Superoxide-NO interaction decreases flow- and agonist-induced dilations of coronary arterioles in Type 2 diabetes mellitus

TY - JOUR

T1 - Superoxide-NO interaction decreases flow- and agonist-induced dilations of coronary arterioles in Type 2 diabetes mellitus

AU - Bagi, Zsolt

AU - Koller, Akos

AU - Kaley, Gabor

PY - 2003/10/1

Y1 - 2003/10/1

N2 - Type 2 diabetes mellitus (T2-DM) markedly increases the incidence of ischemic heart disease (IHD) and, consequently, mortality. However, the underlying mechanisms leading to IHD in T2-DM are not completely understood. We hypothesized that in T2-DM the regulation of coronary microvascular resistance by local mechanisms is altered. Thus, in coronary arterioles (diameter: ∼ 80 μm) isolated from male mice with T2-DM (C57BL/KsJ-db/db) and control littermates, responses to changes in intraluminal pressure, flow, and agonists with known mechanisms of action were studied. Increases in pressure (from 20 to 120 mmHg) resulted in similar myogenic responses of coronary arterioles of control and db/db mice, whereas dilations in response to cumulative concentrations of ACh and the nitric oxide (NO) donor NONOate were significantly decreased compared with those of control vessels. On the other hand, responses to adenosine were not different between vessels of control and db/db mice. Increases in flow (0-20 μl/min) resulted in dilations of control vessels (maximum: 38 ± 4%) that were inhibited by the NO synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). In contrast, arterioles of db/db mice exhibited greatly reduced dilations to flow (maximum: 4 ± 6%) that were unaffected by L-NAME. In carotid arteries of db/db mice, superoxide dismutase (SOD)-sensitive, enhanced superoxide production was detected by dihydroethydine staining and lucigenin enhanced chemiluminescence. Correspondingly, intraluminal administration of SOD significantly augmented flow-, ACh-, and NONOate-induced dilations of diabetic arterioles, and then flow- and ACh-induced responses could be inhibited by L-NAME. Collectively, these findings suggest that in T2-DM, due to an enhanced superoxide production, NO mediation of agonist- and flow-induced dilations of coronary arterioles is reduced. This alteration in the regulation of coronary microvascular resistance may contribute to the development of IHD in T2-DM.

AB - Type 2 diabetes mellitus (T2-DM) markedly increases the incidence of ischemic heart disease (IHD) and, consequently, mortality. However, the underlying mechanisms leading to IHD in T2-DM are not completely understood. We hypothesized that in T2-DM the regulation of coronary microvascular resistance by local mechanisms is altered. Thus, in coronary arterioles (diameter: ∼ 80 μm) isolated from male mice with T2-DM (C57BL/KsJ-db/db) and control littermates, responses to changes in intraluminal pressure, flow, and agonists with known mechanisms of action were studied. Increases in pressure (from 20 to 120 mmHg) resulted in similar myogenic responses of coronary arterioles of control and db/db mice, whereas dilations in response to cumulative concentrations of ACh and the nitric oxide (NO) donor NONOate were significantly decreased compared with those of control vessels. On the other hand, responses to adenosine were not different between vessels of control and db/db mice. Increases in flow (0-20 μl/min) resulted in dilations of control vessels (maximum: 38 ± 4%) that were inhibited by the NO synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). In contrast, arterioles of db/db mice exhibited greatly reduced dilations to flow (maximum: 4 ± 6%) that were unaffected by L-NAME. In carotid arteries of db/db mice, superoxide dismutase (SOD)-sensitive, enhanced superoxide production was detected by dihydroethydine staining and lucigenin enhanced chemiluminescence. Correspondingly, intraluminal administration of SOD significantly augmented flow-, ACh-, and NONOate-induced dilations of diabetic arterioles, and then flow- and ACh-induced responses could be inhibited by L-NAME. Collectively, these findings suggest that in T2-DM, due to an enhanced superoxide production, NO mediation of agonist- and flow-induced dilations of coronary arterioles is reduced. This alteration in the regulation of coronary microvascular resistance may contribute to the development of IHD in T2-DM.

KW - Coronary arteriole

KW - Flow-induced dilation

KW - Nitric oxide

KW - Superoxide

KW - Type 2 diabetes mellitus

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M3 - Article

VL - 285

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 4 54-4

ER -