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Am J Physiol Gastrointest Liver Physiol 292: G1359-G1365, 2007. First published February 8, 2007; doi:10.1152/ajpgi.00403.2006
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NEUROREGULATION AND MOTILITY

Nitrergic contribution to gastric relaxation induced by glucagon-like peptide-1 (GLP-1) in healthy adults

Christopher N. Andrews,1 Adil E. Bharucha,1 Michael Camilleri,1 Phillip A. Low,2 Barbara Seide,1 Duane Burton,1 Kari Baxter,1 and Alan R. Zinsmeister3

1Clinical Enteric Neuroscience Translational and Epidemiological Research Program, 2Department of Neurology, and 3Division of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Submitted 30 August 2006 ; accepted in final form 29 January 2007


   ABSTRACT
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The incretin glucagon-like peptide-1 (GLP-1), which is used to treat diabetes mellitus, delays gastric emptying by inhibiting vagal activity. GLP-1 also increases fasting and postprandial gastric volume in humans. On the basis of animal studies, we hypothesized that nitric oxide mediates the effects of GLP-1 on gastric volumes. To assess the effects of nitrergic blockade on GLP-1-induced gastric accommodation in humans, in this double-blind study, 31 healthy volunteers were randomized to placebo (i.e., saline), GLP-1, or the nitric oxide synthase inhibitor NG-monomethyl-L-arginine acetate (L-NMMA; 4 mg·kg–1·h–1) alone or with GLP-1. Thereafter, 16 additional subjects were randomized to GLP-1 alone or together with a higher dose of L-NMMA (10 mg/kg bolus plus 8 mg·kg–1·h–1 infusion). Gastric volumes (fasting pre- and postdrug, postprandial postdrug) were measured by 99mTc-single-photon-emission computed tomography imaging. GLP-1 increased (P = 0.04) fasting gastric volume by 83 ± 16 ml (vs. 17 ± 11 ml for placebo) and augmented (P ≤ 0.01) postprandial accommodation by 688 ± 165 ml (vs. 542 ± 29 ml for placebo). L-NMMA (low dose) alone did not affect fasting or postprandial gastric volume. L-NMMA (low dose) did not attenuate the effect of GLP-1 on gastric volumes. In contrast, L-NMMA (high dose) did not affect fasting volume but blunted GLP-1-mediated postprandial accommodation (postprandial change = 494 ± 37 ml, P ≤ 0.01 vs. GLP-1 alone). These data are consistent with the hypothesis that nitric oxide partly mediates the effects of GLP-1 on postprandial but not fasting gastric volumes in humans.

accommodation; stomach; postprandial; diabetes; vagus

GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is an incretin produced by enteroendocrine L cells throughout the small intestine (45). The GLP-1 agonist exendin-4 improves glycemic control in patients with Type 2 diabetes mellitus inadequately treated with oral hypoglycemic agents (20). GLP-1 reduces postprandial glycemia not only by its hormonal effects (i.e., reduced glucagon and increased insulin release) (20, 29), but also by its powerful effects on gastrointestinal (GI) motility and secretion (31). Thus GLP-1 is a mediator of the ileal brake, delays gastric emptying, increases gastric volume, and reduces gastric acid secretion in humans (8, 40, 41). These GI effects of GLP-1 may also contribute to its side effects at pharmacological concentrations. For example, in a multicenter study of 551 patients with inadequately controlled Type 2 diabetes mellitus, 57% of patients treated with a GLP-1 agonist reported nausea and 17% reported vomiting, and GLP-1 was discontinued because of these side effects in 6% of patients (18).

