Autonomic control of glands and secretion: A comparative view

Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

Contents lists available at ScienceDirect

Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u

Review

Autonomic control of glands and secretion: A comparative view Susanne Holmgren ⁎, Catharina Olsson Department of Zoology, University of Gothenburg, SE-405 30 Göteborg, Sweden

a r t i c l e

i n f o

Article history: Received 10 February 2010 Received in revised form 21 October 2010 Accepted 22 October 2010 Keywords: Autonomic nervous system Cholinergic Adrenergic Peptidergic Oxynticopeptic Secretion Elasmobranchs Teleosts Amphibians Reptiles Birds

a b s t r a c t The autonomic nervous system together with circulating and local hormones control secretion from glands. This article summarizes histochemical and functional studies on the autonomic innervation and control of secretory glands in non-mammalian vertebrates, including secretion of saliva in the mouth and gastric acid in the stomach, secretion of enzymes and bicarbonate from the pancreas and gut wall, secretion of mucus in the gut epithelium and onto the skin, and salt secretion from salt glands and rectal glands. Cholinergic and adrenergic nerves, directly or indirectly, in combination with different types of peptidergic and other nerves appear to innervate gland tissues and affect secretion in all investigated species. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . Secretion of saliva . . . . . . . . . . . . . . . . . Secretion of gastric acid and pepsinogen . . . . . . . 3.1. The oxynticopeptic cell . . . . . . . . . . . . 3.2. Basal levels of gastric acid secretion . . . . . . 3.3. Feeding and gastric acid secretion. . . . . . . 3.4. Neurohormonal control of gastric acid secretion 3.5. Pepsin/pepsinogen secretion . . . . . . . . . 4. Secretion of bicarbonate from stomach and intestine . 5. Secretion from the pancreas . . . . . . . . . . . . . 5.1. Autonomic innervation of the pancreas . . . . 6. Secretion of mucus . . . . . . . . . . . . . . . . . 6.1. Secretion of gut mucus . . . . . . . . . . . . 6.2. Secretion of skin mucus . . . . . . . . . . . 7. Salt secretion . . . . . . . . . . . . . . . . . . . . 7.1. Secretion from reptile and avian salt glands . 7.2. Secretion from the elasmobranch rectal gland 8. Concluding remarks. . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . .

⁎ Corresponding author. Tel.: + 46 317863672. E-mail address: [email protected] (S. Holmgren). 1566-0702/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2010.10.008

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

103 102 103 103 103 104 104 104 105 106 106 107 107 107 107 108 108 109 109 110

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

103

1. Introduction Most secretory events in a vertebrate are associated with the gastrointestinal canal and with the processing of food. This includes secretion from the salivary glands in the mouth, from mucous glands all along the gut, from oxyntic and peptic gastric glands, from the pancreas and from small glands in the intestinal wall. The glands are all controlled by multiple factors with the autonomic nervous system playing a prominent part. Secretion of mucus in the airways or onto the skin, tears, sweating and secretion of wax are other secretory mechanisms involving the autonomic nervous system. The “thumb rule” for autonomic control of secretory mechanisms is that parasympathetic pathways, in particular cholinergic nerves, stimulate secretion. Sympathetic, adrenergic pathways mainly have their effect through regulation of the blood flow through the glandular tissue (see Sandblom and Axelsson, 2010—this volume, for control of circulation by the autonomic nervous system). Peptidergic transmitters and cotransmitters, as well as nitrergic and possibly purinergic nerves are involved in the control to different degrees, as are several circulating or locally released hormones. In the gut, activities in the enteric nervous system are tightly integrated in the control mechanisms. Our knowledge of the control mechanisms is based on the mammalian systems, and with few exceptions, the information on non-mammalian vertebrates is scattered and patchy. Also, the distinction between the parasympathetic and sympathetic systems is not as clear in non-mammalian vertebrates as in mammals, with no distinct parasympathetic outflow from the sacral region of the spinal cord (see Nilsson, 2010—this volume). Different aspects on gut secretion and its control in non-mammalian vertebrates have been previously reviewed by Smit (1968), Jönsson (1994) and Holmgren and Holmberg (2005). The aim of this text is to update available information on the involvement of the autonomic nervous system in the control of non-mammalian secretory systems, stressing similarities and differences in the control systems. However, there are still too wide gaps in our knowledge to allow more than speculations on evolutionary trends.

Fig. 1. Schematic picture of the control of secretion from salivary glands in an amphibian. Note the differential effect of cholinergic and adrenergic drugs on secretion of a watery fluid (right half of figure) and exocytosis of electron-dense vesicles (enzyme, protein-containing; left half of figure), respectively. The two secretion mechanisms also show different sensitivities to tachykinins. ACh, acetylcholine; Adr, adrenergic drugs; Ele, eledoisins; NKA, neurokinin A; Phy, physalaemin; SP, substance P; TK, tachykinin). Compiled from results of studies on the Tokyo Daruma frog, Rana porosa porosa by Iwasaki et al., 1997, 1998.

(demonstrated as a reduction in the volume of cytoplasm), while adrenergic stimulation with both an α-adrenergic (phenylephrine) and a β-adrenergic (isoprenaline) agent causes exocytosis of electrondense granules (presumably proteins). All effects were blocked by an appropriate specific antagonist. In a further study, it was shown that tachykinins also may stimulate saliva secretion. Interestingly, the more generally occurring neuronal tachykinins substance P and neurokinin A (NKA) mainly evoke a secretion of salivary fluid, while the amphibian skin tachykinins physalaemin or the cephalopod peptide eledoisin both were more potent in causing exocytosis of electron-dense granules. Like in mammals, the effect of substance P and NKA mimicked that of cholinergic drugs (Iwasaki et al., 1998; Fig. 1).

2. Secretion of saliva 3. Secretion of gastric acid and pepsinogen Saliva is a watery solution of electrolytes, enzymes and antibacterial substances, secreted into the mouth cavity from salivary glands. Secreted saliva also contains mucus (for secretion of mucus from salivary glands and other glands along the gut, see Section 6). Salivary glands are found in all terrestrial vertebrate groups. In addition to important functions in lubricating the food, and initial enzymatic digestion, saliva plays a role in taste, vocalisation and buffering pH in the mouth cavity. In its extreme, saliva may be used for capturing food (the sticky tongue of a woodpecker), making nests (swifts and swallows) or killing—the poison glands of snakes are modified labial salivary glands (Tucker, 2007). Anatomically, the salivary glands in the mouth region of nonmammalian tetrapods are innervated by cranial (parasympathetic) pathways running in branches of the facial nerve (VII) and to some extent the glossopharyngeal (IX) cranial nerve (see Nilsson, 1983; Gibbins, 1994). Spinal (sympathetic) fibres running in the sympathetic chains may join the cranial nerves and innervate the glands. Very little is known of the regulatory mechanisms in the control of salivary secretion in non-mammals. The innervation is presumably cholinergic with an adrenergic component, similar to mammals. In a series of light and electron microscopy experiments on salivary glands from amphibian Rana species, Iwasaki and coworkers demonstrate that secretion from lingual glands (and lingual epithelium) can be elicited both with cholinergic and adrenergic agents (e.g. Iwasaki et al., 1997, using the Tokyo Daruma frog, Rana porosa porosa; Fig. 1). Similar to mammals, cholinergic stimulation causes a release of fluid

Gastric acid and pepsinogen are, together with mucus, the dominating secretory products of the vertebrate stomach. Secretion of gastric acid is almost the only secretory mechanism in the gut where comparative studies of non-mammalian vertebrates have been performed to some extent. The secretion of gastric acid is under control of the autonomic nervous system, but as with all other mechanisms of the gut, there is a close interaction between neuronal and local hormonal (endocrine and paracrine) signals to achieve a proper balance in the secretion of acid. In addition to the summary of the control of acid secretion, a short report on what little is known of the control of secretion of pepsinogen from the gut wall is included. 3.1. The oxynticopeptic cell In most non-mammalian vertebrates, so called oxynticopeptic cells secrete both gastric acid and pepsinogen. This was originally determined by classical histochemical methods (Bishop and Odense, 1966; Mattisson and Holstein, 1980; Ezeasor, 1981; Garrido et al., 1993; Gallego-Huidobro and Pastor, 1996). A more recent study in winter flounder, Pseudopleuronectes americanus, using in situ hybridization with RNA probes for two pepsinogen genes and one proton pump gene (indicating the ability to secrete acid) confirms the occurrence of oxynticopeptic cells (Gawlicka et al., 2001). The cells are found in tubular gastric glands in the mucosa, most often in the anterior (cardiac or fundic) part of the stomach (Bishop and Odense,

104

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

1966; Mattisson and Holstein, 1980; Ezeasor, 1981; Garrido et al., 1993; Gallego-Huidobro and Pastor, 1996). This is in contrast to mammals, where separate cells secrete gastric acid (parietal cells) and pepsinogen (chief cells) from glands in distinct areas of the stomach mucosa (Helander, 1981; Koelz, 1992). Of course there are exceptions: not all non-mammalian species, e.g. the elasmobranch shark, Hexanchus griseus, have oxynticopeptic cells, and some others, such as the Atlantic stingray, Dasyatis sabina, may secrete acid from a mixture of purely oxyntic and oxynticopeptic cells (Michelangeli et al., 1988; Smolka et al., 1994). Differences in type and distribution of acid secreting cells may occur even between closely related species. For example, while in H. griseus gastric acid and pepsinogen are secreted from separate cells (Michelangeli et al., 1988), the gastric glands in another elasmobranch shark, Halaelurus chilensis, contain one form of secretory cells only, with a typical oxynticopeptic structure (Rebolledo and Vial, 1979). In the Eurasian toad, Bufo viridis, there seems to be a gradual transition from cells containing a larger amount of pepsinogen granulae in the oral region of the gastric mucosa to cells with less pepsinogen granulae more aborally (Liquori et al., 2002). The extension of the acid secreting mucosa also varies. In the Atlantic cod, Gadus morhua, it is confined to the stomach with a distinct border to the oesophagus (Bishop and Odense, 1966), while in the rainbow trout, Oncorhynchus mykiss, gastric type glands spread into the distal part of the oesophagus (Ezeasor, 1984). Often, they are restricted to the cardiac part of the stomach, as in gilthead seabream, Sparus aurata, and common seabream, Pagrus pagrus (Elbal and Agulleiro, 1986; Darias et al., 2005), but in the Senegalese sole, Solea senegalensis, the gastric glands were found in the fundic and pyloric regions of the stomach (Arellano et al., 2001). Stomachless fish such as cyclostomes, chimaeras, lungfish, cyprinids (carp fish) and labrids (wrasses), but also monotremes (platypuses and echidnas) lack an acid secreting mucosa (e.g. Koelz, 1992). 3.2. Basal levels of gastric acid secretion To keep a low pH in the stomach also between meals, in many species there is a more or less continuous, low level of basal gastric acid secretion, and an interdigestive pH of 0.8–2.0 has been measured in species representing sharks, rays, crocodiles, lizards, tortoises, birds and mammals (Sullivan, 1905–1906; Dobreff, 1927; Smit, 1968). The gastric pH in teleost species in general seems to be higher and vary more, with measured values ranging from below 4 to 7.0 (e.g. Yúfera et al., 2004; Darias et al., 2005; Yúfera and Darías, 2007). This might be correlated to the preferred diet of the animal; a lower pH would be beneficial for carnivores, allowing an effective conversion of pepsinogen to pepsin, which initiates protein metabolism in the stomach (Chakrabarti et al., 1995). Gastric acid secretion in vivo in Atlantic cod, which are unfed for a week, is almost abolished by vagotomy, suggesting that basal acid secretion is controlled largely by a vagal tonus (Holstein and Cederberg, 1980) as in mammals (e.g. Bank et al., 1967). Similarly, basal secretion is suggested to be under vagal control in chicken (Burhol, 1973b). 3.3. Feeding and gastric acid secretion Food intake normally increases gastric acid secretion. This was observed in an elasmobranch species already in 1905 (Sullivan, 1905–1906), and has been repeatedly confirmed in other nonmammalian vertebrates (e.g. Moriarty, 1973; Norris et al., 1973; Maier and Tullis, 1984; Mosher and Duke, 1985; Deguara et al., 2003). Autonomic pathways are probably involved in all the types of reflexes controlling acid secretion that are elicited by food intake. In mammals, three phases of secretion are defined: 1) A cephalic phase, triggered by visual, olfactory, auditory stimuli and even the

