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