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G J Sanger

Publications and source records attributed to G J Sanger.

At least 37 records · Page 2Linked to original sources
PubMed2000

5-HT(1B/D) receptor agonist, SKF99101H, induces locomotor hyperactivity in the guinea pig.

Previous studies in guinea pigs have shown that while a serotonin 5-HT(1B/D) receptor agonist, GR46611, does not induce locomotor activation when given alone, it markedly enhances the locomotor response to selective 5-HT(1A) receptor agonists, 8-OH-DPAT and buspirone. In these studies, we found that another 5-HT(1B/D) agonist, 3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate (SKF99101H), significantly elevated locomotor activity in guinea pigs when given alone. We assessed the relative contribution of 5-HT1(1A) and 5-HT(1B/D) receptors in the mediation of this effect. Activity was measured by photobeam interrupts in opaque Perspex cylinders linked to a computer. SKF99101H (20 mg/kg s. c.) significantly increased the locomotor activity in guinea pigs. The locomotor stimulant effect of SKF99101H (20 mg/kg s.c) was reversed by the selective 5-HT(1B/D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl -1,2,4-oxadiazol-3-yl)[1,1biphenyl]4-carboxamide (GR127935; 0.06-0. 25 mg/kg s.c.). The 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635; 0.05-0.25 mg/kg s.c.), slightly but significantly attenuated the hyperactivity induced by SKF99101H. These findings suggest that 5-HT(1B/D) receptor agonists may require concomitant activation of 5-HT(1A) receptors to induce locomotor activity in guinea pigs. The 5-HT(2A) receptor antagonist 6[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]-ethyl]-7-methyl- 5H-thiazol[3,2-a]pyrimidin-5-one (ritanserin) had no effect on SKF99101H-induced hyperactivity, suggesting that these receptors are not involved in the mediation of SKF99101H-induced hyperactivity. SKF99101H-induced hyperactivity was significantly attenuated by the D(1) dopamine receptor antagonist SCH 23390 (0.005-025 mg/kg), but not by the D(2) dopamine receptor antagonist raclopride (0.25-1.0 mg/kg), possibly suggesting the selective involvement of D(1) dopaminergic receptors in the mediation of the stimulant actions of the 5-HT(1B/D) agonist.

Animals↗
PubMed2000

Rank-order inhibition by omega-conotoxins in human and animal autonomic nerve preparations.

The inhibitory effects of the omega-conotoxins GVIA, MVIIA and MVIIC on electrically-evoked, tetrodotoxin (10(-7) M)-sensitive, autonomic nerve activity were studied using human, rat or guinea-pig vas deferens and intestinal tissues. In each preparation from each species, nM concentrations of omega-conotoxins GVIA and MVIIA prevented the neuronally-mediated contractions, whereas omega-conotoxin MVIIC was either markedly less potent (IC(50)'s 1.4 or 2.9 log units more than for omega-conotoxin GVIA in guinea-pig ileum and rat vas deferens, respectively) or was without significant activity (human vas deferens, human Taenia coli) when tested at similar concentrations. In contrast the differences in potency between omega-conotoxins GVIA and MVIIC were considerably less when assayed directly on Ca(2+) channel currents evoked from rat superior cervical ganglion neurons in culture (approximately 0.1 log unit difference) and from a stable cell line expressing rat alpha(1B), alpha(2)delta, beta(1b) Ca(2+) channel subunits (approximately 0.9 log unit). These different rank-orders of inhibitory activity of the conotoxins support the suggestion that there are pharmacologically distinct N-type Ca(2+) channels in the peripheral nervous system, and that this tissue-dependent difference is seen in man.

Animals↗
PubMed2000

Nerve injury-associated kinase: a sterile 20-like protein kinase up-regulated in dorsal root ganglia in a rat model of neuropathic pain.