anticipation of food. The signals reach the stomach via the vagus nerve. 2) A gastric phase, comprising local and extrinsic reflexes, caused by distension of the oesophagus and stomach wall, by components in the food, or by a high pH in the stomach. 3) An intestinal phase initiated by the entry of food into the duodenum. The presence of the involved reflexes in non-mammalian vertebrates has not been systematically investigated, but a cephalic phase in the control of acid secretion may exist at least in some birds; it has been shown in ducks and great horned owls that the sight of food increases gastric acid secretion. Other birds, like domestic turkeys, chicken, and red-tailed hawk do not show this reflex (Smit, 1968; Mosher and Duke, 1985). Trained ducks may also secrete gastric acid on a signal in anticipation of food (Smit, 1968). Indications of a gastric phase have been obtained in fish and amphibians, where distension of the stomach wall initiates secretion (Smit, 1968). A feedback mechanism reduces the secretory rate in the Atlantic cod stomach mucosa when luminal pH is lowered (Bomgren and Jönsson, 1996), and similarly a feedback mechanism reduces the secretory rate in the whole fish, in vivo, when a glucose load is administered in the proximal intestine (Holstein and Cederberg, 1980). In neither case, the mediating mechanism is identified. 3.4. Neurohormonal control of gastric acid secretion A vagal (parasympathetic) autonomic control of acid secretion via stimulatory cholinergic pathways might be a general vertebrate feature (e.g. Smit, 1968; Ruoff and Sewing, 1972; Holstein, 1976; Ruiz and Michelangeli, 1984). For example, in the Atlantic cod, as in mammals, vagotomy almost completely abolishes gastric acid secretion, and ganglionic blockade inhibits secretion induced by stimulation of the vagus in chickens (Gibson and Colvin, 1975; Holstein and Cederberg, 1980). Atropine blocks the effect of cholinergic drugs in both elasmobranchs and teleosts, indicating the muscarinic character of the receptors also in these species (Smit, 1968; Holstein, 1977; Holstein and Cederberg, 1980). Furthermore, like in mammals, the histamine H2receptor antagonist metiamide blocks the effect of acetylcholine in cod, suggesting an action at least partly via histamine release (Holstein, 1976). In accordance, Ruiz and Michelangeli (1984) demonstrate that acetylcholine acts both directly on the oxynticopeptic cell and indirectly via histamine release in the bullfrog, Rana catesbeiana (Fig. 2). Actually, all extrinsic input to the parietal cell in mammals, not only the autonomic nerves, seems to act at least in part via histamine release. Histamine is synthesized and stored in enterochromaffin cells situated close to the oxynticopeptic cells in the gastric glands (e.g. Håkanson et al., 1986). Histamine stimulates acid secretion in all species investigated, representing all the major vertebrate groups (except cyclostomes) (e.g. Friedman, 1939; Smit, 1968; Burhol and Hirschowitz, 1970; Ruoff and Sewing, 1972; Holstein, 1976; Ruiz and Michelangeli, 1984), although in elasmobranchs, the effect is comparatively weak, and a mechanism different from that in other vertebrates has been suggested (Hogben, 1967). The effect of histamine on the parietal cell is mediated by H2-receptors in mammals. In accordance with this, while H2-receptor antagonists block or reduce acid secretion in the Atlantic cod, H1 antagonists do not (Holstein, 1976; Bomgren and Jönsson, 1996). Also in bullfrog, the receptors appear to be H2-like (Lin et al., 1986). The mechanism of action of histamine on acid secretion may be well conserved amongst vertebrates, possibly with the exception of (some) elasmobranchs. In addition to acetylcholine and histamine, several other neurotransmitters as well as hormones released from gut endocrine cells are involved in the control of the oxynticopeptic cells. There are numerous histochemical studies showing the presence of putative neurotransmitters and hormones in the vicinity of the oxynticopeptic cells in the mucosa of different vertebrates, with a possible effect on acid secretion (see Olsson and Holmgren, 2010-this volume for the presence of neurotransmitters in the enteric nervous system). Looking at

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

105

Fig. 2. Schematic picture of the control of secretion of gastric acid in teleost fish and amphibians. There are basic similarities in the control, but also distinct differences in details. Excitatory effects are indicated by blue neurons or arrows (for hormones), inhibitory effects are in red. ACh(X), acetylcholine, vagus; BM, bombesin; CCK, cholecystokinin; Gas, gastrin; GRP, gastrin-releasing peptide; Hi, histamine; 5-HT, 5-hydroxytryptamine, serotonin; OP, oxynticopeptic cell; PGE2, prostaglandin E2; Phy, physalaemin; SP, substance P; SST, somatostatin; somatostatin; TK, tachykinin; VIP, vasoactive intestinal polypeptide. For references, see text.

function, hormonal gastrin and neuronal or hormonal gastrin-releasing peptide (GRP) play central roles, but several others may have additional effects, as in mammals (mammals: Dockray, 1999; Lindström et al., 2001). Gastrin was early identified as a stimulator of gastric acid secretion, and results from non-mammalian vertebrates show stimulation in e.g. an amphibian, the bullfrog (Davidson et al, 1966; Ruiz and Michelangeli, 1986), the spiny dogfish, Squalus acanthias (Hogben, 1967; Vigna, 1983) and chicken (Dimaline and Lee, 1990). Surprisingly, the effect in the Atlantic cod is the opposite, i.e. inhibitory on acid secretion (Holstein, 1982). A third mechanism may be operating in the skate, Dasyatis pastinaca, where pentagastrin stimulates gastric secretion in general but apparently not acid secretion since there is no change in intraluminal pH (Zaks et al., 1975). It is possible that evolution has led to different mechanisms in fish compared to tetrapods (Vigna, 1983), but it is also a possibility that the mammalian gastrins, which were used for these studies, do not fit the fish receptors perfectly and therefore may have an antagonistic effect (Jönsson and Holmgren, 1989). It is now known that the effect of gastrin in mammals is mainly by an action on histamine cells (Lindström et al., 2001). Both indirect (via histamine) and direct stimulation of the oxynticopeptic cells are reported in amphibians (Ruiz and Michelangeli, 1986). GRP is a signal substance released either from autonomic nerves or endocrine cells, depending on species. The closely related amphibian skin peptide bombesin shows the same as or even better secretagogue properties than GRP, and is often used in pharmacological experiments. As the name implies, GRP stimulates a release of gastrin, which in most vertebrates would in turn lead to a release of gastric acid. This is for example the case in the chicken (Linari et al., 1975). Similarly, using selective antagonists, it was shown in the turkey that GRP acts via release of gastrin, which in turn acts on gastrin/cholecystokinin (CCK) receptors of a CCKB-like type (Campbell et al., 1994). GRP/ bombesin may also stimulate acid secretion by an action directly on the oxynticopeptic cell, like in the bullfrog (Ayalon et al., 1981). An additional mode of action may be revealed in the Atlantic cod, where gastrin is inhibitory on acid secretion, while bombesin is stimulatory and furthermore does not increase plasma levels of gastrin (Holstein and Humphrey, 1980). Instead, inhibition of an inhibitory VIP tonus is suggested to mediate at least part of the effect of bombesin, since bombesin lowers plasma levels of VIP (Holstein and Humphrey, 1980; Holstein, 1983; Fig. 2). There are not many studies on the inhibitory control of acid secretion in non-mammalian vertebrates. VIP, probably neuronal and thus autonomic, and somatostatin (from nearby endocrine cells)

inhibit histamine-induced secretion in the cod (Holstein, 1983; Holmgren et al., 1986; Fig. 2). Somatostatin also inhibits acid secretion in isolated gastric mucosa from Rana pipiens (Kulkarni et al., 1979). Cholecystokinin is inhibitory on secretion in the Atlantic cod, but stimulates secretion in the bullfrog (Holstein, 1982; Nielsen et al., 1998). The inhibition of secretion caused by adrenergic drugs and stimulation of the sympathetic nervous system in elasmobranchs was suggested to be caused mainly by vasoconstriction (Babkin et al., 1935), and in agreement with that, catecholamine-containing fibres present in the submucosa of the spiny dogfish are mainly perivascular (Holmgren and Nilsson, 1983). An interesting piece of physiological curiosity is the inhibition of acid secretion in the stomach of the gastric brooding frog, Rheobatrachus silus, during larval development, which is suggested to be due to secretion of prostaglandin E2 from the developing larvae (Tyler et al., 1983). 3.5. Pepsin/pepsinogen secretion The first step in protein digestion in the alimentary canal is by pepsin formed from pepsinogen in the acidic milieu of the stomach. Pepsinogen-containing cells have been found in species possessing a stomach from all the major non-mammalian groups (Yasugi, 1987; Yasugi et al., 1988). The cells are usually oxynticopeptic cells in the stomach mucosa (Smit, 1968; Helander, 1981; see section 2.1), secreting both pepsinogen and gastric acid. However, some species have purely peptic cells, secreting pepsinogen only like in mammals, as found in the mucosa of the oesophagus in amphibian species (Simpson et al., 1980) and in the gastric mucosa of the elasmobranch shark, H. griseus (Michelangeli et al., 1988). Feeding induces an increased secretion of pepsinogen from a basic interdigestive level, mediated by different signal substances. The effects of neurotransmitters and hormones on pepsinogen secretion are summarized in Table 1. The vagal, cholinergic stimulatory effect on pepsinogen secretion in mammals is likely to be a combination of a direct effect of vagal fibres on the pepsinogen cells and a simultaneous stimulation of acid secreting cells (Blandizzi et al., 1997). A cholinergic, muscarinic, vagal control of pepsinogen release was early demonstrated in birds in vivo and in situ (Friedman, 1939) and later a corresponding cholinergic control was found in ‘pure’ peptic cells from the oesophagus of bullfrog species (Simpson et al., 1980; Shirakawa and Hirschowitz, 1985; Fong et al., 1991). In contrast, acetylcholine has weak effects only in the Atlantic cod (Holstein and Cederberg, 1984). Similarly, the influence of a spinal innervation and/

