| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
© 1999 International Anesthesia Research Society
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
We studied the effects of clonidine (0.5 mg/kg) on hormonal stress response and antioxidant enzymes cold restraint-induced gastric lesions in rats. Rats in the study group were given 0.5 mg/kg intraperitoneal clonidine (n = 12), whereas the control group received 0.5 mL/kg intraperitoneal isotonic sodium chloride solution (n = 9). Animals were then subjected to immobilization at 4°C in restraining devices for 4 h after a starvation period of 24 h. Gastric lesion index, gastric tissue malondialdehyde activity, and plasma cortisol concentrations were assayed. Histopathologic examination demonstrated a stress ulcer index of 3.17 ± 0.92 mm in the clonidine group and 14.0 ± 3.22 mm in the control group (P < 0.05). The tissue malondialdehyde concentrations were slightly higher in the control group than in the clonidine group, but the differences were not statistically significant (P > 0.05). Plasma cortisol levels were lower in the clonidine group (P < 0.05). We concluded that clonidine attenuated the tissue damage and stress response in stress-induced gastric ulceration.
Implications: Stressful circumstances can cause stomach ulcers, which can bleed, exposing patients to potentially life-threatening complications. In the present animal study, we showed that clonidine, a routinely available medication, may be useful in preventing stress-induced stomach ulcers.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Organism homeostasis is commonly perturbed by stress. Both physical and psychological stress cause gastric ulcerations in both animal and human models. Although no single mechanism has been elucidated, increased gastric motility, vagal hyperactivity, mast cell degranulation, decreased gastric blood flow, and decreased prostaglandin levels have all been associated with gastric ulcer generation. However, it has been suggested that the free radical-generating system is closely related to the production of gastric damage. One study seems to confirm that gastric ulcer formation results from an imbalance of offensive and defensive factors (1).
Clonidine can effectively blunt the neurohumoral and hemodynamic stress response to surgery (2–4). In addition, clonidine decreases gastric acid secretion while increasing gastric mucus and pepsin secretion (5,6). Although clonidine has been shown to alter many factors that are associated with ulcer formation, no previous work has investigated the potential for these effects to translate into clinical benefit. Our study was designed to determine whether, through the combined effects of neurohumoral attenuation and the potentially directly protective effect of a favorable balance in local gastric factors, clonidine would reduce stress-induced gastric ulcerations.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The study was approved by the local animal use and care committee. Twenty-one male Sprague-Dawley rats weighing 150–200 g were randomly assigned to a receive either intraperitoneal clonidine (0.5 mg/kg) or placebo (saline). Controls received similar volumes of saline by the same route. Before randomization, the rats were fasted for 20–24 h but were given free access to water. To avoid any diurnal effect, all animals were studied at the same time of day. General anesthesia was induced and maintained with ether. Rectal temperature was maintained at 37°C with a heating pad and monitored continuously.
Forty-five minutes after the intraperitoneal injection, the animals were placed in restraining devices and maintained at 4°C for 4 h, as previously described by Senay and Levine (7). After 4 h of hypothermic restraint, the animals were removed from the restraining devices, maintenance of anesthesia was confirmed by inhalation with ether, and a midline laparotomy was performed. After isolation of pyloric and gastroesophageal regions, a total gastrectomy was performed, and biopsy specimens were obtained for histologic staining and malondialdehyde (MDA) assay. The stomach was opened along the greater curvature, the lumen was rinsed with ice-cold saline, and the mucosa was examined macroscopically. Ulcerative lesion size was determined by measuring each lesion along its greatest diameter. Three confluent petechia were considered equivalent to a 1-mm lesion. Lesions were summed and divided by the number of animals per group to determine the mean lesion index. Blood samples obtained from the heart were assayed for cortisol concentrations by using a single-antibody radioimmunoassay. Animals were killed with an overdose of ether.
Tissue samples were homogenized in 10 volumes of ice-cold 10% trichloracetic acid and 0.5 mL of 5% trichloracetic acid in a tissue homogenizer. Homogenized samples were centrifuged at 4,000 rpm for 15 min at 4°C. Supernatant was removed and centrifuged at 20,000 rpm for 5 min at 4°C. A 1-mL aliquot was removed and added to an equal volume of 0.67% thiobarbituric acid. Samples were placed in a 100°C water bath for 10 min before cooling, recentrifugation, and precipitant removal. Supernatant absorbance was determined at 532 nm (8).
