Augmented Vascular Relaxation to KT-362 in Diabetic Rat Aorta

Abstract

Diabetes-induced alterations in the vasorelaxant properties of the calcium entry blocker diltiazem and a new putative vascular intracellular calcium antagonist KT-362 were studied in isolated thoracic aorta taken from control and chronic (2 months) streptozotocin-induced diabetic rats. Each vessel was contracted with submaximal concentrations of either norepinephrine (NE 10(-6) M) or the adrenoceptor-independent agonist, prostaglandin F2 alpha (PGF2 alpha 10(-5) M). Cumulative additions of diltiazem produced relaxations in both control and diabetic vessels with augmented relaxation in diabetic vessels regardless of which agonist was chosen for contraction. In contrast, KT-362 significantly relaxed control vessels which were precontracted with NE but not with PGF2 alpha. KT-362 produced augmented relaxations in NE-contracted diabetic vessels with a shift in sensitivity of 1 order of magnitude. In the presence of zero calcium, KT-362 (10(-5) M) reduced the phasic contractions to NE by 17% in control vessels as compared with 49% in diabetic vessels despite similar levels of developed tension. KT-362 also augmented the inhibition of NE-induced hydrolysis of phosphatidylinositol (PI) in diabetic vessels. Thus, KT-362 may be a useful tool to investigate intracellular calcium homeostasis in diabetic blood vessels.