106

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

Table 1 Pepsinogen secretion. Summary of neurotransmitters and hormones that influence pepsinogen secretion. ACh is always a neurotransmitter, histamine and gastrin are normally hormones, while the others may be either neuronal or hormonal, or both. Substance

Mammals

Birds

Amphibians

Teleosts

ACh Adr Bombesin/GRP CCK/caerulein Gastrin Histamine Serotonin Somatostatin Tachykinins

+ − + +/0 + +/− 0/− − +

+ 0

+ + (w) +/0 0 0 −

+ 0

+/0 + −/+

−

− (w) + (w) + − (w) +

Legend: +, stimulation; −, inhibition; 0, no effect; (w), weak effect; ACh, acetylcholine (and cholinergic drugs); Adr, adrenaline, noradrenaline (and adrenergic drugs); CCK, cholecystokinin; GRP, gastrin-releasing peptide. For references, see text.

catecholamines both stimulate secretion. Secretion in two amphibian species, bullfrog and mudpuppy (Necturus maculosus), was blocked by atropine in both stomach and intestine, suggesting a cholinergic (probably parasympathetic) stimulatory mechanism like in mammals, while noradrenaline (possibly representing a sympathetic effect) was inhibitory on stomach secretion but excitatory on the intestinal mucosa (Flemström and Garner, 1980; Flemström et al., 1982; Fig. 3). Also a number of endocrine and paracrine agents affected secretion in the amphibians: glucagon was stimulatory in both stomach and intestine, gastric inhibitory peptide (GIP) was inhibitory on stomach secretion and excitatory on the intestine, and CCK stimulated secretion from the gastric mucosa (Fig. 3). However, in contrast to mammals, the amphibian intestinal bicarbonate secretion was unaffected by CCK (Flemström and Garner, 1980; Flemström et al., 1982).

5. Secretion from the pancreas or circulating catecholamines appears to vary. Being inhibitory in mammals, β-adrenergic stimulation increases secretion in bullfrog peptic cells (Shirakawa and Hirschowitz, 1985), but has no measurable effect in pigeon, chicken or the Atlantic cod (Friedman, 1939; Holstein and Cederberg, 1986). Several other presumably autonomic/enteric transmitters and or local endocrine and paracrine substances also affect pepsinogen secretion. For example, tachykinins and serotonin have strong stimulatory effects in the Atlantic cod, in vivo (Holstein and Cederberg, 1984, 1986) and somatostatin inhibits secretion induced by the cholinergic drug bethanechol in the Asian bullfrog Rana tigerina (Fong et al., 1991), and is similarly inhibitory albeit more weakly in the Atlantic cod (Holmgren et al., 1986). Notably, the effect of serotonin is contrary to the effect in rat, where serotonin has little effect on its own and is inhibitory on histamine-induced secretion (Sklyarov et al., 1999). The satiety hormone CCK and its related peptide caerulein stimulate pepsinogen in some birds as in most mammals (Burhol, 1974; Angelucci and Linari, 1970), but have no effect in the bullfrog (Shirakawa and Hirschowitz, 1985). Bombesin stimulates pepsinogen release from bullfrog peptic cells (Shirakawa and Hirschowitz, 1985; Fong et al., 1991). The release mechanisms for gastric acid and pepsinogen, respectively, in many cases show distinct sensitivities to controlling agents. This may allow the oxynticopeptic cells to release gastric acid and pepsinogen separately or in different proportions. For example, pentagastrin stimulates pepsin release more strongly than release of gastric acid in chicken (Burhol, 1973a). On the other hand, the pepsinogen secretion in bullfrog is not stimulated by pentagastrin or histamine (Simpson et al., 1980; Shirakawa and Hirschowitz, 1985), and similarly in teleost species, histamine and carbachol as well as the in fish inhibitory gastrin are more potent on acid secretion (Holstein and Cederberg, 1986; Bomgren et al., 1998). Histamine may even be inhibitory on pepsin secretion in some birds (Friedman, 1939). Furthermore, tachykinins have strong stimulatory effects on pepsinogen secretion but weak effects only on acid secretion in the Atlantic cod (Holstein and Cederberg, 1986).

The pancreas is a compact isolated organ in tetrapode vertebrates, with two types of secretory tissues. Islets of endocrine cells secrete the hormones insulin, glucagon, pancreatic polypeptide and somatostatin to the blood. Acini of exocrine cells in the surrounding tissue secrete bicarbonate and digestive enzymes into a duct system opening in the duodenum/proximal part of the intestine. Amongst fish, a similar compact pancreas is found only in elasmobranchs, while teleosts usually have several aggregates of varying size of endocrine and exocrine cells in the gut mesentery, and even within gut tissues such as intestinal mucosa, liver and adipose tissue. In many teleosts, one or two so called Brockmann bodies, which are large clusters of predominantly endocrine cells, are found (Caruso and Sheridan, in press). Hormones and autonomic nerves interact closely in the control of both endocrine and exocrine secretion from the pancreas. The hormones may be secreted from the intestinal wall after e.g. feeding, like CCK (e.g. Murashita et al., 2007), or may be produced locally. There is a substantial amount of histochemical studies of both mammals and non-mammalian vertebrates, in particular fish species, describing the distribution of ganglion cells, nerve fibres and endocrine cells in the pancreas. All types of neurotransmitters found in the gut (see Olsson and Holmgren, 2010—this volume) seem to be present also in the pancreas. There are also a large number of regulatory substances found within the endocrine cells of the non-mammalian as well as the mammalian pancreas, in addition to the commonly occurring insulin, glucagon, somatostatin and pancreatic peptide (see also Jönsson, 1994 for a detailed account of earlier literature). Comparatively little is known of the effects and mechanisms of action of pancreatic nerves and hormones in non-mammalian vertebrates. In the current text we will concentrate on the non-mammalian pancreas, summarizing the known

4. Secretion of bicarbonate from stomach and intestine Bicarbonate secreted from the stomach mucosa is an important component in the protective mucous barrier, preventing destruction of the mucosa by the acidic milieu in the lumen. Similarly, in the intestine, bicarbonate is needed to neutralize the acid chyme arriving from the stomach, to optimize the effects of secreted enzymes. Bicarbonate secretion is stimulated by a lowered pH in both the stomach and intestine. Parasympathetic as well as sympathetic pathways may be involved in the control in non-mammalian vertebrates as in mammals (e.g. Flemström, 1987; Jönsson, 1994). In mammals, acetylcholine and

Fig. 3. Schematic summary of the control of secretion of bicarbonate from gut mucosa in two amphibian species, bullfrog (Rana catesbeiana) and mudpuppy (Necturus maculosus). Note differences in adrenergic control and GIP control between stomach and intestine. Excitatory effects are indicated by green neurons or arrows (for hormones), inhibitory effects are in red. ACh, acetylcholine; CCK, cholecystokinin; GIP, gastric inhibitory peptide; Gluc, glucagon; HCO− 3 , bicarbonate; NA, adrenergic neuron.

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

effects of neuronal signal substances, along with more recent histochemical findings. 5.1. Autonomic innervation of the pancreas Autonomic nerves and hormones, local or from the gut wall, control the secretory activities of the vertebrate pancreas. The mammalian pancreas is innervated by both vagal and sympathetic pathways, intrapancreatic ganglion cells are common and intrapancreatic nerve nets with cholinergic, adrenergic, serotonergic, GABA-ergic as well as peptidergic fibres are well developed (e.g. Luiten et al., 1986; Adeghate and Ponery, 2003; Furness, 2006). In the non-mammalian pancreas, nerve fibres reach the pancreas in pancreatic nerves following blood vessels to and through the pancreatic tissues (e.g. Trandaburu, 1972, 1974). Intrapancreatic ganglia are present e.g. within the border of the exocrine tissue of the Brockmann bodies in the teleost, Blennius gattorugine (tompot blenny), close also to islet tissue. The ganglia are of different size, containing different numbers of ganglion cells (Putti et al., 2000), and like most enteric nerve cells in fish (Holmgren and Olsson, in press), the pancreatic ganglion cells are unipolar in appearance (Putti et al., 2000). They show immunoreactivity for galanin, oxytocin, peptide YY and glucagon. Intrapancreatic ganglion cells are also found in the chicken (Ohmori et al., 1991; Hiramatsu and Yamasaki, 2009). Although many studies show a dense innervation of pancreatic tissues, some species appear to have a more sparse innervation (Accordi et al., 1998), and the relative importance of nerves versus hormones in the control of pancreatic secretion may vary. There are strong indications of both spinal (sympathetic) and cranial (parasympathetic) autonomic innervations in most vertebrates investigated, with the exception of cyclostomes. For example, in the teleost, Gillichthys mirabilis, pancreatic islets are innervated by vagal fibres and spinal fibres from the celiac ganglion (Patent et al., 1978). The enzyme choline acetyl transferase (ChAT), which is an indicator of synthesis of acetylcholine, is found in the Brockmann body of anglerfish, Lophius americanus, and furthermore the cholinergic agent metacholine stimulates release of insulin, glucagon and somatostatin-14 (Milgram et al., 1991). In the chicken, both tyrosine hydroxylase (TH)-containing (adrenergic) and ChAT-containing (cholinergic) ganglion cells are present, and both adrenergic and cholinergic nerve fibres run along blood vessels, reaching all parts of the pancreatic tissues (Ulas et al., 2003). Acetylcholine stimulates amylase secretion from isolated chicken and duck pancreatic acini (Murai et al., 2000; Wang et al., 2009). It was established in duck that the effect is via a cAMP-independent pathway, in contrast to results from mammals (Wang et al., 2009). Dopamine β-hydroxylase (DBH), another adrenergic enzyme, has been demonstrated in perivascular fibres and fibres associated with glucagon and insulin-cells in Brockmann bodies of Atlantic cod and anglerfish, and adrenergic drugs affect the release of pancreatic hormones in multiple ways (Jönsson, 1991; Milgram et al., 1991). Amongst non-mammalian species, the adrenergic innervation seems well developed, while the cholinergic innervation might be sparser, at least in birds (Trandaburu, 1972, 1974; McAllister and Kendall, 1984: Ulas et al., 2003). Nerves expressing the neuropeptide VIP are common in secretory tissues of vertebrates, and this is also the case in the non-mammalian pancreas. The fibres are observed in all parts of the pancreas: along blood vessel, around acinar cells and ducts of exocrine tissue, running through islets of endocrine tissue and in connective tissue. Intrapancreatic ganglion cells showing VIP-like immunoreactivity are found in e.g. ratfish, Chimaera monstrosa (Yui and Fujita, 1986), and chicken (Hiramatsu and Watanabe, 1989). Chicken VIP (more potent) and mammalian VIP stimulate exocrine secretion in turkey (Dimaline and Dockray, 1979). The chicken pancreas is also innervated by nerves containing the VIP relative PACAP (pituitary adenylate cyclase-activating