Biopsy specimens were prepared in a standard fashion and were evaluated under a light microscope after hematoxylin and eosin staining.
Student's unpaired t-test was used to compare the clonidine and placebo groups. Normal distribution of data was confirmed by Levene's test. All data are presented as mean ± SEM. P < 0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Clonidine was administered to 12 animals, and 9 served as saline-treated controls. Cold restraint lead to multiple gastric ulcerations in all animals. However, the frequency, number, and size of gastric ulcers were significantly reduced in clonidine-pretreated animals. Direct observation also showed a reduction in the average number of petechia found in the clonidine group (Table 1). In addition, clonidine significantly reduced the mean lesion index (Figure 1).
|
|
Clonidine administration significantly reduced plasma cortisol concentrations (0.19 ± 0.04 vs 0.07 ± 0.03 µg/dL), but no change in MDA levels was noted (10.08 ± 0.94 vs 8.93 ± 0.71 nM/g) (Figure 1).
Clonidine administration was associated with a significant difference in the histologic specimens. Control animals displayed a loss of superficial epithelium and necrosis of the upper mucosa. In addition, a dense acute inflammatory call infiltrate, consisting mainly of neutrophils, was noted. In striking contrast, gastric specimens from the clonidine pretreated animals displayed minimal or no changes (Figure 2).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Physiologic stress stimulates adenohypophysial axis and causes a concomitant release of endogenous opiates. Stress also produces severe gastric erosion through the activation of central vagal discharge (9–11). The endogenous opiates released during stress can cause mucosal congestion by a peripheral mechanism, leading to the development of gastric ulcers (12). We assessed clonidine in the outcome of cold restraint-induced gastric injury. The results of our study demonstrate that clonidine can decrease the severity of cold restraint-induced gastric mucosal damage while reducing the cold restraint-induced increases in tissue MDA levels and plasma cortisol levels.
The protective effect of clonidine may have multiple components in its action. By increasing mucosal blood flow by stimulating central 
2 receptors and subsequently decreasing sympathetic outflow, and by decreasing central vagal activity, clonidine may be protective against ulcers (10). Cheng et al. (11) demonstrated that, depending on the dosage used, clonidine stimulated or inhibited gastric acid secretion induced with various secretogogues and suggested that clonidine reduces gastric acid secretion by both central and peripheral mechanisms. The peripheral inhibitory effect is a result of its effect on the 2-adrenergic receptors located on the postganglionic parasympathetic nerve. As the dose is increased, clonidine also stimulates gastric acid secretion, which seems to be mediated by histamine H2 receptor stimulation.
Clonidine has protective effects against stress-induced ulcers and influences variables that directly or indirectly affect gastric ulcer (7,10,11). Modulation of 2 receptor activity, both central and peripheral, could lead to inhibition of gastric acid secretion, gastric motility, and increase in blood flow (13). The antisecretory action of clonidine may involve one or all of the actions. The peripheral 2 receptors located on the intramural parasympathetic ganglia are inhibitory in nature, and stimulation receptors by clonidine decrease the vagally mediated discharge of acetylcholine (10). Del Tacca et al. (14) provided direct evidence for the inhibitory effect of clonidine on acetylcholine release from the vagus nerve. This action on acetylcholine release may be related to the activation of presynaptic receptors on the vagus nerve. The existence of the mechanism is supported by the fact that the inhibitory effect of clonidine was prevented by yohimbine, which preferentially blocks 2 receptors. Although these studies have shown mechanisms that might translate into benefit, none has demonstrated the actual benefit. In our study, acute gastric erosions developed in rat stomachs exposed to cold-restraint stress, and clonidine significantly reduced the lesion index. Data demonstrating the effects of 2-adrenoreceptor stimulation on gastric secretion suggest that clonidine is a potent antisecretory and gastric protective compound (15).
There have been several reports on the effect of 2- adrenoceptor agonist on gastric emptying (16–18). However, the results are inconclusive. In some studies, clonidine delayed gastric emptying of liquids in rats. In other studies, clonidine did not significantly delay gastric emptying. Asai et al. (16) showed that, in the rat, clonidine did so via 2-adrenoceptors, with only a weak inhibitory effect on gastric emptying, even at the maximal tolerable dose.
