title: Local methacholine but not bradykinin potentiates insulin-mediated glucose uptake in muscle in vivo by augmenting capillary recruitment.
abstract: OBJECTIVE
  Insulin has nitric-oxide-dependent vasodilatory effects in muscle, including capillary recruitment, that enhance access for itself and glucose. However, nitric-oxide-dependent vasodilators other than methacholine do not enhance insulin action. Our hypothesis is that methacholine, unlike bradykinin, enhances insulin-mediated glucose uptake in muscle by augmenting capillary recruitment.
  
  
  METHODS
  Local infusion of either methacholine or bradykinin into one leg of the anaesthetised rat was made during physiological insulin (3 mU.kg(-1).min(-1)) infusion under euglycaemic conditions and without affecting systemic blood pressure. Whole-body glucose infusion was determined, as was femoral blood flow, 2-deoxyglucose uptake into calf muscles and the metabolism of infused 1-methylxanthine, a measure of capillary recruitment for each leg.
  
  
  RESULTS
  Methacholine alone (0.3 micromol.l(-1)) increased femoral arterial blood flow, increased capillary recruitment but had no effect on 2-deoxyglucose uptake of the test leg relative to the contra-lateral control leg. Insulin alone (systemically) required a glucose infusion rate of 8.7 mg.kg(-1).min(-1) to maintain euglycaemia, increased 2-deoxyglucose uptake and capillary recruitment, but was without effect on femoral blood flow in either leg. Local methacholine with systemic insulin infusion increased femoral blood flow, 2-deoxyglucose uptake and capillary recruitment in the test leg only. Bradykinin (0.07 micromol.l(-1)), alone or with insulin, administered in a manner that increased femoral blood flow similarly to methacholine, did not affect 2-deoxyglucose uptake or capillary recruitment.
  
  
  CONCLUSIONS
  Methacholine but not bradykinin enhances insulin-mediated muscle glucose uptake in vivo. We conclude that methacholine acts at specific sites in the vasculature of muscle to stimulate capillary recruitment and thereby enhance insulin access.
authors.affiliation: Biochemistry, School of Medicine, University of Tasmania, Private Bag 58, Hobart, Tasmania, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Mahajan
authors.forename: S M
authors.initials: SM
authors.lastname: Richards
authors.forename: S
authors.initials: S
authors.lastname: Rattigan
authors.forename: M G
authors.initials: MG
authors.lastname: Clark
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology*; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007328:Insulin; D016210:Methacholine Chloride; D005947:Glucose; D001920:Bradykinin