Augmented vascular relaxation to KT-362 in diabetic rat aorta: comparison to diltiazem.
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.
Pieper
G M
GM
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
Gross
G J
GJ
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004110:Diltiazem / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013841:Thiazepines / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D013841:Thiazepines; C051271:KT 362; D015237:Dinoprost; D004110:Diltiazem; D011188:Potassium; D009638:Norepinephrine