Partial injury of the rat sciatic nerve elicits a variety of characteristic chemical, electrophysical and anatomical changes in primary sensory neurons and constitutes a physiologically relevant model of neuropathic pain. To elucidate molecular mechanisms that underlie the physiology of neuropathic pain, we have used messenger RNA differential display to identify genes that exhibit increased ipsilateral expression in L4/5 dorsal root ganglia, following unilateral partial ligation of the rat sciatic nerve. One set of partial complementary DNA clones identified in this screen was found to encode a protein kinase, nerve injury-associated kinase. Cloning of the full-length human nerve injury-associated kinase complementary DNA, together with recombinant expression analysis, reveal nerve injury-associated kinase to be a functional member of a subgroup of sterile 20-like protein kinases characterised by the presence of a putative carboxy terminal autoregulatory domain. Induction of nerve injury-associated kinase expression in dorsal root ganglia in the rat neuropathic pain model was confirmed by quantitative reverse transcription-polymerase chain reaction, and RNA in situ hybridization analysis revealed enhanced levels of nerve injury-associated kinase within neurons.Together, our data implicate nerve injury-associated kinase as a novel upstream component of an intracellular signalling cascade that is up-regulated in dorsal root ganglia neurons in response to sciatic nerve injury.

Amino Acid Sequence↗
PubMed2000

Identification of differentially expressed genes in dorsal root ganglia following partial sciatic nerve injury.

Partial sciatic nerve injury, a model of neuropathic pain, elicits a variety of neurochemical, electrophysiological and neuroanatomical changes in primary sensory neurons. We have used the technique of messenger RNA differential display to identify genes with altered expression in these neurons which may contribute to the development of aberrant sensation following such peripheral nerve damage. This approach identified 14 distinct complementary DNA clones, representing transcripts with increased ipsilateral expression in L4/5 dorsal root ganglia, two weeks after unilateral partial ligation of the rat sciatic nerve. Both Zucker diabetic fatty rats and their lean counterparts were used in this study but none of the transcripts identified showed an induction that was confined to one of the two groups. The majority of the clones did not show significant sequence similarity to previously reported genes and therefore may represent novel messenger RNA sequences or, alternatively, unknown regions of partially characterised messenger RNAs. Two of the clones represented transcripts for the known proteins muscle LIM protein and acidic epididymal glycoprotein, neither of which had previously been associated with expression in the nervous system. Reverse transcriptase-polymerase chain reaction analysis and in situ hybridization confirmed that the messenger RNA expression of both muscle LIM protein and acidic epididymal glycoprotein was induced in an ipsilateral-specific manner. Their localisations, examined with in situ hybridization in L5 dorsal root ganglia, were limited in each case to a sub-population of neuronal profiles. Those neuronal profiles that demonstrated muscle LIM protein hybridization were distributed across the profile size range, whereas the distribution of acidic epididymal glycoprotein-positive profiles appeared to be skewed towards smaller profiles. The induction of muscle LIM protein and acidic epididymal glycoprotein in dorsal root ganglia may play an important functional role in the adaptive response of primary sensory neurons following partial sciatic nerve injury.

Animals↗
PubMed2000

Increased defecation during stress or after 5-hydroxytryptophan: selective inhibition by the 5-HT(4) receptor antagonist, SB-207266.

5-HT(4) receptor antagonism prevents the ability of exogenous 5-HT or 5-HTP to sensitize the intestinal peristaltic reflex and increase the rate of defecation, generally without affecting non-stimulated intestinal function. In this study we confirmed the ability of the selective 5-HT(4) receptor antagonist SB-207266 1 - 1000 microg kg(-1) p.o., to prevent the increase in defecation evoked over a 60 min period by 5-HTP 10 mg kg(-1) s.c. in conscious mice, in the absence of an apparent constipating action. The role of endogenous 5-HT in the mechanisms of increased defecation and/or diarrhoea was then investigated in conscious, fed rats. This was evoked by 180 min exposure to restraint stress, which increased both the number and mean weight of formed, faecal pellets excreted over the entire time period. SB-207266 1 - 1000 microg kg(-1) p.o. (dosed 30 min before restraint) did not affect the increase in defecation evoked during the first 60 min of restraint stress, but significantly and dose-dependently reduced or prevented the increased defecation during the remaining 120 min of the experiment; this action occurred in the absence of an apparent constipating action of SB-207266. In fasted rats exposed to restraint stress, watery diarrhoea developed and although there was a tendency for SB-207266 1 - 1000 microg kg(-1) p.o. (dosed 30 min before restraint) to reduce the incidence of diarrhoea, this inhibition was not complete. We conclude that selective 5-HT(4) receptor antagonism prevents disruptions in defecation behaviours caused by exogenous or endogenous enteric 5-HT and that this activity is not accompanied by a concomitant suppression of activity (constipation-like) within the intestine itself.

