lourrid of lnternal Medicine 1990; 228. Suppl. 1 : 103-107

Vagal and sympathetic control of gastric and duodenal bicarbonate secretion L. F A N D R I K S &

c. J O N S O N

From the &prtment of Phgsiologg. Universitg of G6tpborg. G6teborg. Sweden

Abstract. Fandriks L, Jonson C (Department of Physiology, IJniversity of Goteborg. Goteborg. Sweden). Vagal and sympathetic control of gastric and duodenal bicarbonate secretion. journal of Internal Medicine 1990: 228, Suppl. 1 : 103-107. This report summarizes data concerning the extrinsic neural control of bicarbonate secretion by the gastric and duodenal mucosa. Parasympathetic vagal effects have been studied in experimental animals and in man by means of direct electrical vagal stimulation, sham-feeding procedures and intracerebroventricular peptide injections. The results show that the vagal nerves have a stimulatory effect on gastroduodenal bicarbonate secretion. Furthermore. both conventional nicotinic and muscarinic cholinoceptor. as well as non-cholinergic transmission, mediate the vagal effect. Sympathetic splanchnic nerve effects have been investigated by means of nerve sections, direct electrical stimulation, reflex activation and stereotaxic electrical hypothalamic stimulation. The data show that the splanchnic nerves have a predominantly inhibitory action on gastroduodenal bicarbonate secretion by use of peripheral adrenergic neurones and receptors of the alpha-2 subtype. The role of the adrenal glands is not fully understood. It is concluded that gastroduodenal bicarbonate secretion is under autonomic neural control, mainly in the classical antagonistic fashion : the parasympathetic vagal nerves stimulate bicarbonate output, whereas the sympathetic splanchnic nerves are mainly inhibitory. Key words: adrenergic, autonomic nervous system. bicarbonate, cholinergic. mucosa protection, splanchnic nerves, vagal nerves.

Introduction Acid secreted by the gastric parietal cells has an important role in the digestive process. However, the acidity is a potential threat to the organism itself, and several protective mechanisms are utilized to prevent autodigestion. It is now well established that bicarbonate which is secreted by the surface epithelium neutralizes gastric acid [ 1-31. Micro-pH-electrodes have been used to demonstrate the presence of a pH gradient immediately above the epithelial cells, the pH at the cell surface being neutral despite the highly acidic luminal contents [4. 51. The surface transport of bicarbonate is perhaps the most important contributor to protection against gastric acid in the duodenum, whereas it plays a more subordinate role in the stomach [ 1, 61. During recent years data have been obtained which show that the autonomic nervous system influences the rate of bicarbonate

secretion. The autonomic nervous system is classically divided into three components : the parasympathetic, the sympathetic and the enteric nervous system. This report attempts to summarize present knowledge of extrinsic (parasympathetic and sympathetic) neural control of bicarbonate secretion in the stomach and duodenum.

Methods Studies have been conducted on conscious animals and man, as well as on anaesthetized animal preparations. The simultaneous secretion of acid in the stomach hampers direct measurement of bicarbonate, which in acidic environments is released in the form of carbon dioxide. Three different approaches have been developed for measurement of gastric bicarbonate secretion : pH/p,.,,t-measurements, osmolality-acidity measurements and 103

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parietal-cell inhibition + back-titration. Various titration techniques have been used to measure alkaline secretion in isolated segments of the duodenum. Methodological considerations are described by Flemstrom [ 1, 71.

Parasympathetic influences-the nerves

vagal

Gastric bicarbonate secretion Fifty to sixty years ago it was shown that electrical stimulation of the vagal nerves in the cat could induce an alkaline gastric secretion [8, 91. More recently, Nylander et al. showed that electrical stimulation of the vagal nerves increased gastric bicarbonate secretion in anaesthetized cats [lo]. This response was abolished by hexamethonium and partly blocked by atropine (Fig. 1). indicating a conventional ganglionic transmission and involvement of muscarinic transmission. Konturek and coworkers demonstrated in dogs that central activation of the vagal nerves with sham feeding or insulin-hypoglycaemia increased gastric bicarbonate secretion. These responses were atropine-sensitive, whereas indomethacin had no effect [ 111. Three laboratories. utilizing different measurement techniques, have reported that sham feeding in humans increases gastric bicarbonate secretion by a mechanism which is sensitive to muscarinic antagonists [ 12-14].

