Actions of serotonin antagonists on cholera-toxin-induced intestinal fluid secretion.

The effects of several 5-hydroxytryptamine (5-HT) receptor antagonists were tested in rats in vivo on the intestinal fluid secretion evoked by cholera toxin. Five receptor antagonists were used, namely 2-bromolysergic acid diethylamine (2-bromo-LSD), granisetron, ketanserin, methysergide and ondansetron. The drugs were used in doses that inhibited the arterial hypertension and/or bradycardia evoked by 5-HT given i.v. Granisetron and ondansetron markedly diminished cholera-toxin-evoked secretion, whereas ketanserin was without any effect. Methysergide also diminished cholera-toxin-induced fluid secretion particularly when the drug was given as an i.v. infusion. The results are considered in relation to the pathophysiology of cholera secretion and to the current views of receptor subtypes for 5-HT. It is proposed that the receptor involved is a 5-HT3 receptor, possibly also a receptor of the 5-HT1 type. Results from experiments in which 5-HT (20 mM) was placed in the intestinal lumen to evoke an intestinal secretion suggest that the 5-HT3 receptor is located in the villus tissue. It was also demonstrated that zimeldine, an inhibitor of presynaptic 5-HT reuptake, diminished choleraic secretion, an effect that may be ascribed to a 5-HT tachyphylaxis caused by an accumulation of 5-HT in a synaptic cleft.     

5-Hydroxytryptamine receptor characterizations of human cerebral,middle meningeal and temporal arteries: regional differences

We have studied the regional distribution of 5-hydroxytryptamine (5-HT) receptor subtypes in fresh circular segments of human cerebral, middle meningeal, and temporal arteries. Vasomotor responses induced by a series of 5-HT agonists and antagonists with some degree of selectivity were studied by using a sensitive in vitro system. Nine 5-HT agonists were examined for contractile effects on the arteries. In cerebral and meningeal arteries 5-carboxamidotryptamine (5-CT) was more potent than 5-HT. The opposite order of potency (5-HT-5-CT) was found in temporal arteries. In the cerebral arteries 5-methoxytryptamin (5-MeOHT) was more potent than sumatriptan while sumatriptan was more potent than 5-MeOHT in meningeal and temporal arteries. The 5-HT₁, receptor antagonist, methiothepin, competitively antagonized 5-CT-induced contractions in cerebral arteries, with a _P^A₂, value of 9.05. 5-HT-induced contractions were competitively antagonized by ketanserin (5-HT₂) in the temporal arteries _PA₂, value of 9.06). Methiothepin and ketanserin had non-competitive antagonistic effects in the middle meningeal arteries. The 5-HT₃, selective antagonist ondansetron did not cause any shift of the contractions induced by 2-methyl-5-HT in the temporal, cerebral and middle meningeal arteries. These results suggest that the cerebral arteries mainly contain 5-HT_id., or 5-HT₁,-like receptors, and the temporal artery 5-HT₂, receptors; the data further indicate the presence of both receptor subtypes in the middle meningeal artery.     

The effects on net fluid transport of noxious stimulation of jejunal mucosa in anaesthetized rats

A major aim of the present study was to investigate whether exposing the jejunal mucosa to a noxious stimulus induces a net fluid secretion by activating the enteric nervous system (ENS) and, if so, to what extent an axon reflex was involved. Net fluid transport was measured in vivo with a gravimetric method. The intestinal mucosa was exposed to an isotonic solution with an unphysiologically low pH (1.0). This evoked a fluid secretion, which was markedly attenuated by giving hexamethonium (nicotinic receptor antagonist) i.v. or exposing the intestinal serosa to lidocaine (local anaesthetic). Atropine (muscarinic receptor antagonist) had no effect. Luminal acid evoked a fluid secretion of the same magnitude in acutely denervated segments and in segments denervated about 3 weeks prior to the experiments. Luminal capsaicin (1.6–16 m M ) did not influence jejunal net fluid transport. A second aim of the study is to investigate the effect of nifedipine (Ca channel blocker of L-type) on the acid-induced fluid secretion. Nifedipine markedly attenuated acid-induced fluid secretion. In contrast to cholera toxin-evoked secretion, the nifedipine effect was not mediated via 5-hydroxytryptamine (5-HT) as judged by measurements of 5-HT release into the intestinal lumen and the lack of effect of granisetron (5-HT₃ receptor antagonist). It is concluded that the net fluid secretion evoked by hydrochloric acid in the small intestine is mainly mediated via an intramural reflex in the ENS. No experimental evidence was obtained for the involvement of an axon reflex. The site of action of the calcium channel blocker is tentatively discussed.     

