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-mu-M) were significantly greater than control in both the presence and absence of extracellular Ca2+. Basal incorporation of [H-3]myoinositol into total [H-3]inositol phosphates was greater in diabetic than control mesenteric arteries. NA (30-mu-M) resulted in a time-dependent increase in total [H-3]inositol phosphate production, which was also significantly greater in diabetic than in control preparations. The increase in total [H-3]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-mu-M 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.