5-Hydroxytryptophan↗
PubMed1999

Site-specific splice variation of the human P2X4 receptor.

P2X4 receptors are expressed in specific brain areas. We now describe site-specific splice variations of the human P2X4 receptor subunit, occurring at residue [YVIG / WVFV(W)] near the end of the first predicted transmembrane domain. p2X4(b) is formed by the insertion of an additional 16 amino acids. p2X4(C) is formed by deleting a cassette of 130 amino acids, including six of the 10 conserved extracellular cysteine residues. Transfection of P2X4(a), but not p2x4(c), formed functional channels in Xenopus oocytes and human 1321N1 cells. After transfection of p2X4(b) small, inconsistent ATP-evoked responses were detected only in the human cells, but when co-expressed, p2x4(b) may alter the function of P2X4(a) in oocytes. The distribution of splice variant RNA within human brain suggests regionally-dependent expression. These data indicate that the functions of the human P2X4 receptor may be altered by alternative splicing.

Adenosine Triphosphate↗
PubMed1999

5-HT4 receptor antagonism potentiates inhibition of intestinal allodynia by 5-HT3 receptor antagonism in conscious rats.

Acute levels of distension were applied by balloon to the colo-rectal region in conscious rats and visceromotor responses observed as abdominal muscle contraction; the threshold was typically between 10-40 mmHg. In saline-pretreated rats, the selective 5-HT3 (granisetron) and 5-HT4 (SB-207266) receptor antagonists had no effects on the visceromotor thresholds. 5-Hydroxytryptophan 10 mg/kg, subcutaneously (s.c.) decreased the distension threshold, indicating mechanical allodynia. This increased sensitivity was dose-dependently inhibited by granisetron but was unaffected by SB-207266 100 microg/kg, s.c., a dose which maximally and selectively antagonizes at 5-HT4 receptors. However, this dose of SB-207266 potentiated the inhibitory activity of submaximally-effective doses of granisetron, reducing the ED50 from 0.83 to 0.02 microg/kg, s.c., but without changing the maximum response or the bell-shaped nature of the dose-response curve for granisetron. These data suggest that 5-HT4 receptor activation enhances the ability of 5-HT3 receptor activation to induce intestinal allodynia.

Animals↗
PubMed1999

A single pretreatment with MK-801 or cocaine enhances their locomotor stimulant effects in rats.

A single dose of MK-801 (1.0 mg/kg, s.c.) induces an enhanced locomotor response to a subsequent lower dose of MK-801 (0.3 mg/kg) administered 4, 7 or 14 days later in young adult rats (>90 days). MK-801 (1.0 mg/kg) administration did not significantly enhance the effects of cocaine (10, 20 mg/kg) administered 7 days later. Cocaine (20 mg/kg) enhanced the effect of a subsequent dose of 10 mg/kg cocaine, but did not significantly alter the response to a higher dose cocaine (20 mg/kg) or of MK-801 (0.1 or 0.3 mg/kg) again given 7 days later. MK-801 (1.0 mg/kg) did not significantly enhance the locomotor response to a second dose of MK-801 (0.3 mg/kg) in 28-day-old rats tested 7 days after the initial dose, but did enhance the effects of a lower (0.1 mg/kg) dose. These findings indicate that even a single dose of a stimulant such as MK-801 and cocaine can induce enduring changes in sensitivity to subsequent doses of the same stimulants in young adult rats. The lack of significant effects seen in cross-sensitization studies suggests that separate mechanisms maybe involved in the sensitization to cocaine and MK-801. The more pronounced enhancement of activity in the older animals is in accord with previous findings that sensitization processes are developmentally regulated.

Animals↗
PubMed1999

GR46611 potentiates 5-HT1A receptor-mediated locomotor activity in the guinea pig.