Treatment of pruritus: a new indication for serotonin type 3 receptor antagonists

Summary Generalized pruritus is a well-known, distressing symptom of various diseases, especially in hepatic cholestasis and chronic renal insufficiency. Its treatment is often unsatisfactory. In three patients with generalized pruritus, intravenous administration of the serotonin type 3 (5-HT₃) receptor antagonist ondansetron induced a marked relief of itching. The effect was most pronounced in a patient with cholestasis-associated pruritus. It is suggested that serotonin, acting via 5-HT₃ receptors, is involved in the generation and/or sensation of pruritus. Furthermore, 5-HT₃ receptor antagonists may be a novel therapeutic principle for the treatment of pruritus.Abbreviation 5-HT serotonin (5-hydroxytryptamine)     

Role of various types of serotonin receptors in regulation of drinking behavior and salt appetite in vasopressin-deficient brattleboro rats

Serotonin 5-HT_1A receptor agonist 8-OH DPAT suppressed drinking behavior in Brattleboro and Wistar rats. 5-HT_1B agonist CGS-12066A and 5-HT_2A antagonist ketanserin did not affect drinking behavior in Brattleboro rats; 5-HT₃ antagonist ondansetron suppressed water consumption and 5-HT_1A agonist stimulated salt appetite in Brattleboro, but not in Wistar rats. Presumably, vasopressin regulates thirst and salt appetite by modulating sensitivity/density of various types of 5-HT receptors.     

Further evidence on the interaction of muramyl dipeptide with the serotonergic system

The mode of interaction between muramyl dipeptide (MDP), a compound with immunopharma-cological activities, and 5-hydroxytryptamine (5-HT, serotonin) was studied in isolated nerve-smooth muscle preparations of the carp stomach. Application of exogenous 5-HT evoked direct smooth muscle contractions; electric neurogenic stimulation evoked twitches due to the release of 5-HT from nerve endings. Contractions evoked by a high concentration of 5-HT (3–30 μM) were resistant to atropine and potentiated in the presence of MDP. Isamoltan (5-HT_ID antagonist) decreased the amplitude of contractions, whereas ketanserin (5-HT₂ antagonist) and MDL 72 222 (5-HT₃ antagonist) had no effect. The addition of low concentrations (0.1–1.5 μM) of 5-HT did not contract the preparation but caused a decrease in the amplitude of neurogenic twitches, which might be due to the presynaptic inhibition of serotonin release. This effect of 5-HT was not changed by isamoltan or ketanserin, but it was largely reduced in the presence of the 5-HT₃ antagonists tropisetron and MDL 72 222. This inhibitory effect of 5-HT on twitch amplitude was potentiated by MDP. The interaction of MDP with the serotonergic system thus involved not only potentiation of the postsynaptic effect of higher 5-HT concentrations, which might have been mediated via the 5-HT₁ subsystem, but also presynaptic inhibition. MDP enhancement of 5-HT's inhibitory effect, mediated via 5-HT₃ receptors, might represent a new feature in mutual 5-HT-MDP interactions.     

Platelet-vessel wall interactions: Implication of 5-hydroxytryptamine. A review

The evidence for an impact of platelet-derived 5-hydroxytryptamine (5-HT) on local tissue perfusion is reviewed. By interacting with 5-HT₂ serotonergic receptors, 5-HT, directly or through amplification, activates platelets, endothelial and vascular smooth muscle cells producing platelet aggregation, vascular permeability increase and large vessel constriction. Pharmacodissection in experimental animals with selective serotonergic 5-HT₂ receptor antagonists, e.g. ketanserin, shows that 5-HT largely contributes to the platelet-mediated increase in vascular permeability, to platelet-vessel wall interaction during hemostasis, to cardiopulmonary dysfunction provoked by thromboembolism and to the platelet-mediated inhibition of peripheral collateral circulation. Clinical results obtained with ketanserin further substantiate an involvement of platelet-derived 5-HT in the pathogenesis of impaired tissue perfusion in some cardiovascular conditions.     