107

polypeptide). The distribution of the fibres suggest that PACAP is involved in the control of secretion from endocrine insulin and somatostatin cells in B-islets, secretion from exocrine tissues around the secretory ducts and local blood flow (Hiramatsu and Yamasaki, 2009). In duck isolated pancreatic acini, VIP and PACAP both increase the potency of CCK (acting on CCK1-like receptors) to stimulate amylase secretion, by an action via VPAC-like receptors (Xiao and Cui, 2004). In the (European) common frog, Rana temporaria, a few perivascular nerve fibres containing an NPY-like peptide are found (McKay et al., 1992). Similarly, in chicken and in domestic duck, Anas platyrhynchos platyrhynchos, a few NPY-fibres only are found in pancreatic tissues (Ding et al., 1997; Lucini et al., 2000). A neuronal NPY-like peptide is also present in e.g. anglerfish pancreas (Noe et al., 1986). In addition, NPY is often found in pancreatic endocrine cells. In rainbow trout, where so far NPY has been found only in endocrine cells in the pancreas, NPY modulates the release of somatostatins from Brockmann bodies (Jönsson, 1991; Barton et al., 1992; Eilertson et al., 1996). In the domestic duck, NPY coexists with insulin in endocrine islet cells, and it is speculated that NPY has a role in controlling the effects of insulin on blood glucose levels, which are comparatively high in chicken (Lucini et al., 2000). 6. Secretion of mucus 6.1. Secretion of gut mucus A layer of mucus covers and protects the gut mucosa. It consists of glycoproteins, water, macromolecules, electrolytes, cells and microorganisms. Together with bicarbonate (HCO− 3 ) the mucus layer forms a protective barrier, preventing acid and lytic enzymes in the gut lumen from destroying the underlying mucosal epithelium. The effect of this barrier has been studied in bullfrog: at a stage when the luminal pH was 3.0–3.5, the pH between the mucus layer and the epithelium was 6.5 (Takeuchi et al., 1983). Mucus is also important in creating a defence barrier against bacteria, virus and their toxins. In addition to its protective functions, mucus also acts as a lubricant, and it may also be used for prey capture in certain species. Mucin is the gel-forming glycoprotein in mucus. It is produced in and secreted from specialized mucous cells either present in glands, e.g. salivary glands and gastric pits, covering more or less the whole inner surface as in the stomach, or as solitary cells (goblet cells) in the mucosal epithelium of the intestine. Also general epithelial cells may secrete mucins along the gut. The type of mucin varies, depending on the production site and the diet (e.g. Loo and Swan, 1978; Ferri et al., 2001; Scillitani et al., 2008). Studies in mammals show enteric nerves in the vicinity of mucous cells, and cholinergic drugs, bombesin/GRP, VIP, and CCK may evoke mucin secretion from different regions of the gut (e.g. Neutra et al., 1982; Brown et al., 1993; Plaisancié et al., 1998). Information on the autonomic control of mucus secretion in non-mammalian species is utterly scarce. Mucus secretion from the palate of the frog, R. pipiens, is increased by electrical stimulation of the glossopharyngeal nerve (IX) or the palatine nerve (a branch of the facial nerve (VII)). The effect is mimicked by cholinergic agonists and blocked by muscarinic cholinergic antagonists, like in mammals (Slaughter and Aiello, 1982). In the stomach of the European common frog, adrenaline reduces the thickness of the mucosal layer, while cholinergic agonists increase the thickness (Keogh et al., 1997). 6.2. Secretion of skin mucus The most obvious secretions from the skin are sweating in mammals and the production of a mucus layer in fish and amphibians. Sweating is controlled by the autonomic nervous system. However,

108

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

sweating is also a function restricted to mammals, and the mechanisms for its control will not be further discussed here. Fish and amphibians secrete a number of different substances into a mucus layer covering the skin more or less completely. The main components of the mucus layer are mucins (glycoproteins) secreted from epithelial cells, in particular from goblet cells. Most species have a continuous basal secretion of mucins, forming a more or less continuous protective mucous layer on the skin. In addition, feeding or stressful stimuli may initiate a secretion of extruded slime, such as the copious slime production from myxinoid cyclostomes (Shephard, 1994; Subramanian et al., 2008). It has been suggested that the mucous cells of the fish skin lack an autonomic innervation (Gibbins, 1997). However, a special type of neurons, which might be considered autonomic although they lack the characteristic ganglionic synapse in the pathway to the effector, is the supramedullary cells found in some teleosts. These giant neurons are located on the dorsal surface of the spinal cord, and project their axons through the dorsal spinal root to the fish skin (Bennett et al., 1959; Barry et al., 1986). It has been shown in several teleost species that the supramedullary cells express a gastrin/CCK-like peptide, and in the pufferfish, Takifugu niphobles, there is also a dense innervation of mucous gland cells by gastrin/CCK-immunoreactive fibres (Benedetti and Mola, 1988; Benedetti et al., 1993; Funakoshi et al., 1998). It was concluded as likely that the supramedullary cells innervate the skin mucous gland cells. The exact effects of the nerves are so far unknown, but it was proposed that one mechanism might be through axon reflexes, where one branch of an axon causes release of transmitter from another branch. This was based on the observation that free nerve endings in the skin showed the same chemical coding as fibres innervating the mucus producing cells (Funakoshi et al., 1998). More recently it has been demonstrated by immunohistochemistry that the same cells in the wrasse Coris julis and in the pufferfish Tetraodon fluviatilis contain synthesizing hormones for noradrenaline and adrenaline (Mola et al., 2002; Mola and Coughi, 2004) and the supramedullary cells in the pufferfish furthermore contain nitric oxide synthase (NOS) (Coughi et al., 2002). With these findings, it was proposed that the cells are truly sympathetic (spinal), with coexisting adrenergic, peptidergic (gastrin/CCK) and nitrergic transmitters (Mola and Coughi, 2004). In amphibians, it is well established that sympathetic autonomic pathways innervate the skin (for a more extensive review, see Gibbins, 1997). Catecholamine-containing fibres surround cutaneous mucous glands (and poison glands!). Similar to the situation in mammals, the secretomotor neurons have larger cell bodies than vasomotor neurons, and lack the coexisting NPY and galanin (see Gibbins, 1997 for references). The innervation seems primarily to reach myoepithelial cells surrounding the mucus secreting cells in the glands, and contraction or relaxation of the myoepithelial cells presumably determine the secretory rate from the mucous cells (Skoglund and Sjöberg, 1977b). Released transmitters may also reach the mucus producing cells themselves, stimulating secretion in a paracrine mode of action. Even low stimulation rates in the sympathetic nerves cause resistance changes in a skin preparation indicating an increased secretion, and the effect is probably mediated by beta-adrenoceptors. Also, application of substance P increased contraction of the myoepithelial cells and secretion (Skoglund and Sjöberg, 1977a,b). 7. Salt secretion In addition to the general ability to secrete ions by kidneys and the gut, a number of vertebrate species that are exposed to an extra salt load also have extra possibilities to secrete salt from the body, mainly in the form of sodium and chloride ions. Many teleost species thus have chloride cells on their gills or opercula, which in marine fish excrete salt (for references see e.g. Evans et al., 2005). Marine elasmobranchs, reptiles and birds have proper salt-secreting glands, which are inactive

until stimulated by a salt load, for example from eating or drinking marine prey and water. In elasmobranchs, NaCl is secreted by an unpaired gland, the rectal gland, in the mesenterium dorsal to the posterior intestine. Marine birds and turtles have a pair of flat, crescentshaped salt glands close to the eyes, the supraorbital glands, which excrete extra salty “tears” (Fänge et al., 1958a; Schmidt-Nielsen and Fänge, 1958). Marine lizards may have nasal glands that empty into the nasal cavity, where the fluid is prevented from running backwards and being swallowed by a ridge structure (Schmidt-Nielsen and Fänge, 1958). Some marine snakes have an extra efficient ion extrusion from their salivary glands. In estuarine Crocodylus species, lingual salt glands excrete hyperosmotic fluid (Taplin and Grigg, 1981; Taplin et al., 1982; Grigg et al., 1986). 7.1. Secretion from reptile and avian salt glands The secretory cells, the collecting ducts and the blood vessels of salt glands are densely innervated by cranial autonomic (parasympathetic) fibres. In the herring gull, Larus argentatus, secretion from the orbital gland was evoked only by stimulation of a branch of the cranial nerve VII (facial nerve) passing through the ethmoidal ganglion in the orbital cavity, although several other nerve branches were seen entering the ganglion. The effect was muscarinic cholinergic (Fänge et al., 1958b). Subsequent studies suggest that a cholinergic component in the stimulatory control of the salt gland is a general feature, and there is also evidence of an adrenergic innervation of both gland tissue and vessels (for references see Gerstberger and Gray, 1993; Cramp et al., 2007). The main stimulus for increased secretion is activation of central osmoreceptors, but volume receptors or peripheral osmoreceptors may have additive effects. The osmoreceptors in turn activate the autonomic secretory nerves, releasing acetylcholine. Acetylcholine acts on a type of muscarinic receptors showing both M1 and M3 characteristics. Receptor stimulation leads to activation of a Gqprotein, formation of phospholipase C (PLC), and finally increased levels of cytoplasmatic Ca2+ (see Shuttleworth and Hildebrandt, 1999 for references). The cholinergic muscarinic receptors mediate both acute and long-term responses to stimulation, i.e. secretion and proliferation, respectively, depending on the strength and duration of the salt load (Shuttleworth and Hildebrandt, 1999). More recent studies using immunohistochemistry, add a peptidergic component to the innervation. VIP-immunoreactive neurons are found near both secretory tubules and arterioles; indeed, VIP and ACh appear to coexist in and be co-released from the same nerve endings (Lowy et al., 1987; Gerstberger, 1988; Franklin et al., 1996). Binding sites for VIP are demonstrated in the salt gland tissues. It is also found that VIP, like acetylcholine, stimulates both secretion and flow from the gland (Gerstberger et al., 1988; Franklin et al., 1996). The commonly coexisting neuropeptide PACAP is demonstrated in lingual glands of the estuarine crocodile, Crocodylus porosus, but whether VIP and PACAP have distinct effects on the crocodile salt secretion like on secretion of saliva in e.g. ferret salivary glands (Tobin et al., 1995), remains to be elucidated. In addition, substance P/NKA- and CGRP (calcitonin generelated peptide)-immunoreactive neurons are present in the estuarine crocodile. It is worth noting that acclimation of the euryhaline crocodile to sea-water leads to a reduction in innervation density of SP/NKA and PACAP-immunoreactive neurons (Cramp et al., 2007). The presence of NOS in salt gland neurons has been established by NADPH-diaphorase staining in the Peking duck and by using antibodies on the lingual salt glands of the estuarine crocodile (Hübschle et al., 1995; Cramp et al., 2007). Interestingly, the salt-secreting lachrymal gland of another euryhaline species, the turtle Malaclemys terrapin, appears devoid of a cholinergic innervation; both pharmacological and histochemical studies have failed to show a cholinergic control of secretion. This would be a very unusual feature, and it was speculated that it could be