During stress, concentration of catabolic counterregulatory hormones—cortisol, glucagon and catecholamines, epinephrine, norepinephrine—are typically increased. These hormones serve as effector signals in the response to stress (19). Previous studies demonstrated the opposite effect for clonidine on pituitary hormone release in healthy subjects. The effect of clonidine on hormone secretion is mediated through stimulation of 2-adrenergic receptors (20,21).
The effect of clonidine on plasma ACTH and on cortisol has not been clearly determined. The 2-adrenergic receptor agonists have received attention because activation of central 2-adrenoceptors by clonidine diminishes a variety of responses to stress, an action that may be beneficial in many patients after surgery (2,3,21). These effects may be due to inhibition of sympathetic outflow and pituitary ACTH secretion. The effects of clonidine on hormone secretion are mediated through the stimulation of 2-adrenergic receptors, and this effect is at least partly mediated via activation of opiate receptors, which can be blocked by naloxone (20). The adrenergic pathway originating in the locus coeruleus sends collaterals to the hypothalamus, which are under opiate inhibition and thereby modulate the release of corticotrophin releasing factor. Endogenous opiate peptides inhibit the noradrenergic stimulation of corticotrophin releasing factor and, consequently, ACTH and cortisol release (20).
Our results show that clonidine inhibits the release of cortisol in cold-restraint stress. Previous studies have demonstrated that, after clonidine injection in humans, ACTH and cortisol levels decreased (19,22). Evidence suggests that epidurally or intrathecally administered clonidine decreases stress-induced adrenocorticotropic hormone release and, hence, cortisol release, including the stress of the surgery in humans (23,24). However, in humans, the combined administration of oral and transdermal clonidine effectively attenuated the catecholamine response to surgical stress but had no effect on adrenotropic hormone and cortisol concentrations during the postoperative period (25). Data demonstrating the determinants of catecholamine and cortisol responses to surgery suggest that the lack of correlation between catecholamine and cortisol secretion indicates that the stress response may consist of a discrete system responding to different stimuli (26).
Lipid peroxidation as a free radical-generating system may be related to the production of the gastric damage caused by cold-restraint stress (27–29). In the present study, we also assessed the effect of clonidine on lipid peroxidation in the stomach. We did not observe any significant change in MDA levels between the control and clonidine groups. Previous studies have suggested that clonidine does not inhibit gastric peroxidation and increases the production of lipid peroxidation product in stress-induced ulcers in rats (4,13). These results indicate that clonidine does not inhibit gastric lipid peroxidation but has beneficial effects on cold restraint-induced gastric lesions through mechanisms other than reduced lipid peroxidation.
In conclusion, our results suggest that pretreating rats with clonidine inhibits cold-restraint stress-induced gastric mucosal injury and can attenuate the cold restraint-induced increases in cortisol levels.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Ray AP, Sullivan RM, Henke G. Adrenergic modulation of gastric stress pathology in rats. Nerv Syst 1987;20:265–8.
- Pouttu J, Scheinin B, Rosenberg PH, et al. Oral premedication with clonidine : effects on stress responses during general anesthesia. Acta Anaesthesiol Scand 1987;31:730–4.[Web of Science][Medline]
- Kulka PJ, Tryba M, Zenz M. Dose response effects of intravenous clonidine on stress response during induction of anesthesia in coronary artery by pass graft patients. Analg 1995;80:263–8.[Abstract]
-
Hayashi Y, Maze M. Alpha 2 adrenoreceptor agonists and anaesthesia. Br J Anaesth 1993;71:108–18.
[Free Full Text] - Al-Bekairi AM, Rajhi AM, Tariq M. Effect of propranolol and clonidine on stress and chemically induced gastric ulcers in rats. Arc Int Pharmacodyn 1993;323:97–113.
- Soldato PD. Gastric lesion preventing or potentiating activity of clonidine in rats. Jpn J Pharmacol 1986;41:257–9.[Medline]
- Senay EC, Levine RJ. Synergism between cold and restraint for rapid production of stress ulcer in rats. Proc Soc Exp Biol Med 1967;124:1221–3.[Medline]
- Ohkwa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissue by thiobarbituric acid reaction. Anal Biochem 1979;95:351–8.[Web of Science][Medline]
-
Cheng HC, Gleason EM, Nathan BA, et al. Effects of clonidine on gastric acid secretion in rat. J Pharmacol Exp Ther 1981;217:121–6.
