Augmented inositol phosphate production in mesenteric arteries from diabetic rats

The effects of noradrenaline (NA) on contraction and phosphoinositide metabolism were compared in mesenteric arteries from rats with chronic streptozotocin-induced diabetes and from age-matched control rats. Maximum contractile responses of mesenteric arteries from diabetic rats to NA (30 microM) were significantly greater than control in both the presence and absence of extracellular Ca2+. Basal incorporation of [3H]myoinositol into total [3H]inositol phosphates was greater in diabetic than control mesenteric arteries. NA (30 microM) resulted in a time-dependent increase in total [3H]inositol phosphate production, which was also significantly greater in diabetic than in control preparations. The increase in total [3H]inositol phosphates produced by NA in both control and diabetic arteries was blocked by the alpha 1-adrenoceptor antagonist, prazosin. Absolute levels of inositol 1,4,5-trisphosphate (I(1,4,5)P3), measured by protein binding assay, were also increased in response to 30 microM NA in both control and diabetic arteries. Although basal I(1,4,5)P3 levels were not significantly different, NA-induced increases in I(1,4,5)P3 were significantly greater in diabetic than in control arteries at each time-point measured. These data indicate that phosphoinositide metabolism is enhanced in mesenteric arteries from rats with chronic streptozotocin-induced diabetes in response to a maximum concentration of NA. Augmented production of the second messengers I(1,4,5)P3 and, presumably, 1,2-diacylglycerol may contribute to the enhanced maximum contractile responses of the diabetic arteries to NA.