Mechanisms of decreased bradykinin- induced vasodilation in experimental hyperlipemia-hyperglycemia: contribution of nitric oxide and Ca2+-activated K+ channels.
Common complications of diabetes are accelerated atherosclerosis and vascular disturbances. We investigated whether the simultaneous insult of hyperlipemia-hyperglycemia affects the reactivity of the resistance arteries to bradykinin (BK), and if so, what are the mechanisms responsible for this disturbance. Experiments were conducted on male Golden Syrian hamsters rendered hyperlipemic (H) by a fat-rich diet, diabetic (D) by streptozotocin injection, or simultaneously hyperlipemic-diabetic (HD). Normal age-matched animals were used as controls (C). At 24 weeks after the induction of disease(s) the vascular reactivity of the mesenteric resistance arteries to BK (10(-8)-10(-4) M) was assayed by the myograph technique. To explore the role of nitric oxide (NO) in modulating the endothelium-dependent BK-induced relaxation, two experimental approaches were employed: (i) in vivo administration of L-arginine (622.14 mg/kg bw) to H, D, and HD hamsters (for 12 weeks); (ii) in vitro blockage of nitric oxide synthase by N(omega)-nitro- L-arginine methyl ester (10(-4) M). To evaluate the contribution of Ca2+-activated K+ channel(s) to BK-induced relaxation, the resistance arteries were exposed to 10(-3) M tetraethylammonium. Comparatively, the endothelium-independent relaxation was assayed using sodium nitroprusside (10(-8)-10(-4) M). The results showed that compared to the H and D groups, the HD hamsters exhibited the most reduced vasodilation of the resistance arteries to BK (34.09 +/- 1.5%). The diminished vasodilation was found to be due to a dual mechanism: an L-arginine:NO pathway and a NO-independent process, mediated via Ca2+-activated K+ channels. In vivo administration of L-arginine had favourable effects especially in the HD group, which manifested (i) an; 30% improvement of attenuated BK relaxation, (ii) an increase in sensitivity of the response to BK, (iii) a 3-fold diminishment of plasma hyperglycemia. Collectively, these data explain in part, the mechanisms and possible ways to correct the arterial endothelial dysfunction when diabetes is complicated with hyperlipemia.
Georgescu
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A
N. Simionescu Institute of Cellular Biology and Pathology, Bucharest, Romania.
Popov
D
D
Simionescu
M
M
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology; D006949:Hyperlipidemias / Q000150:complications* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D008647:Mesocricetus; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D014655:Vascular Resistance; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D024681:Potassium Channels, Calcium-Activated; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001920:Bradykinin