Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knock-down experiments (ABCA1, TRIB1) and clinical trial results (CCR2, CCR5), with consistent regulation. Finally we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including (gene symbols) EGF, IL16, PAPPA, SPON1, F3, ADM, CASP8, CHI3L1, CXCL16, GDF15, and MMP12. Taken together these findings demonstrate the utility of largescale mapping the genetics of the proteome, and provide a resource for future precision studies of circulating proteins in human health.

Pregabalin increased distension sensory thresholds to normal levels in IBS patients with rectal hypersensitivity. A concomitant increase in rectal compliance appeared to be unrelated to the reduction in sensitivity. These data suggest that alpha(2)delta ligands are worthy of further investigation in the treatment of visceral pain disorders, including IBS.

OBJECTIVESTo characterise the phenotype of Border terriers suspected to be affected by canine epileptoid cramping syndrome and to identify possible contributing factors.METHODSOwners of Border terriers with suspected canine epileptoid cramping syndrome were invited to complete an online questionnaire. The results of these responses were collated and analysed.RESULTSTwenty-nine Border terriers were included. Most affected dogs had their first episode before 3 years of age (range: 0·2 to 7·0 years). The majority of episodes lasted between 2 and 30 minutes (range: 0·5 to 150 minutes). The most frequent observations during the episodes were difficulty in walking (27 of 29), mild tremor (21 of 29) and dystonia (22 of 29). Episodes most frequently affected all four limbs (25 of 29) and the head and neck (21 of 29). Borborygmi were reported during episodes in 11 of 29 dogs. Episodes of vomiting and diarrhoea occurred in 14 of 29, with 50% of these being immediately before or after episodes of canine epileptoid cramping syndrome (7 of 14). Most owners (26 of 29) had changed their dog's diet, with approximately 50% (14 of 26) reporting a subsequent reduction in the frequency of episodes.CLINICAL SIGNIFICANCEThis study demonstrates similarities in the phenotype of canine epileptoid cramping syndrome to paroxysmal dystonic choreoathetosis, a paroxysmal dyskinesia reported in humans. This disorder appears to be associated with gastrointestinal signs in some dogs and appears at least partially responsive to dietary adjustments.

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1 The 5-HT4 receptor has only recently been identified but has yet to be cloned. This paper describes the pharmacology of a potent and selective 5-HT4 receptor antagonist, GR113808, which will be useful in the further characterization of this receptor. 2 On the guinea-pig ascending colon, GRI 13808 (1 nM-0.1 M) behaved as an antagonist of 5-hydroxytryptamine (5-HT)-induced contraction, producing rightward displacements of the concentration-effect curve to 5-HT and a concentration-related depression of the maximum effect. However, the compound had no effect on cholecystokinin (CCK-8)-induced contraction in concentrations up to 1 LM. 3 In the guinea-pig colon preparation, onset and offset of the antagonism by GRI13808 of 5-HTinduced contraction was examined. Incubation of the tissues for either 15 min, 30 min or 60 min produced similar rightward displacements of the concentration-effect curves to 5-HT, with no increase in the degree of depression of the maxima with increasing time of incubation. Experiments examining offset of antagonism (0.01 4M) demonstrated that washout for 30 min was required to reverse fully the effects of the antagonist. 4 Potency estimates in the colon for GRI13808 were made by determining approximate pA2 values (30 min) using the Gaddum equation. The values obtained were 9.2, 9.7 and 9.2 when tested against the agonists 5-HT, 5-methoxytryptamine and R,S-zacopride respectively. 5 On the carbachol-contracted tunica muscularis mucosae preparation of the rat thoracic oesophagus, GR 113808 behaved as an antagonist of 5-HT-induced relaxation, producing no reduction in maximum response. Analysis of these data yielded a pA2 of 9.3. GR1 13808 also antagonised the relaxant effects of 5-methoxytryptamine (pA2 = 9.0) and R,S-zacopride (pA2 = 9.4). The compound had no effect on isoprenaline-induced relaxation of the carbachol-contracted oesophagus at a concentration of 1 gM.6 In tests of selectivity, GR113808 had only low affinity for 5-HT3 receptors (pKi = 6.0) and had no functional activity at either 5-HT2 or 5-HT,-like receptors on vascular smooth muscle preparations. In a range of binding assays, GRi 13808 was shown to have no appreciable affinity for any other receptor type investigated. 7 In the anaesthetized piglet, GRI13808 was a potent antagonist of 5-methoxytryptamine-induced tachycardia (mean DRo = 97.2 gg kg-' h-'). The compound was ineffective against isoprenaline-induced tachycardia. 8 The present results are discussed in comparison with those for existing antagonists at the 5-HT4 receptor. The results of this study indicate that GRI13808 will be a valuable antagonist for studying 5-HT4 receptor mechanisms in vitro and in vivo and validate its use as a radioligand for determining 5-HT4 receptor distribution.