The incretin hormone, glucagon-like peptide (GLP)-1(7-36), is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) into GLP-1(9-36), and although it is agreed that most, if not all, of the metabolic effects are attributable to the intact peptide, the degree to which the cardiovascular effects are due to the cleavage product is unclear. The purpose of this study was to measure the regional haemodynamic effects of GLP-1(7-36), and determine the extent to which the cardiovascular effects of GLP-1(7-36) were influenced by DPP-4 inhibition and reproduced by GLP-1(9-36). Additional experiments investigated the involvement of autonomic mechanisms in the cardiovascular effects of GLP-1(7-36). EXPERIMENTAL APPROACHRegional haemodynamic effects of bolus doses and 4 h infusions of GLP-1(7-36) amide and GLP-1(9-36) amide were measured in conscious, chronically instrumented rats; the influence of DPP-4 inhibition and autonomic blockade on responses to GLP-1(7-36) were also assessed. KEY RESULTSGlucagon-like peptide-1(7-36) had clear regional haemodynamic effects comprising tachycardia, a rise in blood pressure, renal and mesenteric vasoconstriction and hindquarters vasodilatation, whereas GLP-1(9-36) was devoid of any cardiovascular actions. The effects of GLP-1(7-36) were enhanced by DPP-4 inhibition, and the tachycardia and hindquarters vasodilatation were b-adrenoceptor-mediated. CONCLUSIONS AND IMPLICATIONSIn conscious rats, the cardiovascular effects of GLP-1(7-36) resemble those of the GLP analogue, exendin-4, and are attributable to the intact peptide rather than the cleavage product, GLP-1(9-36).

1 Neuromuscular (NM) changes resulting from organo phosphate exposure are known to be complex. After severe acute poisoning recovery from initial depolar isation paralysis may be followed in a limited number of cases by onset of a non-depolarisation paralysis (the Intermediate Syndrome). It is not clear whether this block arises subclinically in all cases of poisoning as a sequel to the initial depolarisation. 2 Single fibre electromyography (SFEMG) is a sensitive clinical neurophysiological technique allowing detec tion of subclinical changes at the neuromuscular junction. In the study reported it has been used to examine changes in NM transmission in the forearm of fit volunteers exposed to a low level of sarin (isopropyl methyl phosphonofluoridate). 3 Small changes in SFEMG were seen at three hours and three days after an exposure sufficient to cause a reduction in red cell acetyl cholinesterase to 60% of normal. The SFEMG changes were not accompanied by any clinical neuromuscular symptoms or signs and returned to normal 2 years after exposure. 4 The results indicate that there are reversible subclini cal changes compatible with the development of non depolarising NM block without frank clinical expres sion. In the small population examined there were individual variations in response which may reflect differences in safety margin at the neuromuscular junction.