Cellular mechanisms responsible for the inotropic action of insulin on failing human myocardium.
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.
Hsu
Chih-Hsueng
CH
Graduate Institute of Medical Sciences, National Defense Medical Center, Neihu, Taipei, Taiwan, ROC.
Wei
Jeng
J
Chen
Yao-Chang
YC
Yang
Shih-Ping
SP
Tsai
Chien-Song
CS
Lin
Cheng-I
CI
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
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