5-HT(1B/D) receptor agonists such as GR46611 (3-[3-(2-Dimethylaminoethyl)-H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide ) are known to lower body temperature in guinea pigs. Although stimulation of their functional analogs in rats, the 5-HT1B receptor induces hyperlocomotion, this effect has yet to be demonstrated with 5-HT(1B/D) receptor agonists in the guinea pig. Previous studies have shown that 5-HT1A agonists increase locomotor activity in guinea pigs. The current study set out to examine the effects of 5-HT(1B/D) receptor stimulation on locomotor activity in the guinea pig and to examine the interaction between 5-HT1A and 5-HT(1B/D) receptor stimulation on locomotor activity in that species. The full agonist at 5-HT1A receptors, 8-OH-DPAT (R(+)-8-Hydroxy-dipropylaminotetralin HBr) dose-dependently increased locomotor activity in guinea pigs (0.3-1.25 mg kg(-1) s.c.), as to a lesser extent, did the partial agonist, buspirone (8-[4-[4-(2-Pyramidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5 ]decane-7,9-dione HCl) (5.0-20.0 mg kg(-1) s.c.). The 5-HT(1B/D) receptor agonist GR46611 had no effect on locomotor activity in guinea pigs at doses up to 40 mg kg(-1) s.c. 8-OH-DPAT-induced behavioural activation was reversed by the selective 5-HT1A receptor antagonist WAY100635 (N-[-2-[4-(-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyrinidyl) cyclo hexanocarboxamide trihydro-chloride), with a minimum effective dose of 0.006 mg kg(-1), but not by the 5-HT(1B/D) receptor antagonist GR127935 (2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c acid [4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]-amide) (0.25-1.0 mg kg(-1)). GR46611, at doses that were without effect given alone (0.5-2.5 mg kg(-1)), significantly enhanced the locomotor response to subthreshold doses of 8-OH-DPAT (0.5 mg kg(-1)) and buspirone (10 mg kg(-1)). The effect of GR46611 on 8-OH-DPAT-induced hyperactivity was reversed by pretreatment with GR127935 and with WAY 100635 indicating that activation of both receptors was required for the expression of locomotor hyperactivity. These findings suggest that activation of 5-HT(1B/D) receptors alone may not stimulate locomotor activity but it does potentiate the locomotion induced by 5-HT1A receptor stimulation in guinea pigs.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Hypersensitivity and hyperreactivity in the irritable bowel syndrome: An opportunity for drug discovery.

The gastrointestinal tract of many patients with irritable bowel syndrome (IBS) is hypersensitive to different stimuli. The mechanisms of this hypersensitivity are unclear, but could involve enteric, visceral afferent/efferent, spinal and/or central nervous systems. Such complexity, the absence of animal models or anatomical, molecular or genetic markers of IBS, means that it is difficult to create new types of drugs which specifically treat the condition of IBS. To help in this process, current pre-clinical and early-clinical approaches are evaluated in terms of their ability to intervene within the gut-spinal cord/brain axis and inhibit gastrointestinal 'hypersensitivity' and 'hyperreactivity'. Thus, by developing a rational process the pharmaceutical industry may better understand how to design truly effective drugs for the treatment of IBS.

Abdominal Pain↗
PubMed1998

5-HT4 receptor antagonism does not affect motor and reward mechanisms in the rat.

5-HT4 receptors are concentrated in areas of the brain which are rich in dopamine neuronal markers, which may suggest that they influence motor and reward processes. We tested this hypothesis by examining the effects of a 5-HT4 receptor antagonist, 8-amino-7-chloro-(N-butyl-4-piperidyl)methylbenzo-1,4-dioxan-5-car boxylate hydrochloride (SB-204070-A) on amphetamine- and nicotine-induced locomotor stimulation in intact rats. In rats with unilateral 6-hydroxydopamine-induced lesions of the ascending nigrostriatal dopaminergic projection, SB-204070-A was tested for its effects on amphetamine-induced rotation. SB-204070-A was also tested for its effects on rewarded behaviour maintained by intracranial self-stimulation. SB-204070-A did not alter behaviour under any of these conditions, suggesting a lack of involvement of the 5-HT4 receptor in motor and reward processes.

Amphetamine↗
PubMed1998

SB-207266: 5-HT4 receptor antagonism in human isolated gut and prevention of 5-HT-evoked sensitization of peristalsis and increased defaecation in animal models.