Cardiovascular and respiratory reflexes of the gulf toadfish (Opsanus beta) during acute hypoxia

The acute cardiovascular and respiratory responses of the gulf toadfish, Opsanus beta, to acute hypoxia or exposure to the O₂ chemoreceptor stimulant, sodium cyanide (NaCN) were characterized and the role of serotonin type 2 (5-HT₂) receptors in mediating these responses was investigated. Toadfish responded to hypoxia or NaCN exposure with a decrease in heart rate (fH) and an increase in breathing amplitude (V_AMP) but no change in breathing frequency (fR). The bradycardia appeared to be mediated to some extent by 5-HT₂ receptors, as methysergide, a non-selective 5-HT_1/2 receptor antagonist, and ketanserin, a 5-HT₂ receptor antagonist, attenuated the response. Injection of α-methyl-5-HT, a 5-HT₂ agonist, also resulted in bradycardia that was inhibited by ketanserin, lending further support for 5-HT₂ receptor involvement, possibly 5-HT_2A or 5-HT_2C, in the regulation of fH. External NaCN exposure resulted in a significant decrease in caudal arterial blood pressure (P_CA) that was attenuated by methysergide. In contrast, injection with α-methyl-5-HT resulted in a substantial increase in P_CA that was not affected by ketanserin, suggesting the possible involvement of 5-HT_2B or 5-HT_2C receptors. These data are the first to suggest a unique distribution of 5-HT_2B/2C receptors may be involved in mediating vasoconstriction of the systemic vasculature of toadfish. These data also provide mechanistic support for why pulsatile urea excretion, believed to be regulated by 5-HT via the toadfish 5-HT_2A receptor, is not triggered by hypoxia or external chemoreceptor activation.     

Neuronal responses to 5-hydroxytryptamine in the red nucleus of rats

The effects of microiontophoretic 5-hydroxytryptamine (5-HT) on the firing rate of red nucleus (RN) neurons were studied in urethane-anesthetized rats. The background discharge rate of almost all the neurons tested (97%) was modified by 5-HT, and generally increased (89%). Responses were dose dependent. Twenty-three percent of the excitatory responses were preceded by a short inhibitory phase. No significant difference in the effect of 5-HT was found between those RN neurons that project to the spinal cord and those that do not. The excitatory responses to 5-HT were blocked or greatly reduced by the 5-HT antagonists methysergide and ketanserin, and were even reversed in some cases. The 5-HT₂/5-HT_1A antagonist spiperone, in small doses, also blocked the transient inhibitory phases in addition to the excitatory effects. In RN neurons exhibiting a short-lasting inhibition in the response to 5-HT, the 5-HT_1A agonist 8-hydroxy-2(di-n-propyl-amino)tetralin (8-OH-DPAT) induced inhibitory effects. These results support the hypothesis that 5-HT exerts control throughout the RN, mostly by acting on 5-HT₂ receptors. Furthermore, an influence of this amine on the electrical activity of small groups of RN neurons by 5-HT_1A receptors, and eventually by different mechanisms, appears probable. The functional significance of serotoninergic control of RN neuronal activity is discussed.     

Involvement of 5-hydroxytryptaminergic transmission for the Mesobuthus tamulus venom-induced depression of spinal reflexes in neonatal rat in vitro

