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SUMMARY:Current theories on the pathophysiology of equine laminitis – th
 e link between the gut and foot - Professor Jonathan Elliott\, Royal Veter
 inary College\, London
DTSTART:20090610T153000Z
DTEND:20090610T163000Z
UID:TALK17878@talks.cam.ac.uk
CONTACT:Suzy Blows
DESCRIPTION:Equine laminitis is a painful debilitating condition that seem
 s to be a product of domestication of horses associated with the practice 
 of feeding carbohydrate rich pasture in excess of requirements\, particula
 rly in ponies.  We have been working on the hypothesis that caecal bacteri
 a\, when presented with carbohydrate in large quantities tend to ferment t
 his.  Fermentation by gram positive bacteria is associated with a fall in 
 pH of the caecal liquor. As a means of providing themselves with increased
  intracellular buffering capacity\, these bacteria produce amino acid deca
 rboxylase enzymes which convert amino acids present in the caecal fluid in
 to primary amines which can act as intracellular buffers.  The reason we t
 hought this might be the case was that foods formed by bacterial fermentat
 ion processes (e.g. cheese and wines) have a high content of amines. Prima
 ry amines derived from some amino acids have vasoactive properties. In the
  1960s it was recognised that human patients taking drugs that inhibit the
  metabolism of amines (monoamine oxidase inhibitors) could suffer from sev
 ere hypertensive crises if they ate cheese or drank red wines with high ty
 ramine content.  This so called ‘cheese effect’ is the result of the i
 ndirect sympathomimetic effect of tyramine which displaces norepinephrine 
 from sympathetic nerve endings leading to a rise in blood pressure. Monoam
 ine oxidase enzymes present in the epithelial cells lining the gut wall an
 d in liver cells normally protect individuals from suffering these hyperte
 nsive crises. We wondered whether amines released from the gut in response
  to ingestion of excessive amounts of carbohydrate might lead to a similar
  reaction in ponies whereby dietary amines caused vasoconstriction of the 
 digital vasculature\, leading to the prodromal phases of laminitis.\n\nOve
 r the last 10 years we have gathered circumstantial evidence that the amin
 e theory may contribute to laminitis. We showed that amines are present in
  the caecal fluid of horses and ponies\, the concentrations being related 
 to diet and increasing when carbohydrate rich pasture is consumed. We also
  showed that feeding an in vitro model of the equine caecum with starch an
 d inulin led to concentration and time related increases in concentration 
 of vasoactive amines and gram positive bacteria proliferated and the pH de
 creased. The amines produced in the caecum could be measured in the plasma
 . Furthermore they were found at higher concentrations in the systemic cir
 culation in ponies turned out onto spring/summer pasture as compared to wh
 en the same ponies were fed winter pasture supplemented with hay. In addit
 ion\, dietary amines can stimulate the release of 5-hydroxytryptamine from
  platelets and cause constriction of isolated digital blood vessels. In so
 me cases\, the plasma concentrations of these amines in the spring/summer 
 are close to the threshold for causing constriction of the digital circula
 tion. Infusion of some of these amines into the systemic circulation was a
 ssociated with a reduced digital blood flow and a concomitant rise in plas
 ma 5-HT concentration and inhibitors of 5-HT receptors have been shown to 
 prevent dietary amine-induced digital vasoconstriction.\n\nThese data\, wh
 ilst interesting\, do not prove the link between these phenomena and pastu
 re-induced laminitis. Nor do they explain why some ponies are prone to rec
 urrent bouts of laminitis whereas others eating exactly the same pastures 
 year after year never suffer from this debilitating problem. The underlyin
 g phenotype of a pony prone to laminitis has recently been suggested to be
  associated with a resistance to the hormone insulin. The insulin resistan
 ce appears to become much more pronounced as the laminitis prone ponies ea
 t carbohydrate rich grass in the spring-summer months.  Laminitis prone po
 nies seem to have higher blood pressure than their ‘normal’ counterpar
 ts in these months whereas in the winter months there is no difference bet
 ween these two groups in their blood pressure. Furthermore\, laminitis pro
 ne ponies have higher circulating triglyceride and uric acid concentration
 s when compared to their non-laminitis prone counterparts eating the same 
 pasture. These observations are substantiated by a number of different gro
 ups working on laminitis throughout the world yet the reason for the assoc
 iation between this metabolic phenotype (which shares some similarities wi
 th ‘metabolic syndrome’ in people) remains to be determined. It is int
 eresting to speculate that the insulin resistant state causes a state of e
 ndothelial cell dysfunction\, predisposing these ponies to excessive vasoc
 onstriction and platelet activation in the digital circulation when the ci
 rculation is exposed to more amines absorbed from the caecum as a result o
 f rapid ingestion of carbohydrate.  It is also interesting to note that th
 e endothelium is involved in amine metabolism by an enzyme called semicarb
 azide sensitive amine oxidase (SSAO) which preferentially metabolises prim
 ary monoamines\, including one that is not vasoactive but is highly abunda
 nt in the caecum\, namely methylamine. When the endothelium metabolise pri
 mary monoamines\, such as methylamine\, it produces ammonia\, hydrogen per
 oxide and the corresponding aldehyde of the amine – in the case of methy
 lamine this is formaldehyde.  The amine metabolites can be damaging to the
  endothelium and contribute to endothelial cell dysfunction. Intriguingly\
 , SSAO expression is known to increase in other species in association wit
 h the diabetic state where its upregulation has been associated with the v
 ascular complications of diabetes.\n\nTo investigate this possibility we h
 ave examined endothelial cell function in vitro in equine digital veins an
 d arteries following incubation with non-vasoactive primary monoamines\, s
 uch as benzylamine and methylamine. Preliminary data suggests that some pr
 oducts of the metabolism of these amines can interfere with endothelial-de
 pendent relaxation\, particularly when the nitric oxide system has been pa
 rtially inhibited.  Further work is necessary to investigate this phenomen
 on further and to determine methods whereby endothelial cell function coul
 d be assessed in vivo to test the hypothesis that ponies predisposed to la
 minitis have endothelial cell dysfunction that is related to their suscept
 ibility to laminitis.  In summary\, a range of trigger possible trigger fa
 ctors continue to be investigated in laminitis research. Dietary amines re
 main possible candidates\, although definitive proof awaits prospective in
 terventional clinical trials.  \n\n
LOCATION:Lecture Theatre 1\, Department of Veterinary Medicine
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