SB-207266 is a new 5-HT4 receptor antagonist which in a pilot study reduced the symptoms of irritable bowel syndrome. To help validate this and further studies, we examined the ability of SB-207266 to antagonize at the human 5-HT4 receptor (human isolated intestine) and to affect the mechanisms of peristalsis (guinea-pig isolated ileum) and defaecation (conscious, fed mice). In the human intestine, the potency of 5-HT4 receptor antagonism (pKB 9.98) was similar to that previously demonstrated using a guinea-pig model of the receptor, validating the use of SB-207266 in clinical trials. In each of the animal models, SB-207266 did not affect normal patterns of intestinal motility measured in the absence of exogenous 5-HT. However, SB-207266 10-1000 pM concentration-dependently antagonized the ability of 5-HT (0.1 microM) to sensitize the peristaltic reflex and lower the distension threshold at which peristalsis was evoked. In mice, oral or subcutaneous (s.c.) doses of SB-207266 dose-dependently prevented the ability of the 5-HT precursor, 5-hydroxytryptophan (5-HTP, 10 mg kg-1 s.c.) to increase both the rate of defaecation of formed faecal pellets and their fluid content. SB-207266 was maximally active at 10 micrograms kg-1 s.c. and 1000 micrograms kg-1 p.o. SB-207266 may therefore represent a new class of therapeutic agent, capable of preventing the actions of an important sensitizer of gut function.

Administration, Oral↗
PubMed1997

Pharmacological characterization of the vanilloid receptor in the rat dorsal spinal cord.

1. In the present study a novel 96-well plate assay system was used to characterize pharmacologically the vanilloid receptor in the dorsal spinal cord of the rat. When activated, this receptor stimulates release of calcitonin gene-related peptide (CGRP) from the central terminals of the afferent nerves. 2. Capsaicin, resiniferatoxin (RTX) and olvanil each evoked a concentration-dependent increase in CGRP release with pEC50 values of 6.55 +/- 0.07, 7.90 +/- 0.24 and 6.19 +/- 0.15 respectively. RTX and olvanil were partial agonists with respect to capsaicin. All concentration-effect curves were bell-shaped. 3. The vanilloid receptor antagonist, capsazepine (10 microM) had no effect on basal peptide release but inhibited the CGRP release evoked by all 3 agonists to a similar extent. These results suggest that the antagonistic effects of capsazepine were agonist-independent. 4. The capsaicin-sensitive cation channel blocker, ruthenium red (10 microM) had no effect on basal CGRP release, but antagonized the peptide release evoked by capsaicin, olvanil and RTX. 5. The pharmacology of the vanilloid receptor in the rat dorsal spinal cord is not identical to that previously found in other systems. The reason for these differences is unclear, but the possibility of multiple classes of receptor cannot at this stage be ruled out.

Animals↗
PubMed1996

Increased defaecation caused by 5-HT4 receptor activation in the mouse.

The precursor to 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan, (5-HTP, 5-50 mg.kg-1) administered subcutaneously (s.c.) to conscious, fed mice caused a dose dependent increase in faecal pellet and fluid output. To avoid provoking watery diarrhoea, all experiments were performed using 5-HTP at 10 mg.kg-1. This dose caused maximal increases in the fluid content (471 +/- 41%) and number of formed faecal pellets defaecated (328 +/- 13% n = 25), 10 and 20 min respectively after administration, when compared to saline-treated mice. In both saline- and 5-HTP-treated mice methiothepin, ketanserin, mianserin and granisetron reduced defaecation at high s.c. doses (100 micrograms.kg-1 or 1000 micrograms.kg-1). The 5-HT4 receptor antagonists, DAU 6285 (endo-6-methoxy-8-methyl-8-azabicyclo[3.2.1]oct-3-yl-2,3-dihydro-2-oxo-1 H-benzimidazole-1-carboxylate hydrochloride), SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) and SB 204070 ([1-butyl-4-piperidinylmethyl]-8-amino-7-chloro-1,4-benzodioxan -5- carboxylate), had no effects when administered s.c. to saline-treated mice, but dose-dependently inhibited the 5-HTP-evoked responses. Only SB 204070 at 1000 micrograms.kg-1 completely inhibited the responses to 5-HTP returning them to normal levels. We conclude that SB 204070 is a potent antagonist for the investigation of 5-HT4 receptor function in both normal and disturbed gastrointestinal activity.

4-Aminobenzoic Acid↗
PubMed1996

5-Hydroxytryptamine and functional bowel disorders.