An intact vagus nerve is necessary for GLP-1 to delay gastric emptying in rats and pigs (21, 48) and to inhibit acid secretion in humans (49). GLP-1 also inhibits the plasma pancreatic polypeptide response to sham feeding in humans, indicative of vagal inhibition (39, 40). However, how GLP-1 increases gastric volumes is not understood. Since vagally mediated nitric oxide (NO) release is partly responsible for gastric accommodation (9, 23, 27, 43), vagal inhibition would be anticipated to reduce (not increase) fasting gastric volume and postprandial accommodation. There is increasing evidence to suggest that several effects of GLP-1 [e.g., inhibition of small bowel motility (33, 46) and relaxation of pulmonary arterial smooth muscle in rats (14, 37)] are mediated by NO. Therefore, we hypothesized that GLP-1 relaxes the stomach by stimulating nitrergic pathways. To examine this hypothesis, we assessed the effects of the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) and GLP-1, alone and in combination, on fasting and postprandial gastric volumes in humans.


   METHODS
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This report is part of a large study assessing modulation of gastric volumes by GLP-1, nitrergic, and adrenergic pathways in 64 subjects. Observations from 17 subjects on the adrenergic modulation of gastric volumes and the interaction between GLP-1 and the adrenergic nervous system will be reported separately. Forty-seven healthy adults aged 18–54 yr (mean age 31 yr; 35 women and 12 men) participated in this study. None had previous GI surgery (other than appendectomy or cholecystectomy), significant underlying illnesses, or medication use. Functional GI disorders, anxiety, and depression were excluded by validated screening questionnaires (44), a clinical interview, and a physical examination. Glucose intolerance and diabetes mellitus were excluded by checking the fasting serum glucose. The studies were approved by the Mayo Clinic Institutional Review Board.

Experimental Design for Experiment 1

The experimental protocol is summarized in Fig. 1. Fasting and postprandial gastric volumes, plasma catecholamines, and hemodynamic parameters were studied during intravenous infusion of placebo or medication, before and after a meal. Two peripheral venous cannulae were used for drug infusion, and a separate peripheral venous cannula was used for blood sampling. Medications were given as a 10-min bolus followed by a continuous infusion lasting for the duration of the study (i.e., 55 min). Subjects were randomized, in a double-blind manner, to one of six arms [i.e., placebo, GLP-1, the NOS inhibitor L-NMMA, the {alpha}2-adrenoreceptor antagonist yohimbine, GLP-1 combined with L-NMMA (low dose), or GLP-1 combined with yohimbine]. This randomization was balanced on sex and body mass index (BMI; i.e., ≤25 vs. >25 kg/m2). Because of this stratification, the number of subjects randomized to each group was similar but not identical. As control or placebo, we administered 15 ml of 0.9% saline as a "bolus" followed by an infusion at 42.9 ml/h for the entire study. When only one drug was administered, saline was administered through the second intravenous cannula. As noted above, data for subjects randomized to yohimbine alone or GLP-1 and yohimbine will be reported separately.


Figure 1
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  		Fig. 1. Experimental design. In addition to fasting and postprandial gastric volumes, hemodynamic parameters and plasma catecholamines were assessed during the study. Asterisks indicate time points when blood samples were obtained. SPECT, single-photon-emission computed tomography.

 
99mTc-SPECT for Measuring Gastric Volume and Accommodation

Gastric volumes were assessed by single-photon-emission computed tomography (SPECT) as described previously (2, 3, 25). After intravenous injection of 99mTc-labeled sodium pertechnetate (10 mCi), dynamic tomographic images of the gastric wall were acquired during fasting and for a total of 32 min after ingestion of a 300-ml nutrient drink (Ensure, 1 kcal/ml, Ross Laboratories, Abbott Park, IL) through a straw by a dual-head gamma camera (Helix SPECT System, Elscint, Haifa, Israel) in a multiorbit-mode system. Since the 99mTc is taken up by gastric parietal and mucus-secreting epithelial cells, the entire gastric mucosa is visualized by this technique. A three-dimensional rendering of the stomach and its volume was obtained by using the AVW 3.0 (Core B; Biomedical Imaging Resource, Mayo Foundation, Rochester, MN) image processing libraries.

Medications

GLP-1 and L-NMMA were used under investigator-initiated Investigational New Drug approvals from the US Food and Drug Administration. All infusions were prepared by standard practice in the Mayo General Clinical Research Center Research Pharmacy using current American Society of Health-System Pharmacists class III procedures for sterile preparation.