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

109

due to several related reasons: the turtle being euryhaline, the fact that in this particular species the gland acts as both truly lachrymal (producing tears to moisten the eye) and as a salt gland, the low secretory rate of the gland, etc. (Belfry and Cowan, 1995). Instead, secretion appears to be controlled mainly by neurons showing both VIP-like and NPY-like immunoreactivity, which innervate both acini and ducts of the gland. Distinct populations of NPY-immunoreactive and DBH-immunoreactive (i.e. adrenergic/noradrenergic) fibres innervate local arterioles, and may be important in controlling the blood flow within the gland (Belfry and Cowan, 1995). 7.2. Secretion from the elasmobranch rectal gland The rectal gland of elasmobranchs (and the coelocanth Latimeria) is a small distinct cylindrical organ built of secreting cells facing a system of collecting ducts, which finally join and open into the posterior part of the intestine. The mass of secretory cells is surrounded by a layer of smooth muscle and outermost a capsule of connective tissue (Evans and Piermarini, 2001). The gland increases the capacity of the fish to deal with the hyperosmolarity in the blood caused by the presence of urea. The solution secreted by the rectal gland of the spiny dogfish, e.g., is of about twice the osmolarity as the blood plasma (Burger and Hess, 1960). For a detailed review on the structure and function of the rectal gland, see Olson (1999). The predominant initial stimulus to increase secretion from the gland seems to be the increase in central venous plasma volume after a salt load. Possibly also volume receptors within the rectal gland itself are involved in the control of the gland (Evans and Piermarini, 2001). This activates hormonal as well as neuronal control systems. Although circulating agents such as scyliorhinin II and natriuretic peptides may be dominating, autonomic nerves clearly play an important part in this control (Olson, 1999). Immunohistochemistry has e.g. demonstrated the presence of networks of nerve fibres showing VIP-, gastrin/ CCK-, somatostatin, and GRP/bombesin-like immunoreactivity throughout the gland (Holmgren and Nilsson, 1983; Chipkin et al., 1988; Stoff et al., 1988; Yui et al, 1990; Masini et al., 1994). The most potent stimulator of secretion from the rectal gland is the tachykinin scyliorhinin II (initially called rectin before it was fully sequenced), probably acting as a hormone (Shuttleworth and Thorndyke, 1984; Thorndyke and Shuttleworth, 1985; Anderson et al., 1995). Scyliorhinin II has been isolated from the gut wall of lesser spotted dogfish, Scyliorhinus canicula (Anderson et al., 1995), and since tachykinin immunoreactivity is found in numerous endocrine cells of the intestine and rectum in the spiny dogfish, but not in the rectal gland (Holmgren and Nilsson, 1983). Anderson et al. (1995) suggested that food (containing a salt load) reaching the intestine would release scyliorhinin II to the blood, thus activating secretion from the rectal gland. In the spiny dogfish, secretion from the gland can, in addition, be stimulated by VIP (Stoff et al., 1979), which is present in a dense network of nerve fibres in the rectal gland. Part of this effect could possibly be attributed to an increase in blood flow through the gland caused by fibres surrounding the vessels (Holmgren and Nilsson, 1983; Thorndyke et al., 1989), but VIP-fibres are found near the glandular cells and VIP also binds to the gland cells (Silva et al., 1985; Fig.4). The action of VIP is via shark-specific VIP receptors (Bewley et al., 2006) causing an increase in the intracellular levels of cAMP. Somatostatin, which is present in rectal gland nerves (Holmgren and Nilsson, 1983), inhibits VIP-induced increase in (chloride) secretion, by inhibiting the formation of cAMP when VIP binds to its receptors (Silva et al., 1985). Bombesin, in turn, may release somatostatin from the nerve terminals, thus causing an indirect inhibition of the secretion (Silva et al., 1990). NPY, which similarly is inhibitory on provoked secretion, on the other hand appears to have a direct action on the gland cells at a site distal to the formation of ATP (Silva et al., 1993).

Fig. 4. Schematic picture of the autonomic nervous control of secretion from the elasmobranch rectal gland. In addition, scyliorhinin II and natriuretic peptide have dominating hormonal effects. The innervation of vessels and its effects on blood flow and indirectly on secretion rate is not shown. Ado, adenosine; BM/GRP, bombesin/ gastrin-releasing peptide; gl, gland cell; NPY, neuropeptide Y; SST, somatostatin; VIP, vasoactive intestinal polypeptide. For references, see text.

Adenosine, possibly released from purinergic nerves, is inhibitory on secretion from the rectal gland in spiny dogfish, acting through adenosine A1-receptors via a cAMP-independent mechanism (Kelley et al, 1990, 1991). There are thus distinct differences in the control of the elasmobranch rectal gland in comparison to the salt glands of reptiles and birds. Volume receptors are the important sensors of a salt load in elasmobranchs, while osmoreceptors are the predominant sensory units in reptiles and birds. In reptiles and birds, neuronal pathways exert the dominating control, and hormonal effects might be modulatory, while the situation appears to be opposite in elamobranchs. Finally, the predominant second messenger systems activated seems to be PLC in birds and cAMP in elasmobranchs. 8. Concluding remarks In can be concluded that autonomic pathways are involved in the control of most if not all secretory cells and glands, either directly or through the control of blood flow through the secreting tissue. It must, however, be emphasized that hormonal mechanisms are as important or even dominating in the control of most glands. As outlined in the introduction, a stimulatory control of secretion via cholinergic cranial autonomic pathways, has been established wherever it has been looked for. Spinal, adrenergic pathways may have their effect mainly through regulation of the blood flow. A large number of other transmitters have been demonstrated in glandular tissue or in the enteric plexa, using immunohistochemistry, and many of these have also been found to control secretion in experimental conditions. These include e.g. VIP, tachykinins, bombesin/GRP, NPY and somatostatin. Although there are large general similarities in the control of secretion from glands and glandular cells throughout vertebrates, such as cholinergic autonomic pathways that stimulate secretion, there are several notable differences in the detailed mechanisms of actions. The expression of different subtypes of receptors may lead to different effects on secretion in different tissues of the same animal. This is a common feature when adrenergic mechanisms are involved, such as the stimulatory effect of noradrenaline in the stomach and inhibitory effect in the intestine on secretion of bicarbonate from the epithelium. Another intriguing example is the differential secretion of watery or enzyme-rich saliva by activation of different subtypes of tachykinin receptors with distinct affinities for different tachykinins.

110

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

Substances that are stimulatory in most vertebrates may be inhibitory in some species, indicating either the expression of a different type of receptor, a different site of action or involvement in a different chain of signals. For example, GRP, neuronal in many species and hormonal in others, stimulates the release of gastrin as the name indicates in mammals and birds, but has a direct stimulatory effect on oxynticopeptic cells in the investigated amphibian species, and an inhibitory effect via inhibition of VIP release in the Atlantic cod. The occurrence of such divergences is more or less unpredictable, and must be kept in mind when generalisations are made about large animal groups where only few species have been investigated. It is impossible at the time being to speculate on evolutionary trends, since available information is scattered and seldom involves systematic investigation of any features over several animal groups.

References Accordi, F., Bracci, M.A., Ventola, F., 1998. Pancreatic endocrine cells in Bufo bufo: immunocytochemistry and ultrastructure. J. Anat. 192, 195–202. Adeghate, E., Ponery, A., 2003. Pancreatic peptides, neuropeptides and neurotransmitters in diabetes mellitus: a review. Int. J. Diab. Metab. 11, 1–6. Anderson, W.G., Conlon, J.M., Hazon, N., 1995. Characterisation of the endogenous intestinal peptide that stimulates the rectal gland of Scyliorhinus canicula. Am. J. Physiol. 268, 1359–1364. Angelucci, L., Linari, G., 1970. The action of caerulein on gastric secretion of the chicken. Eur. J. Pharmacol. 11, 204–216. Arellano, J.M., Storch, V., Sarasquete, C., 2001. Histological and histochemical observations in the stomach of the Senegal sole, Solea senegalensis. Histol. Histopathol. 16, 511–521. Ayalon, A., Yazigi, R., Devitt, P.G., Rayford, P.L., Thompson, J.C., 1981. Direct effect of bombesin on isolated gastric mucosa. Biochem. Biophys. Res. Commun. 99, 1390–1397. Babkin, B.P., Friedman, M.H.F., Mackay-Sawyer, M.E., 1935. Vagal and sympathetic innervation of the stomach of the skate. J. Biol. Board Can. 1, 239–250. Bank, S., Marks, I.N., Louw, J.H., 1967. Histamine- and insulin-stimulated gastric acid secretion after selective and truncal vagotomy. Gut 8, 36–41. Barry, M.A., Weiser, M., Baker, R., Bennett, M.V.L., 1986. Comparative organization of supramedullary neurons in toadfish, spiny boxfish, and puffer. Biol. Bull. 171, 490–491. Barton, C.L., Shaw, C., Halton, D.W., Johnston, C.F., Buchanan, K.D., 1992. Distribution and characterization of neuropeptide-Y immunoreactivity in the brain and gastrointestinaltract of the rainbow-trout, Oncorhynchus mykiss. Comp. Biochem. Physiol. 103C, 175–180. Belfry, C.S., Cowan, F.B.M., 1995. Peptidergic and adrenergic innervation of the lachrymal gland in the euryhaline turtle, Malaclemus terrapin. J. Exp. Zool. 273, 363–375. Benedetti, I., Mola, L., 1988. Survey of neuropeptide-like immunoreactivity in supramedullary neurons of Coris juris (L.). Brain Res. 449, 373–376. Benedetti, I., Mola, L., Marini, M., Calzolari, C., 1993. Neuroanatomical and immunohistochemical studies on the dorsal neurons in the spinal cord of Trigla lucerna L. and Scorpaena porcus L. (Scorpaeniformes). Ann. Anat. 175, 77–80. Bennett, M.V.L., Crain, S.M., Grundfest, H., 1959. Electrophysiology of supramedullary neurons in Spheroides maculatus. I. Orthodromic and antidromic responses. J. Gen. Physiol. 43, 159–188. Bewley, M.S., Pena, J.T., Plesch, F.N., Decker, S.E., Weber, G.J., Forrest Jr., J.N., 2006. Shark rectal gland vasoactive intestinal peptide receptor: cloning, functional expression, and regulation of CFTR chloride channels. Am. J. Physiol. 291, R1157–R1164. Bishop, C., Odense, P.H., 1966. Morphology of the digestive tract of the Atlantic cod, Gadus morhua. J. Fish. Res. Board Can. 23, 1607–1615. Blandizzi, C., Colucci, R., Carignani, D., Lazzeri, G., Del Tacca, M., 1997. Positive modulation of pepsinogen secretion by gastric acidity after vagal cholinergic stimulation. J. Pharmacol. Exp. Ther. 283, 1043–1050. Bomgren, P., Jönsson, A.-C., 1996. Basal, H2-receptor stimulated and pH-dependent gastric acid secretion from an isolated stomach mucosa preparation of the Atlantic cod, Gadus morhua, studied using a modified pH-static titration method. Fish Physiol. Biochem. 15, 275–285. Bomgren, P., Einarsson, S., Jönsson, A.-C., 1998. Similarities and differences in oxynticopeptic cell ultrastructure of one marine teleost, Gadus morhua, and one freshwater teleost, Oncorhynchus mykiss, during basal and histamine-stimulated phases of gastric acid secretion. Fish Physiol. Biochem. 18, 285–296. Brown, J.F., Keates, A.C., Hanson, P.J., Whittle, B.J., 1993. Nitric oxide generators and cGMP stimulate mucus secretion by rat gastric mucosal cells. Am. J. Physiol. 265, G418–G422. Burger, J.W., Hess, N.W., 1960. Function of the rectal gland in the spiny dogfish. Science 131, 670–671. Burhol, P.G., 1973a. Gastric secretory relationship between H+ and pepsin in fistula chickens. Scand. J. Gastroenterol. 8, 283–288. Burhol, P.G., 1973b. Stimulation by 2-deoxy-D-glucose and inhibition by insulin of gastric secretion in fistula chickens. Scand. J. Gastroenterol. 8, 761–764. Burhol, P.G., 1974. Gastric stimulation by intravenous injection of cholecystokinin and secretin in fistula chickens. Scand. J. Gastroenterol. 9, 49–53. Burhol, P.G., Hirschowitz, B.I., 1970. Single subcutaneous doses of histamine and pentagastrin in gastric fistula chickens. Am. J. Physiol. 218, 1671–1675.

