Characteristics and mechanisms of tachyphylaxis of cardiac contractile response to insulin.
Although insulin is known to cause internalization of its own receptors, the physiological significance of this phenomenon is not clear. In the isolated rat heart we observed that the positive inotropic effect of 25 munits/ml insulin was completely abolished if the heart was preperfused with insulin for 10 min. This tachyphylactic response to insulin began to appear 3-4 min after starting preperfusion with insulin and was partially reversible after 30 min of washing. Preperfusion with insulin did not affect the action of vanadate, which has insulin-like effect on glucose transport, or the actions of the other positive inotropic agents, isoproterenol and ouabain. The presence of propranolol in the perfusion medium, unlike atenolol, phenoxybenzamine, guanethidine, verapamil or quinidine, modified the inotropic as well as tachyphylactic responses to insulin. The positive inotropic and tachyphylactic responses to insulin were not altered in hearts from reserpine-treated animals. Perfusion of heart with glucose-free solution abolished the tachyphylaxis due to insulin. Likewise, no tachyphylactic response to insulin was evident when iodoacetate, but not sodium fluoride, was added in medium containing glucose. These results suggest that ATP formed during glycolysis may play an important role in insulin-induced tachyphylaxis with respect to cardiac contractile activity.
Sethi
R
R
Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Rupp
H
H
Naimark
B J
BJ
Barwinsky
J
J
Beamish
R E
RE
Dhalla
N S
NS
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D006019:Glycolysis; D007328:Insulin / Q000494:pharmacology*; D007461:Iodoacetates / Q000494:pharmacology; D019807:Iodoacetic Acid; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology; D010477:Perfusion; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013618:Tachyphylaxis / Q000502:physiology; D013997:Time Factors; D014638:Vanadates / Q000494:pharmacology
D007328:Insulin; D007461:Iodoacetates; D014638:Vanadates; D010042:Ouabain; D000255:Adenosine Triphosphate; D011433:Propranolol; D007545:Isoproterenol; D019807:Iodoacetic Acid