[Abstract/Free Full Text] - Morley JE, Levine AS, Silvis SE. Endogenous opiates and stress ulceration. Life Sci 1982;31:693–9.[Web of Science][Medline]
- Taylor JA, Mir GN. Alpha adrenergic receptors and gastric function. Drug Dev Res 1982;2:105–22.
- Kunchandy J, Khanna S, Kulkarni K. Effect of alpha-2 agonists clonidine, guanfacine and B-HT 930 on gastric acid secretion and ulcers in rats. Arch Int Pharmacodyn 1985;275:123–38.
- Del Tacca M, Soldani G, Bernardini C, Martinotti E. Pharmacological studies on the mechanisms underlying the inhibitory and excitatory effects of clonidine on gastric acid secretion. Pharmacol 1982;81:255–61.
- Glavin GB, Pare WP, Sandbak T, et al. Restraint stress in biomedical research : an update. Neurosci Behav Rev 1994;18:223–49.[Web of Science][Medline]
- Glavin GB, Smyth DD. Effects of the selective I1 imidazoline receptor agonist, monoxidine, on gastric secretion and gastric mucosal injury in rats. Br J Pharmacol 1995;114:751–4.[Web of Science][Medline]
-
Asai T, Mapleson WW, Power I. Differential effects of clonidine and dexmedetomidine on gastric emptying and gastrointestinal transit in the rat. Br J Anaesth 1997;78:301–7.
[Abstract/Free Full Text] - Fargeas MJ, Fioramonti J, Bueno L. Central alpha-2 adrenergic control of the pattern of small intestinal motility in rats. Gastroenterology 1986;91:1470–5.[Web of Science][Medline]
- Nagata M, Osumi Y. Central alpha-2 adrenoceptor mediated inhibition of gastric motility in rats. Jpn J Pharmacol 1993;62:329–30.[Medline]
- Bessey P, Downey RS, Monafo WW. Metabolic response to injury and critical illness. In: Civetta JM, Taylor RW, Kirby RR, eds. Critical care. 3rd ed. New York:Lippincott-Raven, 1997:325.
- Barnowska B. The effect of clonidine on hormone release mediated through activation of opiate receptors. Cardiovasc Drugs Ther 1990;4:1113–7.[Web of Science][Medline]
- Amsterdam JD, Maislin G, Skolnick B, et al. Multiple hormone responses to clonidine administration in depressed patients and healthy volunteers. Biol Psychiatry 1989;26:265–78.[Web of Science][Medline]
- Gaumann DM, Tassonyi E, Rivest RW, et al. Cardiovascular and endocrine effects of clonidine premedication in neurosurgical patients. Can J Anaesth 1991;38:837–43.[Web of Science][Medline]
- Eisenach JC, Dewan DM. Intrathecal clonidine in obstetrics. Anesthesiology 1990;72:663–8.[Web of Science][Medline]
-
Lund C, Qvitzau S, Greulich A, et al. Comparison of the effects of extradural clonidine with those of morphine on postoperative pain, stress responses, cardiopulmonary function and motor and sensory block. Br J Anaesth 1989;63:516–9.
[Abstract/Free Full Text] - Dorman T, Clarkson K, Rosenfeld BA, et al. Effects of clonidine on prolonged postoperative sympathetic response. Med 1997;25:1147–52.
- Breslow MJ, Parker SD, Frank SM, et al. Determinants of catecholamine and cortisol responses to lower extremity revascularization. Anesthesiology 1993;79:1202–9.[Web of Science][Medline]
- Das D, Bandyopadhyay D, Bhattacharjee M, Banerjee RK. Hydroxyl radical is major causative factor in stress-induced gastric ulceration. Free Radical Biol Med 1997;23:8–18.[Web of Science][Medline]
- Vainshtein SG, Zvershkhanovskii FA. Lipid peroxidation in patients with gastric ulcer and cancer. Onkol 1984;30:39–41.
- Moore RM, Muir WW, Granger DN. Mechanisms of gastrointestinal ischemia-reperfusion injury and potential therapeutic interventions. J Vet Intern Med 1995;9:115–32.[Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  C. Bregonzio, I. Armando, H. Ando, M. Jezova, G. Baiardi, and J. M. Saavedra Anti-inflammatory effects of angiotensin II AT1 receptor antagonism prevent stress-induced gastric injury Am J Physiol Gastrointest Liver Physiol, July 7, 2003; 285(2): G414 - G423. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
