THROMBOXANE-A(2) PROSTAGLANDIN-H(2) RECEPTORS IN STREPTOZOTOCIN-INDUCED DIABETES - EFFECTS OF INSULIN THERAPY IN THE RAT

Thromboxane A2 (TXA2) and prostaglandin H-2 (PGH2) are potent vasoacti ve and proaggregatory agents whose synthesis has been shown to be elev ated in diabetes mellitus. In the present study the effects of strepto zotocin (STZ)-induced uncontrolled diabetes (Severe) and insulin-treat ed STZ diabetes (Moderate) on TXA2/PGH2 receptor density and affinity in platelets, glomerular membranes and aortic membranes were determine d using [I-125]-BOP, a TXA2/PGH2 receptor agonist. The affinity and de nsity of platelet TXA2/PGH2 receptors in Control, Moderate and Severe groups and glomerular membranes were not significantly different. Howe ver, daily insulin therapy caused significant changes in both TXA2/PGH 2 receptor affinity and density of aortic membranes: K(d) (nM) = 0.67 +/- 0.09, (n = 5), for Control; 0.27 +/- 0.05, (n = 6), Moderate; and 0.74 +/- 0.16, (n = 5), Severe; B(max) (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. Unt reated diabetes mellitus (Severe) was associated with a decreased resp onsiveness of aortic segments without affecting maximum contractile re sponses (EC50 = 24.6 +/- 5.9 nM, (n = 10);*p < 0.05) compared to Cont rol 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 Co ntrol (EC50 = 11.4 +/- 1.2 nM, (n = 10); *p < 0.05 compared to Severe ). These results suggest that insulin therapy in the diabetic state si gnificantly influences aortic TXA2/PGH2 receptors, as well as vascular responsiveness to TXA2/PGH2 mimetics.