Mesobuthus tamulus (MBT) venom is shown to depress the spinal reflexes through a mechanism unrelated to the NMDA receptors. 5-Hydroxytryptamine (5-HT) is another excitatory transmitter in the spinal cord therefore, the present study was undertaken to examine the involvement of 5-HT in the venom-induced depression of reflexes. The experiments were performed on isolated hemisected spinal cords from 4 to 6-day-old rats. Stimulation of a dorsal root with supramaximal strength evoked monosynaptic reflex (MSR) and polysynaptic reflex (PSR) potentials in the corresponding segmental ventral root. MBT venom (0.3 μg/ml) depressed the spinal reflexes in a time-dependent manner and the maximal depression was seen at 10 min. The time to produce 50% depression (T-50) of MSR and PSR was 8.1 ± 1.41 and 6.8 ± 0.5 min, respectively. Pretreatment with pindolol (1 μM; 5-HT_1A/1B receptor antagonist) blocked the reflexes up to 15 min. On the other hand, ketanserin (10 μM; 5-HT_2A/2C receptor antagonist) or ondansetron (0.1 μM; 5-HT₃ receptor antagonist) blocked the venom-induced depression of MSR and PSR during entire exposure time (30 min). The 5-HT concentration of the cords exposed to venom (1.6 ± 0.04 μg/g tissue) was significantly greater than the control group (0.98 ± 0.08 μg/g tissue). The results indicate that venom-induced depression of spinal reflexes is mediated via 5-HTergic transmission involving 5-HT_1A/1B, 5-HT_2A/2C and 5-HT₃ receptors.     

Excitation and inhibition of rat medial vestibular nucleus neurones by 5-hydroxytryptamine

The effects of 5-hydroxytryptamine (5-HT) and related compounds on the discharge rate of tonically active medial vestibular nucleus (MVN) neurones were studied in an in vitro slice preparation of the dorsal brainstem of the rat. The majority (87 of 107, 82%) of MVN neurones were excited by 5-HT. Nine cells (8%) showed a biphasic response to 5-HT, which consisted of a brief inhibition followed by excitation. Eleven cells (10%) were inhibited by 5-HT. The excitatory effects of 5-HT were mimicked by alpha-methyl-5-HT and antagonised by ketanserin and ritanserin, indicating the involvement of the 5-HT₂ subtype of 5-HT receptor. In biphasic cells, blockade of 5-HT₂ receptors by ketanserin reduced the excitatory component of the response and revealed an enhanced initial inhibition. The inhibitory effects in biphasic cells, and in cells that showed a pure inhibition in response to 5-HT, were blocked by pindobind-5-HT and mimicked by 8-hydroxy-2-(di-n-propylamino)-tetralin indicating the involvement of 5-HT1A receptors. The significance of these findings in relation to the effects of 5-HT on vestibular reflex function is discussed.     

Changes in cyclic 3'5‘-adenosine monophosphate tissue concentration and net fluid transport in the cat's small intestine elicited by cholera toxin,arachidonic acid,vasoactive intestinal polypeptide and 5-hydroxytryptamine

We have analysed tissue cyclic 3'5′-adenosine monophosphate (cAMP) concentration in different fractions of the cat's small intestinal mucosa during secretion elicited in vivo by four different secretagogues: cholera toxin (administered intraluminally), vasoactive intestinal polypeptide (VIP; given i.a.), arachidonic acid (AA; administered intraluminally) and 5-hydroxytryptamine (5-HT; given i.a.). Cholera toxin was found to increase cAMP concentration in the villi but not in the crypts. The VIP, AA and 5-HT did not influence tissue cAMP concentration despite a profuse net fluid secretion. Hexamethonium inhibited secretion elicited by cholera toxin and AA but did not significantly influence tissue cAMP concentration. There is strong evidence for the view that villus and crypt regions of the small intestinal mucosa have different functions, secretion taking place in the crypts and absorption in the villi. However, the lack of cAMP increase in the crypts reported in this study suggests that cholera toxin in this model does not reach the crypts. The results are not in agreement with a role for cAMP in mediating secretion from the crypts, but are compatible with a role of cAMP in inhibiting absorption in the villi. It is suggested that the observed fluid secretion from the crypts elicited by cholera toxin, AA and 5-HT is to a major part mediated by intramural enteric reflexes.     

