title: Cellular mechanisms responsible for the inotropic action of insulin on failing human myocardium.
abstract: BACKGROUND
  An increase in intracellular calcium transients is responsible for the positive inotropic effect of insulin on human myocardium, but the mechanisms involved in this increase in [Ca2+]i remain unclear.
  
  
  METHODS
  We studied isolated trabeculae or cardiomyocytes from end-stage failing hearts of 38 patients undergoing heart transplantation. The effect of insulin on isometric twitch force (37 degrees C, 0.5 Hz) and L-type Ca2+ current (whole-cell voltage clamp) was assessed.
  
  
  RESULTS
  Crystalline insulin increased the contractile force in a dose-dependent manner (0.01 to 10 micromol/liter), with a maximum increase of 45 +/- 8% (p < 0.05) at 1 micromol/liter. It also increased L-type Ca2+ peak current density by 26 +/- 6% (p < 0.05). This insulin-mediated positive inotropic effect was unchanged in the presence of propranolol (1 micromol/liter). Positive inotropy was partially independent of glucose. L-type Ca2+ channel blockade (diltiazem, 5 micromol/liter), and sarcoplasmic reticulum (SR) Ca2+-release channel blockade (ryanodine, 0.1 micromol/liter) did not affect the inotropic response to insulin. However, blockade of SR Ca2+-ATPase (cyclopiazonic acid, 10 micromol/liter), inhibition of Na+-H+ exchange (HOE642, 10 micromol/liter), and inhibition of Na+-Ca2+ exchange (SEA0400, 1 micromol/liter) partially prevented the inotropic response to insulin.
  
  
  CONCLUSIONS
  Positive inotropy of insulin was not related to catecholamine release and subsequent stimulation of beta-adrenergic receptor, but it may enhance the activity of SR Ca2+-ATPase and trans-sarcolemmal Ca2+ entry, mainly via reverse-mode Na+-Ca2+ exchange and insulin-mediated activation of Na+-H+ exchange. We hypothesize that these changes in [Ca2+]i might be secondary to the activation of reverse-mode Na+-Ca2+ exchange, presumably via elevated intracellular Na+ concentration.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Neihu, Taipei, Taiwan, ROC.
authors.forename: Chih-Hsueng
authors.initials: CH
authors.lastname: Hsu
authors.forename: Jeng
authors.initials: J
authors.lastname: Wei
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Yang
authors.forename: Chien-Song
authors.initials: CS
authors.lastname: Tsai
authors.forename: Cheng-I
authors.initials: CI
authors.lastname: Lin
mesh_terms: D000328:Adult; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000502:physiology; D002303:Cardiac Output, Low / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D019831:Sodium-Calcium Exchanger / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D002395:Catecholamines; D007328:Insulin; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D014665:Vasodilator Agents; D011433:Propranolol; D000252:Calcium-Transporting ATPases; D004110:Diltiazem; D002118:Calcium