Campbell, B.J., Garner, A., Dockray, G.J., Hughes, J., Dimaline, R., 1994. The mechanism of action of gastrin releasing peptide (GRP) in stimulating avian gastric acid secretion. Regul. Pept. 49, 249–255. Caruso, A.C., Sheridan, M.A., in press. Pancreas. in: Olsson, C., Holmgren, S., Stevens E.D., Farrell A.P. (Eds.), Encyclopedia of Fish Physiology: From Genome to Environment. Chakrabarti, I., Gani, M.A., Chaki, K.K., Sur, R., Misra, K.K., 1995. Digestive enzymes in 11 freshwater teleost fish species in relation to food habits and niche segregation. Comp. Biochem. Physiol. 112A, 167–177. Chipkin, S.R., Stoff, J.S., Aronin, N., 1988. Immunohistochemical evidence for neuronal mediation of VIP activity in the dogfish rectal gland. Peptides 9, 119–124. Coughi, B., Marini, M., Mola, L., 2002. Histochemical and immunohistochemical localization of nitric oxide synthase in the supramedullary neurons in the pufferfish Tetraodon fluviatilis. Brain Res. 938, 1–6. Cramp, R.L., Hudson, N.J., Holmberg, A., Holmgren, S., Franklin, C.E., 2007. The effects of saltwater acclimation on neurotransmitters in the lingual salt glands of the estuarine crocodile, Crocodylus porosus. Regul. Pept. 140, 55–64. Darias, M.J., Murray, H.M., Martínez-Rodrígueza, G., Cárdenasc, S., Yúfera, M., 2005. Gene expression of pepsinogen during the larval development of red porgy (Pagrus pagrus). Aquaculture 248, 245–252. Davidson, W.D., Lemmi, C.A.E., Thompson, J.C., 1966. Action of gastrin on the isolated gastric mucosa of the bullfrog. Proc. Soc. Exp. Biol. 121, 545–547. Deguara, S., Jauncey, K., Agius, C., 2003. Enzyme activities and pH variations in the digestive tract of gilthead sea bream. J. Fish Biol. 62, 1033–1043. Dimaline, R., Dockray, G.J., 1979. Potent stimulation of the avian exocrine pancreas by porcine and chicken vasoactive intestinal polypeptide. J. Physiol. 294, 153–163. Dimaline, R., Lee, C.M., 1990. Chicken gastrin: a member of the gastrin/CCK family with novel structure-activity relationships. Am. J. Physiol. 259, G882–G888. Ding, W.G., Kimura, H., Fujimura, M., Fujimiya, M., 1997. Neuropeptide Y and Peptide YY immunoreactivities in the pancreas of various vertebrates. Peptides 18, 1523–1529. Dobreff, M., 1927. Experimentelle Studien über die vergleichende Physiologie der Verdauung. Arch. Gesamte Psychol. 217, 221–234. Dockray, G.J., 1999. Topical review. Gastrin and gastric epithelial physiology. J. Physiol. 518, 315–324. Eilertson, C.D., Carneiro, N.M., Kittilson, J.D., Comley, C., Sheridan, M.A., 1996. Cholecystokinin, neuropeptide Y and galanin modulate the release of pancreatic somatostatin-25 and somatostatin-14 in vitro. Regul. Pept. 63, 105–112. Elbal, T., Agulleiro, B., 1986. A histochemical and ultrastructural study of the gut of Sparus aurata (Teleostei). J. Submicrosc. Cytol. 18, 335–337. Evans, D.H., Piermarini, P.M., 2001. Contractile properties of the elasmobranch rectal gland. J. Exp. Biol. 204, 59–67. Evans, D.H., Piermarini, P.M., Choe, K.P., 2005. The multifunctional fish gill: dominant site of gas exchange, osmoregulation, acid-base regulation, and excretion of nitrogenous waste. Physiol. Rev. 85, 97–177. Ezeasor, D.N., 1981. The fine structure of the gastric epithelium on the rainbow trout, Salmo gairdneri, Richardson. J. Fish Biol. 19, 611–627. Ezeasor, D.N., 1984. Light and electron microscopic studies on the oesophageal epithelium of the rainbow trout, Salmo gairdneri. Anat. Anz. 155, 71–83. Fänge, R., Schmidt-Nielsen, K., Osaki, H., 1958a. The salt gland of the herring gull. Biol. Bull. (Woods Hole) 115, 162–171. Fänge, R., Schmidt-Nielsen, K., Robinson, M., 1958b. Control of secretion from avian salt gland. Am. J. Physiol. 195, 321–326. Ferri, D., Liquori, G.E., Natale, L., Santarelli, G., Scillitani, G., 2001. Mucin histochemistry of the digestive tract of the red-legged frog Rana aurora aurora. Acta Histochem. 103, 225–237. Flemström, G., 1987. Gastric and duodenal mucosal bicarbonate secretion, In: Johnson, L.R., Christensen, J., Jacobson, E.D., Jackson, M.J., Walsh, J.H. (Eds.), Physiology of the gastrointestinal tract, 2nd ed. Raven Press, New York, pp. 1011–1029. Flemström, G., Garner, A., 1980. Stimulation of gastric acid and bicarbonate secretions by calcium in guinea pig stomach and amphibian isolated mucosa. Acta Physiol. Scand. 110, 419–426. Flemström, G., Heylings, J.R., Garner, A., 1982. Gastric and duodenal HCO-3 transport in vitro: effects of hormones and local transmitters. Am. J. Physiol. 242, G100–G110. Fong, J.C., Hong, S.-J., Wang, F.-F., 1991. Somatostatin inhibits pepsinogen secretion via a cyclic AMP-independent pathway. Regul. Pept. 31, 351–360. Franklin, C.E., Holmgren, S., Taylor, G.C., 1996. A preliminary investigation of the effects of vasoactive intestinal peptide on secretion from the lingual salt glands of Crocodylus porosus. Gen. Comp. Endocrinol. 102, 74–78. Friedman, M.H.F., 1939. Gastric secretion in birds. J. Cell. Comp. Physiol. 13, 219–234. Funakoshi, K., Kadota, T., Atobe, Y., Nakano, M., Goris, R.C., Kishida, R., 1998. Gastrin/ CCK-ergic innervation of cutaneous mucous gland by the supramedullary cells of the puffer fish Takifugu niphobles. Neurosci. Lett. 258, 171–174. Furness, J.B., 2006. The enteric nervous system. Blackwell Publishing. Gallego-Huidobro, J., Pastor, L.M., 1996. Histology of the mucosa of the oesophagogastric junction and the stomach in adult Rana perezi. J. Anat. 188, 439–444. Garrido, M.V.O., Torres, M.I.N., Equisoain, M.A.A., 1993. Histological, histochemical, and ultrastructural analysis of the gastric mucosa in Oncorhynchus mykiss. Aquaculture 115, 121–132. Gawlicka, A., Leggiadro, C.T., Gallant, J.W., Douglas, S.E., 2001. Cellular expression of the pepsinogen and the gastric proton pump genes in the stomach of winter flounder as determined by in situ hybridization. J. Fish Biol. 58, 529–536. Gerstberger, R., 1988. Functional vasoactive intestinal polypeptide (VIP)-system in salt glands of the Pekin duck. Cell Tissue Res. 252, 39–48. Gerstberger, R., Gray, D.A., 1993. Fine structure, innervation and functional control of avian salt glands. Int. Rev. Cytol. 144, 129–215. Gerstberger, R., Sann, H., Simon, E., 1988. Vasoactive intestinal peptide stimulates blood flow and secretion of avian salt glands. Am. J. Physiol. 255, R575–R582.

