Thromboxane A2/prostaglandin H2 receptors in streptozotocin-induced diabetes: effects of insulin therapy in the rat.
Thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) are potent vasoactive and proaggregatory agents whose synthesis has been shown to be elevated in diabetes mellitus. In the present study the effects of streptozotocin (STZ)-induced uncontrolled diabetes (Severe) and insulin-treated STZ diabetes (Moderate) on TXA2/PGH2 receptor density and affinity in platelets, glomerular membranes and aortic membranes were determined using [125I]-BOP, a TXA2/PGH2 receptor agonist. The affinity and density of platelet TXA2/PGH2 receptors in Control, Moderate and Severe groups and glomerular membranes were not significantly different. However, daily insulin therapy caused significant changes in both TXA2/PGH2 receptor affinity and density of aortic membranes: Kd (nM) = 0.67 +/- 0.09, (n = 5), for Control; 0.27 +/- 0.05*, (n = 6), Moderate; and 0.74 +/- 0.16, (n = 5), Severe; Bmax (fmoles/mg protein) = 38.6 +/- 3.1, Control; 20.2 +/- 4.2*, Moderate; and 37.1 +/- 4.1, Severe: (*p < 0.05 compared to Control and Severe). Contractile responses of aortic segments to the TXA2/PGH2 receptor agonist U46619 were determined. Untreated diabetes mellitus (Severe) was associated with a decreased responsiveness of aortic segments without affecting maximum contractile responses (EC50 = 24.6 +/- 5.9* nM, (n = 10); *p < 0.05) compared to Control rats (EC50 = 11.8 +/- 1.6 nM, (n = 13)). Insulin therapy reversed the decrease seen in the Severe group to a value not different from Control (EC50 = 11.4 +/- 1.2* nM, (n = 10); *p < 0.05 compared to Severe). These results suggest that insulin therapy in the diabetic state significantly influences aortic TXA2/PGH2 receptors, as well as vascular responsiveness to TXA2/PGH2 mimetics.
Morinelli
T A
TA
Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston 29425.
Tempel
G E
GE
Jaffa
A A
AA
Silva
R H
RH
Naka
M
M
Folger
W
W
Halushka
P V
PV
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects; D008297:Male; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011463:Prostaglandins H; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000187:drug effects* / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000187:drug effects* / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2
D007328:Insulin; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid