Insulin-receptor binding characteristics in perfused SHR and WKY rat hearts.
This work uses a new heart-perfusion technique to measure 125I-insulin binding on capillary endothelium and myofiber cell membranes in Wistar-Kyoto and spontaneously hypertensive rats. Ringer-Lock buffer was infused at a rate of 1 ml min-1 in the presence of 20 meq l-1 K+ and 125I-insulin through an aortic cannula. The effluent was collected through a catheter introduced into the right atrium. The capillary endothelial lining was removed by detergent treatment to expose the cardiac myocyte surfaces. A physical model describing a 1:1 binding stoichiometry of 125I-insulin with its receptors is proposed and the derived mathematical equations allow for the calculation of binding constants (kn), unbinding constants (k-n), dissociation constants (kd), and residency time constants (tau). The results showed that in the spontaneously hypertensive rats' hearts significant alterations were not noticed in the kinetics of insulin binding with its receptor at the capillary endothelial site compared to hearts of the normotensive control Wistar-Kyoto rats. However, at the myocyte site and in the spontaneously hypertensive rats, steric, configurational, and/or structural modifications for insulin binding with the receptor were observed as indicated by changes in insulin affinity for its receptor. Hence, alterations in insulin binding rather than reduction in insulin receptor number due to hyperinsulinemia, can be considered among the peculiarities of insulin resistance in the spontaneously hypertensive rats. Hyperinsulinemia, therefore, may be considered an upregulatory process as a consequence of insulin-resistance. The results support the hypothesis that insulin-resistance on the myocytes could be a pathophysiologic defect in insulin-receptor structure, function and affinity, and therefore myocardial function.
Bikhazi
A B
AB
Department of Physiology, Faculty of Medicine, American University of Beirut, Lebanon. ab04@aub.edu.lb
Saadeh
F A
FA
Haddad
R E
RE
Nahle
Z A
ZA
Abou Fares
M F
MF
Bitar
K M
KM
Birbari
A E
AE
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002793:Cholic Acids / Q000494:pharmacology; D003902:Detergents / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D006946:Hyperinsulinism / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism* / Q000493:pharmacokinetics; D007333:Insulin Resistance / Q000502:physiology; D007457:Iodine Radioisotopes; D008432:Mathematical Computing; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure*; D010477:Perfusion; D011485:Protein Binding; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011972:Receptor, Insulin / Q000378:metabolism*
D002793:Cholic Acids; D003902:Detergents; D007328:Insulin; D007457:Iodine Radioisotopes; D011972:Receptor, Insulin; C028213:3-((3-cholamidopropyl)dimethylammonium)-1-propanesulfonate