Effect of chronic activation of 5-HT3 receptors on 5-HT3, 5-HT1A and 5-HT2A receptors functional activity and expression of key genes of the brain serotonin system

Among serotonin (5-HT) receptors, the 5-HT₃ receptor is the only ligand-gated ion-channel. Little is known about the interaction between the 5-HT₃ receptor and other 5-HT receptors and influence of 5-HT₃ chronic activation on other 5-HT receptors and the expression of key genes of 5-HT system. Chronic activation of 5-HT₃ receptor with intracerebroventricularly administrated selective agonist 1-(3-chlorophenyl)biguanide hydrochloride (m-CPBG) (14 days, 40 nmol, i.c.v.) produced significant desensitization of 5-HT₃ and 5-HT_1A receptors. The hypothermic responses produced by acute administration of selective agonist of 5-HT₃ receptor (m-CPBG, 40 nmol, i.c.v.) or selective agonist of 5-HT_1A receptor (8-hydroxy-2-(di-n-propylamino)tetralin) (8-OH-DPAT, 1 mg/kg, i.p.) was significantly lower in m-CPBG treated mice compared with the mice of control groups. Chronic m-CPBG administration failed to induce any significant change in the 5-HT_2A receptor functional activity and in the expression of the gene encoding 5-HT_2A receptor. Chronic activation of 5-HT₃ receptor produced no considerable effect on the expression on 5-HT₃, 5-HT_1A, and 5-HT transporter (5-HTT) and tryptophan hydroxylase-2 (TPH-2) genes – the key genes of brain 5-HT system, in the midbrain, frontal cortex and hippocampus. In conclusion, chronic activation of ionotropic 5-HT₃ receptor produced significant desensitization of 5-HT₃ and postsynaptic 5-HT_1A receptors but caused no considerable changes in the expression of key genes of the brain 5-HT system.     

Interactions between the serotoninergic and noradrenergic systems of the brain and their role in the regulation of animal behavior

Studies were carried out using DBA/2 mice on the relationship between the behavioral effects of antagonists of different types of 5-HT receptors and the level of activity of α₂-adrenoceptors. The 5-HT_1c receptor antagonists mianserin (2 mg/kg) and cyproheptadine (2 mg/kg) and the 5-HT₂ receptor antagonist ketanserin (3 mg/kg) had no effect on movement activity, while the 5-HT₃ and 5-HT₄ receptor antagonists zacopride (1 mg/kg) and ICS 205-930 (1 mg/kg) reduced movement behavior in intact animals. On a background of treatment with the α₂-adrenoceptors blocker yohimbine (0.5 mg/kg), mianserin, cyproheptadine, and ketanserin inhibited movement activity and significantly reduced the sensitivity of animals to audiogenic convulsions. These data indicate that administration of α₂-adrenoceptors antagonists increases the efficiency with which serotonin receptors regulate behavior. Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia; Department of Pharmacology, Scientific Health Center, University of Texas, San Antonio, USA. Translated from Fiziologicheskii Zhurnal im.I. M. Sechenova, Vol. 81, No. 8, pp. 101–103, August, 1995.     

The effects on net fluid transport of noxious stimulation of jejunal mucosa in anaesthetized rats.

A major aim of the present study was to investigate whether exposing the jejunal mucosa to a noxious stimulus induces a net fluid secretion by activating the enteric nervous system (ENS) and, if so, to what extent an axon reflex was involved. Net fluid transport was measured in vivo with a gravimetric method. The intestinal mucosa was exposed to an isotonic solution with an unphysiologically low pH (1.0). This evoked a fluid secretion, which was markedly attenuated by giving hexamethonium (nicotinic receptor antagonist) i.v. or exposing the intestinal serosa to lidocaine (local anaesthetic). Atropine (muscarinic receptor antagonist) had no effect. Luminal acid evoked a fluid secretion of the same magnitude in acutely denervated segments and in segments denervated about 3 weeks prior to the experiments. Luminal capsaicin (1.6-16 mM) did not influence jejunal net fluid transport. A second aim of the study is to investigate the effect of nifedipine (Ca channel blocker of L-type) on the acid-induced fluid secretion. Nifedipine markedly attenuated acid-induced fluid secretion. In contrast to cholera toxin-evoked secretion, the nifedipine effect was not mediated via 5 hydroxytryptamine (5-HT) as judged by measurements of 5-HT release into the intestinal lumen and the lack of effect of granisetron (5-HT3 receptor antagonist). It is concluded that the net fluid secretion evoked by hydrochloric acid in the small intestine is mainly mediated via an intramural reflex in the ENS. No experimental evidence was obtained for the involvement of an axon reflex. The site of action of the calcium channel blocker is tentatively discussed.     