GLP-1. GLP-1 (7–36 amide) (Bachem, San Diego, CA) was infused at 2.4 pmol·kg–1·min–1 for 10 min followed by 1.2 pmol·kg–1·min–1 for the remainder of the study. This dosing regimen produced supraphysiological plasma levels, inhibited antroduodenal contractility, and increased pyloric tone in healthy subjects (39).

L-NMMA. L-NMMA (Clinalfa, Läufelfingen, Switzerland), a NOS inhibitor, was infused at 4 mg·kg–1·h–1. In healthy subjects, this dose stimulated small intestinal motility (38) and reduced postprandial accommodation (42).

Plasma Catecholamines and Glucose

Because L-NMMA can suppress sympathetic nerve activity (28), plasma catecholamines were measured during drug infusions. A 10-ml venous blood sample was drawn before and after drug infusion during fasting conditions, at 10 min, and at 20 min after a meal. Blood samples were collected in tubes containing 0.05 ml of 10% sodium metabisulfite. Plasma was obtained by refrigerated centrifugation and fast frozen in dry ice and acetone before storage at –70°C until assayed. Catecholamines were extracted from plasma (11) and subjected to HPLC with electrochemical detection (19). In addition to plasma epinephrine and norepinephrine, plasma dihydroxyphenylglycol (DHPG), which is the main metabolite produced by deamination of norepinephrine, was also measured (10). Plasma glucose concentrations were measured at the same time points using a glucose oxidase method (i.e., with a glucose analyzer).

Experimental Design and Procedures in Experiment 2

After completing experiment 1, 16 additional healthy subjects were evenly randomized to GLP-1 alone or to GLP-1 combined with L-NMMA; the L-NMMA dose of experiment 2 was higher (i.e., 10 mg/kg bolus over 10 min followed by 8 mg·kg–1·h–1 infusion) compared with experiment 1. A comparable dose of L-NMMA reduced fasting gastric volume and postprandial gastric accommodation in humans (26). Because the effect of L-NMMA on fasting gastric volume may be delayed (26), the fasting postdrug period was lengthened from 15 min in experiment 1 to 30 min in experiment 2. Otherwise, the experimental design for experiments 1 and 2 were similar.

Statistical Analysis

Overall treatment effects on fasting post-drug and postprandial post-drug parameters were assessed by analyses of covariance (ANCOVA) using sex, BMI, and the corresponding fasting predrug values as covariates. Because of the two-phase nature of the study, the analyses evaluated treatment effects nested within phase, e.g., GLP-1 alone was considered as a distinct treatment category for experiment 1 and separately for experiment 2. In addition, a one-way ANCOVA considering the combined GLP-1 groups from experiments 1 and 2 was used to assess the overall treatment effects for all subjects who received GLP-1. After assessing overall treatment effects, we examined specific pairwise comparisons. A formal comparison between placebo and GLP-1 (experiment 1) was tested; the similar comparison of GLP-1 (experiment 2) assumed that similar placebo values would have been obtained in experiment 2. Comparisons between placebo and L-NMMA (low dose only), between GLP-1 and GLP-1 + L-NMMA (low dose), and, separately, GLP-1 (experiment 2) vs. GLP-1 + L-NMMA (high dose) were also examined. Statistical significance was set at an {alpha} level of 0.05, and pairwise comparisons were only considered significant when overall treatment effects were also significant. A rank transformation was used for parameters that were not normally distributed. Because this was an intent-to-treat analysis, missing data were imputed by using the corresponding mean value over all nonmissing data values. The error degrees of freedom in the respective ANCOVA models were decreased by one for each missing value imputed for a given response parameter. The data presented in the text, tables, and figures are the "raw" means (± SE), unadjusted for covariates, and do not include any imputed values.


