The effect of insulin treatment and of islet transplantation on the resistance artery function in the STZ-induced diabetic rat.
1. This study was designed to investigate the influence of insulin treatment and islet transplantation on the smooth muscle contractility and endothelium-dependent and independent relaxation of resistance arteries in the chemically induced streptozotocin (STZ) diabetic rat after 6-8 weeks, and 12-14 weeks of diabetes, compared to non-diabetic age-matched controls. 2. The morphology, and contractile responses to high potassium physiological salt solution (KPSS), KPSS containing 10(-5) M noradrenaline (NAK), and concentration-response curves to noradrenaline (NA) of mesenteric resistance arteries were recorded, along with the endothelium-dependent relaxation responses to acetylcholine (ACh) and bradykinin (BK), and endothelium-independent relaxation to sodium nitroprusside (SNP). Concentration-response curves were then repeated in the presence of a nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NOARG). 3. Insulin-treated diabetic rats in the 12 week study demonstrated enhanced vascular contractility to KPSS, NAK and NA, compared to age-matched non-diabetic controls. 4. Incubation with L-NOARG resulted in both a significant increase in maximum contractile response, and sensitivity (pD2) to NA in the untreated diabetic group (6 weeks). A significant shift in sensitivity was also seen in the insulin-treated diabetic group. In the 12 week study, incubation with L-NOARG resulted in an increased maximum contractile response and sensitivity to NA in the insulin-treated diabetics. An increase in sensitivity was also observed in the untreated diabetic group. 5. Endothelium-dependent relaxation to ACh was significantly augmented in the untreated diabetics (6-weeks), compared to the control group. In the 12-week study, relaxation to both ACh and BK was not significantly different in any of the experimental groups when compared to the sham-operated non-diabetic controls. 6. Incubation with L-NOARG resulted in a significant attenuation of the maximum relaxation response to ACh and BK in all of the experimental groups, in the 6- and the 12-week study. 7. There was no significant difference in the maximum relaxation response or sensitivity to sodium nitroprusside between the diabetic groups and their age-matched controls in either the 6-week or the 12-week study. 8. The results of this study suggest an enhanced release of nitric oxide in the early stages of diabetes, which is more evident in the untreated diabetic rats than the insulin treated, and appears to normalize as the duration of diabetes progresses. This study also shows that the alteration in vascular reactivity of the resistance arteries can be restored to within normal limits by the transplantation of islets of Langerhans, and that islet transplantation is an effective strategy in the correction of the metabolic abnormalities associated with insulin-dependent diabetes.
Department of Medicine, Leicester Royal Infirmary.
K M
KM
Heygate
J
J
Davies
M
M
Holmes
R F
RF
James
H
H
Thurston
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000494:pharmacology*; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D013311:Streptozocin; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects*
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D019335:Nitroarginine; D009569:Nitric Oxide; D013311:Streptozocin; D001920:Bradykinin