The possibility that 5-hydroxytryptamine (5-HT) acts as a key sensitising agent in the aetiology of irritable bowel syndrome (IBS) is reviewed. The strategic locations of 5-HT and its receptors are described, the most dominant being the 5-HT3 and 5-HT4 type. 5-HT, acting mostly at 5-HT3 or 5-HT3-like receptors, enhances the sensitivity of visceral neurones projecting between the gut and the central nervous systems. 5-HT, acting at 5-HT4 receptors promotes the sensitivity of enteric neurones that react to luminal stimuli. 5-HT4 and 5-HT3 receptors also mediate, respectively, sensitising and physiological actions of 5-HT on gastro-intestinal motor and secretory functions. This distribution implies that some 5-HT3 receptor antagonists might reduce certain symptoms of IBS, such as pain, by reducing the reactivity of the visceral afferent neurones linking the gut with the brain and spinal cord. However, such antagonists are not likely to find widespread clinical acceptance because they can also affect normal lower bowel function and promote constipation. 5-HT4 receptor antagonists, by contrast, reduce 5-HT-induced enteric nerve hypersensitivity without notably affecting the function of the normal bowel. Accordingly, these agents may reduce the symptoms of IBS directly, by reducing the incidence of defecation and diarrhoea and indirectly, by reducing both 'rebound' constipation and the post-prandial discomfort and pain associated with gastrointestinal hyper-reactivity.

Colonic Diseases, Functional↗
PubMed1996

Selective and functional 5-hydroxytryptamine4 receptor antagonism by SB 207266.

1. The pharmacology of a novel 5-HT4 receptor antagonist, SB 207266 has been evaluated in vitro in the guinea-pig distal colon longitudinal muscle myenteric plexus (LMMP) and in vivo in the dog Heidenhain pouch. 2. SB 207266 is a highly potent antagonist of 5-HT-evoked, cholinergically-mediated contractions in the guinea-pig distal colon. Low concentrations (0.1-10 nM) produced a parallel shift to the right of the concentration-effect curve (apparent pA2 10.6 +/- 0.1) with no significant effect on the maximum response. With higher concentrations of SB 207266 (30 nM and above) the maximum response to 5-HT was reduced. 3. The antagonism seen with SB 207266 cannot be attributed to a non-selective effect since high concentrations (1 microM) had no effect on cholinergically-mediated contractions evoked by the nicotinic receptor agonist DMPP in the same preparation. 4. SB 207266 is not an irreversible antagonist since the effects of the compound were reversible upon washing of the tissue. 5. In the dog Heidenhain pouch, oral (0.1-100 micrograms kg-1) and intravenous (0.1-100 micrograms kg-1) administration of SB 207266 produced a dose-dependent antagonism of the contractions evoked by a bolus intravenous injection of 5-HT. An ID50 for SB 207266 of 1.3 micrograms kg-1 was obtained following i.v. administration and 9.6 micrograms kg-1 following oral administration. 6. The antagonistic effects of SB 207266 (0.1-100 micrograms kg-1) in the dog Heidenhain pouch were long lasting since, following oral administration, the response to 5-HT was reduced for at least 135 min. 7. SB 207266 is a highly potent, highly selective and orally active 5-HT4 receptor antagonist. This compound is the first orally active amide to be identified in this class of antagonists and as such is an important new tool in the evaluation of 5-HT4 receptor function both in vitro and in vivo.

Animals↗
PubMed1996

Pharmacological characterization of the vanilloid receptor in the rat isolated vas deferens.

The present study set out to further characterize the vanilloid receptor in the rat isolated vas deferens. In this preparation, both capsaicin and resiniferatoxin (RTX) evoked a concentration-dependent inhibition in the amplitude of electrically-evoked contractions with pEC50 values of 7.62 +/- 0.03 and 12.2 +/- 0.21 respectively. Responses to capsaicin were fast in onset and faded rapidly over a 30-min exposure period, whereas those to RTX were slow in onset and well maintained, an observation believed to reflect pharmacokinetic differences in the rate of penetration to the vanilloid receptor. Responses to both agonists showed mutual cross-desensitization and were antagonized by both the vanilloid-receptor antagonist capsazepine and the ion-channel blocker ruthenium red. The capsaicin analogue, olvanil failed to either mimic or antagonize capsaicin-evoked responses in the rat isolated vas deferens, an effect at variance with previous observations in other tissues. The reason for these differences is unclear, but the possibility of multiple classes of receptor cannot at this stage be ruled out.

Animals↗