Jpn. J. Pharmacol. 80 (4), 359 - 370 (1999)

Biological Evaluation of the Nitric Oxide-Trapping Agent, N-Methyl-d-glucamine Dithiocarbamate-Fe2+, as a Probe of Nitric Oxide Activity Released From Control and Diabetic Rat Endothelium

Galen M. Pieper (1) and Ching-San Lai (2)

(1) Department of Transplant Surgery, Medical College of Wisconsin, Froedtert Memorial Hospital, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
(2) Medinox, Inc., San Diego, CA 92121, USA

Abstract: We utilized the nitric oxide (NO) scavenger N-methyl-d-glucamine dithiocarbamate-Fe2+ (MGD-Fe) to characterize the role of NO in basal and acetylcholine (ACh)-stimulated relaxation arising from the endothelium of control vs diabetic rat aortic rings. In phenylephrine-contracted rings, MGD-Fe produced an additional increment in tension that was indomethacin-insensitive (i.e., excluding a role of prostanoids in this action). This MGD-Fe-sensitive component was more pronounced in control rings than diabetic rings and of the same magnitude achieved in rings without MGD-Fe treatment after removal of endothelium or treatment with the NO synthase inhibitor l-nitroarginine (L-NA). This suggests complete scavenging of basal NO by MGD-Fe and supports reduced basal NO in diabetic rings. ACh fully relaxed both control and diabetic rings. This relaxation was abolished by removal of the endothelium and was inhibited by L-NA (by 100% and 90% in control and diabetic rings, respectively). In contrast, MGD-Fe only partially inhibited ACh-induced relaxation in control (65}5% inhibition) and diabetic (41}11% inhibition) rings. The MGD-Fe-resistant component was not further modified by indomethacin. Addition of l-arginine (L-ARG) (but not d-arginine (D-ARG) enhanced the ACh-induced relaxation of MGD-Fe-treated diabetic (but not control) rings. These data provide evidence about endothelium-dependent relaxation in control and diabetic rings which cannot be discerned by use of L-NA alone. This study suggests that ACh produces a NO synthase-dependent vasodilation, a portion of which is due to free NO radical (ENO) or due to NO in a form or location that is unavailable for scavenging by MGD-Fe.

Keywords: Nitric oxide, Endothelium, Dithiocarbamate, Arginine, Diabetes mellitus

CopyrightŠ The Japanese Pharmacological Society 1999

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