography(ic); cpm, cycles per minute; nNOS, neuronal NO synthase.
Address correspondence to: Dr. William L. Hasler, 3912 Taubman Center, Box 0362, Ann Arbor, MI 48109. E-mail: whasler{at}umich.edu
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