Duodenal bicarbonate secretion Vagotomy lowers duodenal alkaline secretion, indicating a stimulatory action of these nerves [ 15, 161. Furthermore, direct electrical vagal stimulation increases duodenal bicarbonate secretion in cats, rats and pigs [ l o , 16. Jonson, unpublished observations]. In the cat and rat the responses were abolished by hexamethonium, whereas atropine inhibited the response by approximately 50% in the cat, but was without effect in the rat [ l o , 161. In rabbits, however, vagal nerve stimulation somewhat decreased the secretion [ 171, although the reason for this species difference is not known. Basal bicarbonate secretion in the rabbit is 10-fold higher than that, for example, in the cat. It is possible that the rabbit has a different epithelial constitution and/or secretoneuronal arrangement. The vagal nerves have also been activated by intracerebroventricular (i.c.v.) infusions of neuropeptides. Flemstrom and Jedstedt demonstrated in the rat that thyrotropin releasing hormone (TRH). when administered as an i.c.v. infusion, stimulated duodenal bicarbonate secretion [ 181. This effect was sensitive to hexamethonium and vagotomy, but was resistant to atropine. Other peptides have also been tested. For example, corticotropin releasing factor (CRF),gastrin releasing peptide (GRP),and bombesin stimulated duodenal bicarbonate secretion, whereas cholecystokinin (CCK) and beta-endorphin were without effect [ 181. Furthermore, central vagal activation by means of sham feeding in dogs [ 11, 191 and in man [20] have been shown to stimulate duodenal bicarbonate secretion by means of a partially atropine-sensitive mechanism.

Sympathetic influences-the splanchnic nerves and the adrenal glands Gastric bicarbonate secretion

Fig. 1. The effect of bilateral vagal nerve stimulation (10 Hz. supramaximal intensity, for 10 min) and administration of atropine ( 1 mg kg-’ administered intravenously) in anaesthetized cats ( n = 6). Data from [lo].

Indirect evidence for a n inhibitory effect of the splanchnic nerves on gastric bicarbonate secretion has been presented. For example, basal gastric bicarbonate secretion in anaesthetized cats with severed splanchnic nerves is higher than that in animals with intact splanchnic nerves (Fig. 2) [21]. Activation of sympathetic nerves by applying negative pressure to the lower body, which increases venous pooling and mimics a hypovolaemic situation, decreases gastric bicarbonate secretion in man

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Duodenal bicarbonate secretion Splanchnicotomy increased basal duodenal alkaline secretion in the cat [15, 2 11. Furthermore, the vagally induced increases in duodenal bicarbonate secretion were greater in splanchnicotomized animals than in animals with intact splanchnic nerves (Fig. 2) [21, 241. Direct electrical stimulation of the splanchnic nerves decreased the basal duodenal bicarbonate secretion and inhibited vagally-induced increases, as well as the rise in secretion in response to exposure to acid [23, 26, 271. This inhibitory effect of the splanchnic nerves on duodenal bicarbonate secretion could be blocked by the administration of guanethidine or yohimbine, whereas prazosin or propranolol, even at quite high doses, were without effect [23, 271 (Fig. 3). The data thus suggest that the sympathetic splanchnic nerves can inhibit duodenal bicarbonate secretion by using adrenergic neurones and alpha-2-adrenoceptors. This view is supported by the fact that the alpha-2adrenoceptor clonidine inhibits secretion by a yohimbine-sensitive mechanism [23, 28. 291. Sympatho-adrenergic inhibition of duodenal bicarbonate secretion elicited from several levels ' in the central nervous system has been investigated in the anaesthetized rat. Electrical stimulation of mesenteric afferents from the jejunum inhibited bicarbonate secretion in the duodenum. This effect was apparently due to a spinal reflex, as it was well preserved after cervical cord transection but was blocked by bilateral splanchnicotomy [301. Furthermore, a modest hypovolaemia. obtained by means of an arterial bleeding of approximately 10% of total blood volume, lowered duodenal bicarbonate secretion and inhibited the increase in secretion in response to acid exposure [26, 31, 321. This inhibitory effect was probably due to unloading of

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Fig. 2. Vagal stimulation in anaesthetized cats with intact splanchnic nerves ( 0 )(n = 6) and in splanchnicotomized cats (0) (n = 6). Data from [25].