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None of the subjects experienced significant adverse events during these studies. At baseline, there were no clinically important differences in age, sex, BMI, fasting serum glucose, plasma norepinephrine, plasma DHPG, or fasting gastric volume among groups in either experiment 1 or experiment 2 of these studies (Table 1).


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  		Table 1. Demographic and baseline characteristics

 
Effects of GLP-1 and L-NMMA on Fasting and Postprandial Gastric Volume

Overall treatment effects on post drug fasting gastric volume were significant (P = 0.035) (Table 2, Fig. 2). GLP-1 increased (P = 0.03) fasting gastric volume, to a greater extent in experiment 2 (mean change = 101 ml, P = 0.001 vs. placebo) than in experiment 1 (mean change = 61 ml, P = 0.051 vs. placebo).


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  		Table 2. Effects of drugs on fasting and postprandial gastric volumes

 

Figure 2
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  		Fig. 2. Effects of drugs on gastric volumes. During saline infusion, gastric volume increased after a meal, reflecting postprandial accommodation. Glucagon-like peptide-1 (GLP-1) increased fasting and postprandial gastric volume (*P = 0.051 vs. placebo, {dagger}P ≤ 0.001 vs. placebo). The postprandial change in gastric volume was lower ({ddagger}P = 0.004) for GLP-1 and NG-monomethyl-L-arginine acetate (L-NMMA; high dose) compared with GLP-1 alone.

 
The postprandial gastric volume change (i.e., postprandial minus fasting volume) was 542 ± 29 ml for placebo and overall treatment effects were significant (P < 0.001) (Table 2, Fig. 2). The GLP-1-induced postprandial change was greater in part 2 (752 ± 62 ml, P < 0.001 vs. placebo) than in part 1 (605 ± 31 ml, P = 0.22 vs. placebo). Thus, for experiments 1 and 2 combined, GLP-1 increased the postprandial gastric volume change (i.e., accommodation) compared with placebo (P = 0.004).

The low dose of L-NMMA did not affect fasting or postprandial gastric volumes. Fasting gastric volume was not significantly different for GLP-1 and L-NMMA (high dose) combined compared with GLP-1 alone. However, the postprandial gastric volume change was lower (P = 0.004) for GLP-1 combined with L-NMMA (high dose) (494 ± 37 ml) than for GLP-1 alone (752 ± 62 ml) (Table 2, Fig. 2). In contrast, the postprandial gastric volume change was not significantly different for GLP-1 and L-NMMA (low dose) compared with GLP-1 alone (experiment 1).

Effects on Hemodynamic Parameters

Treatment effects on hemodynamic parameters were as anticipated (Table 3). During the fasting period, L-NMMA (low dose) increased (P ≤ 0.04) the mean arterial pressure compared with placebo and the combination of GLP-1 and L-NMMA (low dose) increased (P = 0.03) the mean arterial pressure compared with GLP-1 alone. During fasting and both postprandial periods, L-NMMA (low dose) reduced (P ≤ 0.01) the heart rate compared with placebo and GLP-1 + L-NMMA (low and high doses) reduced the heart rate compared with GLP-1 alone.


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  		Table 3. Effects of drugs on hemodynamic parameters

 
Effects on Plasma Catecholamine and Glucose Concentrations

In experiment 1, GLP-1 alone, L-NMMA, and GLP-1 combined with L-NMMA did not affect plasma norepinephrine concentrations (Fig. 3). During experiment 2, fasting postdrug plasma norepinephrine but not DHPG concentrations were lower (P = 0.02) during infusion of GLP-1+L-NMMA (high dose) compared with GLP-1 alone. In contrast, drug effects on plasma DHPG levels were not significant (data not shown). Plasma epinephrine concentrations were below the threshold of detection for the assay (i.e., <20 pg/ml) in most subjects (data not shown).


Figure 3
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  		Fig. 3. Effects of drugs on plasma norepinephrine. Fasting plasma norepinephrine concentrations were lower (*P = 0.02) among subjects who received GLP-1 and L-NMMA (high dose) compared with GLP-1 alone.