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112 Gibbins, I.L., 1994. Comparative anatomy and evolution of the autonomic nervous system. In: Burnstock, G. (Series Ed), The Autonomic Nervous System. Nilsson, S., Holmgren, S. (Vol. Eds.) Comparative Physiology and Evolution of the Autonomic Nervous System. Harwood Academic Publisher, Chur, Switzerland pp. 1-67. Gibbins, I.L., 1997. Autonomic pathways to cutaneous effectors. In: Morris, J.L., Gibbins, I.L. (Eds.), Autonomic Innervation of the Skin. Harwood Academic, Amsterdam, pp. 1–56. Gibson, R.G., Colvin Jr., H.W., 1975. Vagal stimulation of gastric secretion in Gallus domesticus. Comp. Biochem. Physiol. 50A, 229–232. Grigg, G.C., Taplin, L.E., Green, B., Harlow, P., 1986. Sodium and water fluxes in free-living Crocodylus porosus in marine and brackish conditions. Physiol. Zool. 59, 240–253. Håkanson, R., Böttcher, G., Ekblad, E., Panula, P., Simonsson, M., Dohlsten, M., Hallberg, T., Sundler, F., 1986. Histamine in endocrine cells in the stomach. A survey of several species using a panel of histamine antibodies. Histochemistry 86, 5–17. Helander, H.F., 1981. The cells of the gastric mucosa. Int. Rev. Cytol. 70, 217–289. Hiramatsu, K., Watanabe, T., 1989. Immunohistochemical study on the distribution of vasoactive intestinal polypeptide (VIP) containing nerve fibres in the chicken pancreas. Z. Mikrosk. Anat. Forsch. 103, 689–699. Hiramatsu, K., Yamasaki, A., 2009. Immunohistochemical study on the innervation of the chicken pancreas by pituitary adenylate cyclase-activating polypeptides (PACAPs)-containing nerves. J. Poult. Sci. 46, 234–239. Hogben, C.A.M., 1967. Response of the isolated dogfish gastric mucosa to histamine. Proc. Soc. Exp. Biol. Med. 124, 890–893. Holmgren, S., Holmberg, A., 2005. Control of gut motility and secretion in fasting and fed nonmammalian vertebrates. In: Starck, J.M., Wang, T. (Eds.), Physiological and Ecological Adaptations to Feeding in Vertebrates. Science Publishers, Enfield, New Hampshire, pp. 325–355. Holmgren, S., Nilsson, S., 1983. Bombesin-, gastrin/CCK-, 5-hydroxytryptamine-, neurotensin-, somatostatin-, and VIP-like immunoreactivity and catecholamine fluorescence in the gut of the elasmobranch, Squalus acanthias. Cell Tissue Res. 234, 595–618. Holmgren, S., Olsson, C., in press. Nervous system of the gut. in: Olsson, C., Holmgren, S., Stevens E.D., Farrell A.P. (Eds.) Encyclopedia of Fish Physiology: From Genome to Environment. Holmgren, S., Jönsson, A.-C., Holstein, B., 1986. Gastrointestinal peptides in fish. In: Nilsson, S., Holmgren, S. (Eds.), Fish physiology — recent advances. Croom Helm Ltd, London, pp. 119–139. Holstein, B., 1976. Effect of the H2-receptor antagonist metiamide on carbachol- and histamine-induced gastric acid secretion in the Atlantic cod, Gadus morhua. Acta Physiol. Scand. 97, 189–195. Holstein, B., 1977. Effect of atropine and SC-15396 on stimulated gastric acid secretion in the Atlantic cod, Gadus morhua. Acta Physiol. Scand. 101, 185–193. Holstein, B., 1982. Inhibition of gastric acid secretion in the Atlantic cod, Gadus orhua, by sulphated and desulphated gastrin, caerulein, and CCK-octapeptide. Acta Physiol. Scand. 114, 453–459. Holstein, B., 1983. Effect of vasoactive intestinal polypeptide on gastric acid secretion and mucosal blood flow in the Atlantic cod, Gadus morhua. Gen. Comp. Endocrinol. 52, 471–473. Holstein, B., Cederberg, C., 1980. Effect of vagotomy and glucose administration on gastric acid secretion in the Atlantic cod, Gadus morhua. Acta Physiol. Scand. 109, 37–44. Holstein, B., Cederberg, C., 1984. Effects of 5-HT on basal and stimulated secretions of acid and pepsin and on gastric volume outflow in the in vivo gastrically and intestinally perfused cod, Gadus morhua. Agents Actions 15, 290–305. Holstein, B., Cederberg, C., 1986. Effects of tachykinins on gastric acid and pepsin secretion and on gastric outflow in the Atlantic cod, Gadus morhua. Am. J. Physiol. 250, G309–G315. Holstein, B., Humphrey, C.S., 1980. Stimulation of gastric acid secretion and suppression of VIP-like immunoreactivity by bombesin in the Atlantic codfish, Gadus morhua. Acta Physiol. Scand. 109, 217–223. Hübschle, T., Körtje, K.H., Gerstberger, R., 1995. Localization of NADPH-diaphorase activity in the salt gland of the saltwater-acclimated Pekin duck. Neurosci. Lett. 24, 163–166. Iwasaki, S., Iwabuchi, Y., Asami, T., 1997. Histological and ultrastructural study of the effects of cholinergic and adrenergic agonists on salivary secretion from the lingual epithelium and the lingual gland of the Tokyo Daruma pond frog. Tissue Cell 29, 323–338. Iwasaki, S., Iwabuchi, Y., Okumura, Y., 1998. Histological and ultrastructural studies of the effects of tachykinins on protein secretion from the lingual epithelium and the lingual gland of the Tokyo daruma pond frog (Rana porosa porosa). Arch. Oral Biol. 43, 463–471. Jönsson, A.-C., 1991. Regulatory peptides in the pancreas of two species of elasmobranchs and in the Brockmann bodies of four teleost species. Cell Tissue Res. 266, 163–172. Jönsson, A.-C., 1994. Glands. In: Nilsson, S., Holmgren, S. (Eds.), Comparative Physiology and Evolution of the Autonomic Nervous System. Harwood Academic Publisher, Chur, Switzerland, pp. 169–192. Jönsson, A.-C., Holmgren, S., 1989. Gut secretion. In: Holmgren, S. (Ed.), The comparative physiology of regulatory peptides. Chapman and Hall, London, New York, pp. 256–271. Kelley, G.G., Poeschla, E.M., Barron, H.V., Forrest, J.N.J., 1990. A1 adenosine receptors inhibit chloride transport in the shark rectal gland. Dissociation of inhibition and cyclic AMP. J. Clin. Invest. 85, 1629–1636. Kelley, G.G., Aassar, O.S., Forrest, J.N.J., 1991. Endogenous adenosine is an autacoid feedback inhibitor of chloride transport in the shark rectal gland. J. Clin. Invest. 88, 1933–1939. Keogh, J.P., Allen, A., Garner, A., 1997. Relationship between gastric mucus synthesis, secretion and surface gel erosion measured in amphibian stomach in vitro. Clin. Exp. Pharmacol. Physiol. 24, 844–849.

111

Koelz, H.R., 1992. Gastric acid in vertebrates. Scand. J. Gastroenterol. Suppl. 193, 2–6. Kulkarni, P.G., Hoffman, F.M., Shoemaker, R.L., 1979. Inhibition of H+ secretion in frog gastric mucosa by somatostatin. Am. J. Physiol. Endocrinol. Metab. 236, E784–E787. Lin, T.M., Evans, D.C., Warrick, M.W., Pioch, R.P., 1986. Actions of nizatidine, a selective histamine H2-receptor antagonist, on gastric acid secretion in dogs, rats and frogs. J. Pharmacol. Exp. Ther. 239, 406–410. Linari, G., Baldieri, M., Angelucci, L., 1975. The action of bombesin on gastric secretion of the chicken. Eur. J. Pharmacol. 34, 143–150. Lindström, E., Chen, D., Norlén, P., Andersson, K., Håkanson, R., 2001. Control of gastric acid secretion: the gastrin-ECL cell–parietal cell axis. Comp. Biochem. Physiol. 128A, 505–514. Liquori, G.E., Scillitani, G., Mastrodonato, M., Ferri, D., 2002. Histochemical investigations on the secretory cells in the oesophagogastric tract of the Eurasian green toad, Bufo viridis. Histochem. J. 34, 517–524. Loo, S.K., Swan, M., 1978. Epithelial mucins of the gastro-intestinal tract of Egernia cunninghami. Acta Anat. 102, 341–347. Lowy, R.J., Schreiber, J.H., Ernst, S.A., 1987. Vasoactive intestinal peptide stimulates ion transport in avian salt gland. Am. J. Physiol. 253, R801–R808. Lucini, C., Romano, A., Castaldo, L., 2000. NPY immunoreactivity in endocrine cells of duck pancreas: an ontogenetic study. Anat. Rec. 259, 35–40. Luiten, P.G.M., Horst, G.J., ter Buijs, R.M., Steffens, A.B., 1986. Autonomic innervation of the pancreas in diabetic and non-diabetic rats. A new view on intramural sympathetic structural organization. J. Auton. Nerv. Syst. 15, 33–44. Maier, K.J., Tullis, R.E., 1984. The effects of diet a digestive cycle on the gastrointestinal tract pH values in the goldfish, Carassius auratus L., Mozambique tilapia, Oreochromis mossambicus (Peters), and channel catfish, Ictalurus punctatus (Rafinesque). J. Fish Biol. 25, 151–165. Masini, M.A., Uva, B., Devecchi, M., Napoli, L., 1994. Renin-like activity, angiotensin Iconverting enzyme-like activity, and osmoregulatory peptides in the dogfish rectal gland. Gen. Comp. Endocrinol. 93, 246–254. Mattisson, A., Holstein, B., 1980. The ultrastructure of the gastric glands and its relation to induced secretory activity of cod, Gadus morhua (Day). Acta Physiol. Scand. 109, 51–59. Mcallister, R.M.R., Kendall, M.D., 1984. The nerves of the accessory pancreatic ducts of the common starling (Sturnus vulgaris): an ultrastructural and light microscopic study. J. Anat. 139, 437–447. McKay, D.M., Shaw, C., Halton, D.W., Thim, L., Buchanan, K.D., 1992. The primary structure and tissue distribution of an amphibian neuropeptide Y. Regul. Pept. 37, 143–153. Michelangeli, F., Ruiz, M.C., Dominguez, M.G., Parthe, V., 1988. Mammalian-like differentiation of gastric cells in the shark Hexanchus griseus. Cell Tissue Res. 251, 225–227. Milgram, S.L., McDonald, J.K., Noe, B.D., 1991. Neuronal influence on hormone release from anglerfish islet cells. Am. J. Physiol. 261, E444–E456. Mola, L., Coughi, B., 2004. The supramedullary neurons of fish: present status and goals for the future. Brain Res. Bull. 64, 195–204. Mola, L., Sassi, D., Coughi, B., 2002. The supramedullary cells of the teleost Coris julis (L.): a noradrenergic neuronal system. Eur. J. Histochem. 46, 329–332. Moriarty, D.J.W., 1973. The physiology of digestion of blue-green algae in the cichlid fish, Tilapia nilotica. J. Zool. 171, 25–39. Mosher, J.A., Duke, G.E., 1985. Cephalic control of avian gastric secretion. Comp. Biochem. Physiol. 82A, 935–937. Murai, A., Satoh, S., Okumura, J., Furuse, M., 2000. Factors regulating amylase secretion from chicken pancreatic acini in vitro. Life Sci 66, 585–591. Murashita, K., Fukada, H., Hosokawa, H., Masumoto, T., 2007. Changes in cholecystokinin and peptide Y gene expression with feeding in yellowtail (Seriola quinqueradiata): relation to pancreatic exocrine regulation. Comp. Biochem. Physiol. B 146, 318–325. Neutra, M.R., O'Malley, L.J., Specian, R.D., 1982. Regulation of intestinal goblet cell secretion. II. A survey of potential secretagogues. Am. J. Physiol. 242, G380–G387. Nielsen, K.G., Bomgren, P., Holmgren, S., Johnsen, A.H., 1998. Gastrin and cholecystokinin of the bullfrog, Rana catesbeiana, have distinct effects upon gallbladder motility and gastric acid secretion in vitro. Gen. Comp. Endocrinol. 112, 247–254. Nilsson, S., 1983. Autonomic nerve function in the vertebrates. Springer Verlag, Berlin, Heidelberg, New York. Nilsson, S., 2010-this volume. Comparative Anatomy of the Autonomic Nervous System. Autonomic Neuroscience: Basic and Clinical. Noe, B.D., McDonald, J.K., Greiner, F., Wood, J.D., 1986. Anglerfish islets contain NPY immunoreactive nerves and produce the NPY analog aPY. Peptides 7, 147–154. Norris, J.S., Norris, D.O., Windell, J.T., 1973. Effect of simulated meal size of gastric acid and pepsin secretory rates in bluegill (Lepomis macrochirus). J. Fish. Res. Board Can. 30, 201–204. Ohmori, Y., Wakita, T., Watanabe, T., 1991. Number and density of intrapancreatic ganglion cells in the chicken. J. Auton. Nerv. Syst. 34, 139–145. Olson, K.R., 1999. Chapter 13. Rectal gland and volume homeostasis. In: Hamlett, W.C. (Ed.), Sharks, Skates and Rays: The Biology of Elasmobranch Fishes, pp. 329–352. Olsson, C., Holmgren, S., 2010- this volume. Autonomic Control of Gut Motility: A Comparative View. Autonomic Neuroscience: Basic and Clinical. Patent, G.J., Kechele, P.O., Tomichek Carrano, V., 1978. Nonconventional innervation of the pancreatic islets of the teleost fish, Gillichthys mirabilis. Cell Tissue Res. 191, 305–315. Plaisancié, P., Barcelo, A., Moro, F., Claustre, J., Chayvialle, J.-A., Cuber, J.-C., 1998. Effects of neurotransmitters, gut hormones, and inflammatory mediators on mucus discharge in rat colon. Am. J. Physiol. 275, G1073–G1084. Putti, R., Maglio, M., Odierna II, G., 2000. An immunocytochemical study of intrapancreatic ganglia, nerve fibres and neuroglandular junctions in Brockmann

