Possible modulation by endothelin-1, nitric oxide, prostaglandin I2 and thromboxane A2 of vasoconstriction induced by an α-agonist in mesenteric arterial bed from diabetic rats

We hypothesized that in diabetes arterial reactivity to constrictors is attenuated by certain endothelium-derived substances. We examined the vasoconstriction induced by methoxamine (alpha(1)-agonist) in isolated mesenteric arterial beds from streptozotocin (STZ)-induced diabetic rats and age-matched control rats. The dose-response curve for methoxamine was shifted to the right and the maximum contractile response was impaired in mesenteric arterial beds from diabetic rats. The methoxamine vasoconstriction was reduced in endothelium-denuded preparations from controls rats, but increased in those from diabetic rats. Treatment with the nitric oxide synthase inhibitor N-G-nitro-L-arginine enhanced the vasoconstrictions induced by methoxamine in both control and diabetic rats. Indomethacin had no effect on the methoxamine vasoconstriction in control rats, but it shifted the dose-response curve to the left in diabetic rats. Whether given with or without indomethacin, BQ-123, (an ETA-receptor antagonist) plus BQ-788 (an ETB-receptor antagonist) shifted the dose-response curve for methoxamine to the right in control rats (while reducing the maximum response) but to the left in diabetic rats. The methoxamine-stimulated release of 6-keto-prostaglandin F-1 alpha from the mesenteric arterial bed in diabetic rats was approximately four times that seen in the control rats, while the methoxamine-induced release of thromboxane B-2 (TXB2), a metabolite of thromboxane A(2) (TXA(2)), was less in diabetic rats than in the control animals. These results suggest that an increased production of prostaglandin I-2 (PGI(2)) and decreased formation of TXA(2) could be: responsible for the attenuation of the methoxamine-induced mesenteric vasoconstriction seen in diabetic rats, and these changes in the diabetic state could be partly responsible for the lower blood pressure seen in our diabetic rats.