Serotonergic and noradrenergic facilitation of the visceromotor reflex evoked by urinary bladder distension in rats with inflamed bladders

Bladder inflammation resulting from intravesical administration of zymosan significantly enhances the visceromotor reflex (VMR) evoked by urinary bladder distension (UBD). The present study examined whether intrathecal (i.t.) administration of receptor antagonists to either noreprinephrine (NE) or serotonin (5-HT) altered this enhancement effect. I.t. administration of the non-specific 5-HT receptor antagonist methysergide (30 μg), the 5-HT₃ receptor antagonist ondansetron, or the 5-HT_1A receptor antagonist WAY 100635 eliminated the enhancement effect produced by intravesical zymosan and also tended to reduce electromyographic (EMG) responses to UBD in non-inflamed rats. I.t. administration of either the non-specific NE receptor antagonist phentolamine (30 μg) or the α₁ antagonist WB 4101 also eliminated the enhancement effect, whereas i.t. administration of the α₂ antagonist yohimbine failed to significantly affect the enhancement effect. The effects of phentolamine and methysergide were not mediated by changes in bladder compliance. This is the first study to demonstrate that bladder hypersensitivity resulting from bladder inflammation is partly mediated by 5-HT and NE facilitatory effects. Based on these and previous findings we conclude that the net nociceptive response to bladder distension under conditions of bladder inflammation represents a complex interaction of facilitatory influences of spinal 5-HT and NE, and inhibitory influences of spinal opioids.     

Serotonin 5-HT2 and 5-HT1A-like receptors differentially modulate aggressive behaviors in Drosophila melanogaster

Aggressive behavior is widespread throughout the animal kingdom, and is a complex social behavior influenced by both genetics and environment. Animals typically fight over resources that include food, territory, and sexual partners. Of all the neurotransmitters, serotonin (5-HT) has been the most implicated in modulating aggressive behaviors in mammalian systems. In the fruit fly, Drosophila melanogaster, the involvement of 5-HT itself in aggressive behaviors has been recently established, however, the underlying mechanisms have largely remained elusive. Here we describe the influence of different 5-HT receptor subtypes on aggressive behaviors in Drosophila. Drosophila express homologs of three mammalian 5-HT receptors: the 5-HT_1A, 5-HT₂, and 5-HT₇ receptors. Significantly, these receptors mediate important behaviors in mammalian systems ranging from feeding, aggression, and sleep, to cognition. To examine the role of the 5-HT₂Dro receptor, we utilized the selective 5-HT₂ receptor agonist (R)-1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI), and the 5-HT₂ receptor antagonist, ketanserin. To examine the role of 5-HT_1A-like receptors we used the 5-HT_1A receptor agonist 8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT), and the 5-HT_1A receptor antagonist WAY100635. We find that activation of 5-HT₂ receptors with (R)-DOI appears to decrease overall aggression, whereas activation of 5-HT_1A-like receptors with 8-OH-DPAT increases overall aggression. Furthermore, the different 5-HT receptor circuitries appear to mediate different aspects of aggression: 5-HT₂ receptor manipulation primarily alters lunging and boxing, whereas 5-HT_1A-like receptor manipulation primarily affects wing threats and fencing. Elucidating the effects of serotonergic systems on aggression in the fly is a significant advancement not only in establishing the fly as a system to study aggression, but as a system relevant to elucidating molecular mechanisms underlying aggression in mammals, including humans.     

5-Hydroxytryptamine inhibits Na absorption and stimulates C1 secretion across canine tracheal epithelial sheets

Background 5-Hydrozytryptamine (5-HT) can be released from mast cells and platelets through an IgE-dependent mechanism and may play a role in the pathogenesis of allergic bronchoconstriction. However, the effect of 5-HT on ion transport by airway epithelium remains uncertain. Objective To determine whether 5-HT alters electrical and ion transport properties of C1-secreting epilhelia and, if so, what subtype of 5-HT receptors is involved, we studied canine tracheal epithelium under short-circuit conditions in vitro. Methods Canine tracheal mucosa was mounted in Lucite half-chambers and the responses of short-circuit current (lsc), transepithelial potential difference (PD) and tissue conductance (G) were measured. ln addition, ion fluxes were directly measured using ²²Na and ³⁶C1. Results Mucosal addition of 5-HT caused a rapid increase in lsc, which was accompanied by the increases in PD and G, whereas submucosal 5-HT had no effect. In the presence of amiloride, 5-HT and its receptor agonists dose-dependently increased lsc, with the rank order of potency being 5-HT > α-methyl-5-HT>2-methyl-5HT>5-carboxamidotryptamine. The effect of 5-HT was inhibited by ketanserin and spiperone but not by ondansetron. 5-HT increased C1 flux from the submucosa to the mucosa with a slight inhibition of Na flux to the opposite direction. Conclusion 5-HT inhibits airway epithelial Na absorption and stimulates C1 secretion. The latter action predominates the former and is mediated by 5-HT₂ receptors. These effects may result in the increase in water movement toward the airway lumen.     