[22]. However, direct electrical stimulation of the whole splanchnic nerve trunk in cats induced either no effect, or else a slight increase in gastric bicarbonate secretion [2 31. The latter finding indicates that the splanchnic nerves may also contain nerve fibres which have a stimulatory effect on the gastric bicarbonate-secreting epithelium. The inhibitory action of the splanchnic nerves could be blocked by the adrenolytic agent guanethidine or by the alpha-2-adrenoceptor blocker yohimbine [23-2 51. The alpha- 1-adrenoceptor prazosin and the beta-blocker propranolol were both without effect, indicating that the splanchnic neural inhibition of gastric bicarbonate secretion is mediated via adrenergic neurones and peripheral alpha-2adrenoceptors [23, 251. Exclusion of the adrenal glands by ligation decreased gastric bicarbonate secretion in the cat, suggesting that a stimulatory factor was released from these glands [21].

Fig. 3. The effect of direct stimulation of the solanchnic nerves on duodenal bicarbonate secretion in groups of anaesthetized rats with different pharmacological treament ( n = 6 in each group). Data are expressed as the induced net change+SE (doses: guandethidine. 8 mg kg-' i.v.: prazosin. 1 mg k g ' x h i.v.: yohimbine. 0.1 mg kg-' x h i.v.: propranolol. 1 mg kg-' x h i.v.: controls received no drug). Data from [28).

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arterial baroreceptors, and thus constitutes a reflex via the vasomotor centre in the brain stem [31]. Higher brain structures could also influence duodenal bicarbonate secretion via the sympatho-adrenergic route. Stereotaxic electrical stimulation in the perifornical region of the hypothalamus inhibited duodenal bicarbonate secretion. an effect which could be counteracted by epidural anaesthesia or by the adrenolytic agent guanethidine. This indicates that there is mediation via spinal (presumably splanchnic) nerves and adrenergic transmission [ 3 31. Ligation of the adrenal glands increased basal duodenal bicarbonate secretion in the rat [ 161. However, hypovolaemia-induced inhibition of duodenal bicarbonate secretion was not affected by exclusion of the adrenal glands, suggesting that this response was predominantly mediated by direct adrenergic innervation [ 3 11. The adrenal glands appear to be unimportant for duodenal bicarbonate secretion in the cat 12 11.

Functional considerations The data reviewed here suggest the existence of a complex central neural control of gastroduodenal alkaline secretion. To date, only some parts of this regulatory system have been established. The two extrinsic components of the autonomic nervous system appear to act mainly in a classical antagonistic fashion : the vagal nerves stimulate gastroduodenal bicarbonate secretion, involving cholinergic as well as non-cholinergic transmission mechanisms. The sympathetic nerves are mainly inhibitory, and influence bicarbonate transport by means of adrenergic neurones (Fig. 4). The neural modulation of secretion can be a result of a direct effect on the epithelium, or an indirect effect via Vagal nerve

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Splanchnic nerve

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enteric secretomotor neurones. It is also possible that neurogenic alterations of the mucosal blood circulation to some extent contribute to changes in secretion. The functional role of the above-mentioned neural arrangement is only speculative at present. The vagal neural pathway can be utilized by the central nervous system to increase gastroduodenal neutralizing capacity and thus prepare the mucosa for imminent exposure to gastric acid. The vagal effect on bicarbonate secretion thus acts in parallel to the cephalic phase of gastric acid secretion. The functional role of the sympatho-inhibitory arrangement is less obvious. The sympatho-adrenal system is often regarded as being an emergency system which is activated in response to various stimuli which are. or may be, harmful to the organism, for example, trauma or blood loss, or during fight or flight behaviour. Such situations are often associated with a risk of metabolic acidosis. It may be speculated that the organism, while making several other homeostatic adjustments, also inhibits alkaline secretion in order to retain the bicarbonate ions within the circulation. As mentioned in the Introduction, the maintenance of mucosal integrity is dependent on the balance between aggressive digestive factors, e.g. gastric acid, and protective factors such as neutralizing bicarbonate [ 1-31. An imbalance between these counterparts, for example by the predominance of sympathoadrenergic inhibition of gastroduodenal bicarbonate secretion, may predispose the mucosa to injury and disease.

Acknowledgements The experiments performed in our laboratory were financed by the Swedish Medical Research Council (grants 0016. 2855, 8429, 8 6 6 3 ) . Stockholm, the Goteborg Medical Society, Goteborg, and the Swedish Medical Society, Stockholm.

References ,I?

4 HCO;4 4 Fig. 4. Hypothetical arrangement of the extrinsic autonomic nerves that influence gastroduodenal bicarbonate secretion.

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Vagal and sympathetic control of gastric and duodenal bicarbonate secretion.

This report summarizes data concerning the extrinsic neural control of bicarbonate secretion by the gastric and duodenal mucosa. Parasympathetic vagal...
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