 
Neither GLP-1 nor L-NMMA alone or in combination significantly affected fasting plasma glucose concentrations (data not shown). Overall treatment effects on postprandial glucose concentrations at 10 (P = 0.07) and 20 min (P = 0.03) after a meal were observed. Pairwise comparisons revealed that plasma glucose was lower (P ≤ 0.03) during GLP-1 (78 ± 3 mg%) than placebo (88 ± 2 mg%) at 10 min after a meal. Similar differences were observed at 20 min after a meal (data not shown).


   DISCUSSION
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These data confirm our previous observations that GLP-1 increased gastric volume in healthy subjects, increasing fasting gastric volume by 33% and augmenting postprandial gastric accommodation by 27% (8). Moreover, a high dose of L-NMMA blocked postprandial augmentation of gastric volume by GLP-1, suggesting that the effects of GLP-1 on postprandial gastric volume are mediated by NO.

Postprandial gastric accommodation allows time and room for solids to be triturated before they are emptied from the stomach. Postprandial accommodation is primarily attributed to nutrient-driven stimulation of vagal activity, which activates enteric nitrergic pathways to relax the stomach (9, 23, 27, 43). Thus L-NMMA blunted postprandial accommodation in healthy subjects (26, 42). Several previous studies have demonstrated that GLP-1 administered at doses comparable or lower to those given in this study inhibited vagal activity, thereby inhibiting gastric antral motility and acid secretion in humans (8, 39). Therefore our observations suggest that GLP-1 increases postprandial gastric accommodation by activating nitrergic neurons without centrally stimulating vagal activity. An alternative explanation is that L-NMMA (high dose) blocked NO-mediated postprandial accommodation (i.e., independent of GLP-1). However, the mean postprandial gastric volume change was lower for GLP-1 + L-NMMA (high dose) than not only for GLP-1 alone but also for placebo. This suggests that GLP-1 increased postprandial gastric volume via NO-dependent mechanisms. Several other effects of GLP-1 [i.e., inhibition of small bowel motility (46), protection against ethanol-induced gastric mucosal lesions (22), and relaxation of vascular endothelium (35)] are also dependent on NO. Indeed, the interaction between GLP-1 and NO may be beneficial since GLP-1 also improved endothelial function in patients with Type 2 diabetes mellitus and coronary disease (36). GLP-1 may modulate vagal activity not only by central but also by peripherally mediated effects. Thus, in rats, physiological doses of GLP-1 activated vagal afferents (4) and intraportal administration of a truncated form of GLP-1 stimulated afferents in the hepatic vagus, thereby activating efferents in pancreatic branches of the vagus nerve (32). These observations suggest that GLP-1 may modulate GI functions via GLP-1 receptors on vagal afferents, which in turn activate vagovagal pathways. Similar to enteropancreatic and other vagovagal reflexes, these pathways probably entail sensory vagal afferents that travel to brain stem vagal nuclei and subsequently project to excitatory cholinergic or inhibitory nonadrenergic noncholinergic postganglionic neurons in the stomach to complete the loop (15, 34).

The postprandial change in gastric volume measured by SPECT reflects the sum total of the ingested meal, gastric secretion, swallowed air, gastric relaxation, and gastric emptying. However, SPECT does not clarify the relative contributions of these components to measured gastric volume. A recent study in which gastric volumes and emptying were simultaneously assessed demonstrated that the gastric volume measured by SPECT was, on average, 200 ml greater than the calculated volume (i.e., ingested volume corrected for gastric emptying) at 15 min after a meal (5). Gastric secretion, which is ~90 ml/10 min, can explain a significant proportion of this difference (30). In addition to gastric relaxation, it is conceivable that GLP-1 may also increase postprandial gastric volume by slowing gastric emptying. However, it is unlikely that delayed gastric emptying contributes to the effects of GLP-1 on fasting gastric volume. GLP-1 reduces gastric acid secretion (48, 49), which would be anticipated to reduce and not increase gastric volumes. Finally, it is conceivable that GLP-1 increased the volume of swallowed air, which is another putative component of postprandial volume change, perhaps by influencing transient lower esophageal sphincter relaxation. However, the effects of GLP-1 on transient lower esophageal sphincter relaxation are unknown.