Effects of calcium channel blockade on intestinal fluid secretion: sites of action

Most intestinal secretagogues, including cholera toxin, evoke fluid secretion in part by activating the enteric nervous system (ENS). The enterotoxins that, due to size, cannot pass the intestinal epithelial lining have been proposed to activate the ENS via the release of amines/peptides from the intestinal endocrine cells. It has been shown that calcium channel blockers of the L-type attenuate intestinal fluid secretion. This study was performed on rat jejunal segments to elucidate where calcium channel antagonists interact with the secretory nervous reflex(es) of the ENS. In vivo, net fluid transport, transmural potential difference (PD) and luminal release of serotonin from the enterochromaffin cells were monitored before and after exposing the intestinal mucosa to cholera toxin (20 μg/mL) or the calcium ionophore A23187 (0.5 mm ). In vitro, the effects of transmural electrical field stimulation (EFS) on short circuit current (SCC) was investigated using the Ussing chamber method. Cholera toxin and A23187 evoked a net fluid secretion, an increased PD and an augmented luminal release of 5-HT. These effects were markedly attenuated by giving the calcium channel blocker nifedipine i.v. (5.75 μmol kg^?1 body wt). On the other hand, nifedipine (0.02 mm ) had no significant effect on the increased SCC caused by EFS in vitro. The results obtained in the in vivo experiments suggest that the nifedipine markedly attenuates the initial event in cholera toxin- and A23187-induced secretion, the release of amines and probably also of peptides from the intestinal endocrine cells. The in vitro experiments seem to exclude an effect of the calcium channel blockade on the efferent part of the secretory nervous reflex.     

5-HT2 receptors modulate excitatory neurotransmission to cardiac vagal neurons within the nucleus ambiguus evoked during and after hypoxia

To examine the role of 5-HT2 receptors in the central cardiorespiratory network, and in particular the respiratory modulation of parasympathetic activity to the heart, we used an in vitro medullary slice that allowed simultaneous examination of rhythmic inspiratory-related activity recorded from hypoglossal rootlet and excitatory inspiratory-related neurotransmission to cardioinhibitory vagal neurons (CVNs) within the nucleus ambiguus (NA). Focal application of ketanserin, a 5-HT2 receptor antagonist, did not significantly alter the frequency of spontaneous excitatory postsynaptic excitatory currents (EPSCs) in CVNs in control conditions. However, ketanserin diminished spontaneous excitatory neurotransmission to CVNs during hypoxia. The inhibitory action of ketanserin was on 5-HT3 mediated EPSCs during hypoxia since these responses were blocked by the 5-HT3 receptor antagonist ondansetron. In addition, a robust inspiratory-related excitatory neurotransmission was recruited during recovery from hypoxia. Focal application of ketanserin during this posthypoxia period evoked a significant augmentation of the frequency of inspiratory-related, but not spontaneous EPSCs in CVNs. This excitatory effect of ketanserin was prevented by application of the purinergic receptor blocker pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS). These results demonstrate 5-HT2 receptors differentially modulate excitatory neurotransmission to CVNs during and after hypoxia. Activation of 5-HT2 receptors acts to maintain excitatory neurotransmission to CVNs during hypoxia, likely via presynaptic facilitation of 5-HT3 receptor-mediated neurotransmission to CVNs. However, activation of 5HT2 receptors diminishes the subsequent inspiratory-related excitatory neurotransmission to CVNs that is recruited during the recovery from hypoxia likely exerting an inhibitory action on inspiratory-related purinergic signaling.