112

S. Holmgren, C. Olsson / Autonomic Neuroscience: Basic and Clinical 165 (2011) 102–112

bodies of the tompot blenny (Blennius gattorugine), a marine teleost. Histochem. J. 32, 607–616. Rebolledo, I.M., Vial, J.D., 1979. Fine structure of the oxynticopeptic cell in the gastric glands of an elasmobranch species (Halaelurus chilensis). Anat. Rec. 193, 805–822. Ruiz, M.C., Michelangeli, F., 1984. Evidence for a direct action of acetylcholine on the gastric oxyntic cell of the amphibian. Am. J. Physiol. 246, G16–G25. Ruiz, M.C., Michelangeli, F., 1986. Stimulation of oxyntic and histaminergic cells in the gastric mucosa by gastrin C-terminal tetrapeptide. Am. J. Physiol. 251, G529–G537. Ruoff, H.J., Sewing, K.-F., 1972. Inhibition of gastric acid secretion in chickens by atropine, insulin and 2-deoxy-D-glucose. Naunyn-Schmiedebergs Arch. Pharmacol. 19, 296–300. Sandblom, E., Axelsson, M., 2010- this volume. Autonomic Control of the Circulatory System: A Comparative View. Autonomic Neuroscience: Basic and Clinical. Schmidt-Nielsen, K., Fänge, R., 1958. Salt glands in marine reptiles. Nature 182, 783–785. Scillitani, G., Liquori, G.E., Mastrodonato, M., Ferri, D., 2008. Histochemical and immunohistochemical characterization of exocrine cells in the foregut of the redeared slider turtle, Trachemys scripta (Emydidae). Arch. Histol. Cytol. 71, 279–290. Shephard, K.L., 1994. Functions for fish mucus. Rev. Fish Biol. Fish. 4, 401–429. Shirakawa, T., Hirschowitz, B.I., 1985. Interaction between stimuli and their antagonists on frog Rana catesbeiana esophageal peptic glands. Am. J. Physiol. 249, G668–G673. Shuttleworth, T.J., Hildebrandt, J.P., 1999. Vertebrate salt glands: short- and long-term regulation of function. J. Exp. Zool. 283, 689–701. Shuttleworth, T.J., Thorndyke, M.C., 1984. An endogenous peptide stimulates secretory activity in the elasmobranch rectal gland. Science 225, 319–321. Silva, P., Stoff, J.S., Leone, D.R., Epstein, F.H., 1985. Mode of action of somatostatin to inhibit secretion by shark rectal gland. Am. J. Physiol. 249, R329–R334. Silva, P., Lear, S., Reichlin, S., Epstein, F.H., 1990. Somatostatin mediates bombesin inhibition of chloride secretion by rectal gland. Am. J. Physiol. 258, R1459–R1463. Silva, P., Epstein, F.H., Karnaky Jr., K.J., Reichlin, S., Forrest Jr., J.N., 1993. Neuropeptide Y inhibits chloride secretion in the shark rectal gland. Am. J. Physiol. 265, R439–R446. Simpson, L., Goldenberg, D., Hirschowitz, B.I., 1980. Pepsinogen secretion by the frog esophagus in vitro. Am. J. Physiol. 238, G79–G84. Sklyarov, A.Y., Maslyanko, A.M., Bondarchuk, T.I., 1999. Combined effects of neurotransmitters upon secretory function of the rat stomach at different functional states of the gastric mucosa. Neurophysiology 31, 56–58. Skoglund, C.R., Sjöberg, E., 1977a. In vitro studies of frog mucous glands. Acta Physiol. Scand. 100, 457–470. Skoglund, C.R., Sjöberg, E., 1977b. In vivo studies of individual mucous glands in the frog. Acta Physiol. Scand. 100, 471–484. Slaughter, M., Aiello, E., 1982. Cholinergic nerves stimulate mucociliary transport, ciliary activity, and mucus secretion in the frog palate. Cell Tissue Res. 227, 413–421. Smit, H., 1968. Gastric secretion in the lower vertebrates and birds. In: Code, C.F. (Ed.), Handbook of Physiology, sect 6: Alimentary canal, volume V: Bile, digestion, ruminal physiology: Am. Physiol. Soc. , pp. 2791–2805. Smolka, A.J., Lacy, E.R., Luciano, L., Reale, E., 1994. Identification of gastric H, K-ATPase in an early vertebrate, the Atlantic stingray Dasyatis sabina. J. Histochem. Cytochem. 42, 1323–1332. Stoff, J.S., Rosa, R., Hallac, R., Silva, P., Epstein, F.H., 1979. Hormonal regulation of active chloride transport in the dogfish rectal gland. Am. J. Physiol. 237, F138–F144. Stoff, J.S., Silva, P., Lechan, R., Solomon, R., Epstein, F.H., 1988. Neural control of shark rectal gland. Am. J. Physiol. 255, R212–R216. Subramanian, S., Ross, N.W., Mackinnon, S.L., 2008. Comparison of the biochemical composition of normal epidermal mucus and extruded slime of hagfish (Myxine glutinosa L.). Fish Shellfish Immunol. 25, 625–632. Sullivan, M.X., 1905-6. The physiology of the digestive tract of elasmobranchs. Am. J. Physiol. 15, 42–45.

Takeuchi, K., Magee, D., Chritchlow, J., Matthews, J., Silen, W., 1983. Studies of the pH gradient and thickness of frog gastric mucus gel. Gastroenterology 84, 331–340. Taplin, L.E., Grigg, G.C., 1981. Salt glands in the tongue of the estuarine crocodile Crocodylus porosus. Science 212, 1045–1047. Taplin, L.E., Grigg, G.C., Harlow, P., Ellis, T.M., Dunson, W.A., 1982. Lingual salt glands in Crocodylus acutus and Crocodylus johnstoni and their absence from Alligator mississippiensis and Caiman crocodilus. J. Comp. Physiol. 149, 43–47. Thorndyke, M.C., Shuttleworth, T.J., 1985. Biochemical and physiological studies on peptides from the elasmobranch gut. Peptides 6 (Suppl. 3), 369–372. Thorndyke, M.C., Riddell, J.H., Thwaites, D.T., Dimaline, R., 1989. Vasoactive intestinal polypeptide and its relatives - biochemistry, distributions and functions. Biol. Bull. 177, 183–186. Tobin, G., Asztely, A., Edwards, A.V., Ekström, J., Håkanson, R., Sundler, F., 1995. Presence and effects of pituitary adenylate-cyclase activating peptide in the submandibulargland of the ferret. Neuroscience 66, 227–235. Trandaburu, T., 1972. Comparative observations on adrenergic innervation and monoamine content in endocrine pancreas of some amphibians, reptiles and birds. Endokrinologie 59, 260–264. Trandaburu, T., 1974. Ultrastructural and acetylcholinesterase investigations on the pancreas intrinsic innervation of two bird species (Columbia livia domestica Gm. and Euodice cantans Gm.). Gegenbaurs Morphol. Jb 120, 888–904. Tucker, A.S., 2007. Review. Salivary gland development. Semin. Cell Dev. Biol. 18, 237–244. Tyler, M.J., Shearman, D.J., Franco, R., O'Brien, P., Seamark, R.F., Kelly, R., 1983. Inhibition of gastric acid secretion in the gastric brooding frog, Rheobatrachus silus. Science 220, 609–610. Ulas, M., Penkowski, A., Lakomy, M., 2003. Adrenergic and cholinergic innervation of the chicken pancreas. Folia Morphol. 62, 243–246. Vigna, S.R., 1983. Evolution of endocrine regulation of gastrointestinal function in lower vertebrates. Am. Zool. 23, 729–738. Wang, B.J., Liang, H.Y., Cui, Z.J., 2009. Duck pancreatic acinar cell as a unique model for independent cholinergic stimulation–secretion coupling. Cell. Mol. Neurobiol. 29, 747–756. Xiao, R., Cui, Z.J., 2004. Mutual dependence of VIP/PACAP and CCK receptor signalling for a physiological role in duck exocrine pancreatic secretion. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R189–R198. Yasugi, S., 1987. Pepsinogen-like immunoreactivity among vertebrates: Occurrence of common antigenicity to an anti-chicken pepsinogen antiserum in stomach gland cells of vertebrates. Comp. Biochem. Physiol. 86B, 675–680. Yasugi, S., Matsunaga, T., Mizuno, T., 1988. Presence of pepsinogens immunoreactive to anti-embryonic chicken pepsinogen antiserum in fish stomachs: possible ancestor molecules of chymosin of higher vertebrates. Comp. Biochem. Physiol. 91A, 565–569. Yúfera, M., Darías, M.J., 2007. Changes in the gastrointestinal pH from larvae to adult in Senegal sole (Solea senegalensis). Aquaculture 267, 94–99. Yúfera, M.C.F.-D., Vidaurreta, A., Cara, J.B., Moyano, F.J., 2004. Gastrointestinal pH and development of the acid digestion in larvae and early juveniles of Sparus aurata L. (Pisces:Teleostei). Mar. Biol. 144, 863–869. Yui, R., Fujita, T., 1986. Immunohistochemical studies on the pancreatic islets of the ratfish Chimaera monstrosa. Arch. Histol. Cytol. 51, 109–111. Yui, R., Shimada, M., Fujita, T., 1990. Immunohistochemical studies on peptide- and amine-containing endocrine cells and nervesin the gut and rectal gland of the ratfish Chimaera monstrosa. Cell Tissue Res. 260, 193–201. Zaks, M.G., Gazhala, E.M., Gzgzian, D.M., Kuzina, M.M., Pesennikova, D.I., 1975. Comparative physiological characteristics of the action of pentagastrin on gastric secretion in fish, frogs, turtles and chickens. Zh. Evol. Biokhim. Fiziol. 11, 594–600.