In contrast to the postprandial state, L-NMMA did not prevent the effects of GLP-1 on fasting gastric volume. This effect may also be mediated via vagovagal pathways. Because direct arterial infusion of GLP-1 did not inhibit antral or pyloric motor activity in dogs, a direct effect of GLP-1 on gastric smooth muscle seems unlikely (6). Although GLP-1 can release somatostatin (24), which increases fasting gastric volume (13), the inhibitory effect of GLP-1 on fasting small bowel motility is not mediated by somatostatin (46). In rats, GLP-1 increases blood pressure and heart rate and reduces intestinal motility via sympathetic stimulation (50, 51). However, the effect of GLP-1 on sympathetic tone seems species dependent, because GLP-1 did not increase blood pressure in monkeys (52) or during continuous subcutaneous infusion for 6 wk in humans (53). The combination of GLP-1 and a high dose of L-NMMA reduced plasma catecholamines, consistent with previous studies demonstrating that a high dose of L-NMMA can reduce sympathetic nervous system activity by reflex mechanisms (17). However, the high dose of L-NMMA did not prevent the effect of GLP-1 on fasting volume. There is no evidence to demonstrate that GLP-1 interacts with other inhibitory neurotransmitters (e.g., VIP or ATP).

The GI effects of GLP-1 facilitate glycemic control by delaying the delivery of nutrients to the small intestine. Although GLP-1 agonists are associated with GI side effects (e.g., increased satiety) in therapeutic trials (18), it is conceivable that by slowing gastric emptying and improving gastric accommodation they may improve symptoms (e.g., early satiety) in diabetic patients with rapid gastric emptying or impaired gastric accommodation, respectively. Although GLP-1 increases satiety via central mechanisms in rats (47), peripherally administered GLP-1 also increased satiety in humans (12, 16). It is conceivable that increased satiety is partly attributable to the observed effect of GLP-1 on gastric emptying and volumes. Indeed, atropine, which also increases gastric volume, delays gastric emptying, and reduces plasma pancreatic polypeptide response to sham feeding, induced GI symptoms (e.g., nausea and bloating) in response to an oral nutrient load at maximal satiation and at 30 min thereafter (7). It is difficult to dissect the relative contributions of delayed gastric emptying and increased gastric volumes to GI symptoms (e.g., satiety) related to GLP-1. Because experiments 1 and 2 employed similar protocols and the analyses corrected for interindividual variations in fasting volume, it is unclear why GLP-1 increased fasting and postprandial gastric volume to a greater extent in experiment 2 than in experiment 1. Further studies are necessary to understand whether the observed interindividual differences in these effects explain the GI side effects of GLP-1 and whether these differences can be explained by inherited polymorphisms resulting in loss of function at the GLP-1 receptor (1).

In summary, these observations suggest that, in humans, GLP-1 increases fasting gastric volume and augments postprandial accommodation via different mechanisms. The effects of GLP-1 on postprandial but not fasting gastric volumes in humans are mediated in part by NO. Further studies are required to understand how GLP-1 increases fasting gastric volume in humans.


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This study was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK-068254, and by the General Clinical Research Center grant RR-00585 from the National Institutes of Health in support of the Physiology Laboratory and Patient Care Cores.


   ACKNOWLEDGMENTS
 
We thank the Mayo Clinic Research Pharmacy and the nursing staff of the General Clinical Research Center.

This research was presented in abstract form at the American Motility Society Meeting, Santa Monica, CA, September 22–25, 2005.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. E. Bharucha, Clinical Enteric Neuroscience Translational and Epidemiological Research Program (C.E.N.T.E.R.), Mayo Clinic, 200 First St. S.W., Rochester, MN 55905 (e-mail: bharucha.adil{at}mayo.edu)

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.


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