Augmented Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxations Attenuate Endothelial Dysfunction in Femoral and Mesenteric, but Not in Carotid Arteries from Type I Diabetic Rats

Abstract

Individual vascular beds exhibit differences in vascular reactivity. The present study investigates the effects of streptozotocininduced type I diabetes on endothelium-dependent responses of rat carotid, femoral, and mesenteric arteries. Rings with and without endothelium, suspended in organ chambers for isometric tension recording, were contracted with phenylephrine and exposed to increasing concentrations of acetylcholine. In carotid and femoral arteries, acetylcholine produced concentration-and endothelium-dependent relaxations that were abolished by N -nitro-L-arginine methyl ester (L-NAME; specific nitric-oxide synthase inhibitor) and were impaired slightly in preparations from streptozotocin-treated rats (STZ-rats). This impairment could be prevented by L-arginine. In femoral arteries incubated with L-NAME, acetylcholine caused endotheliumdependent contractions that were abolished by 3-[(6-amino-(4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronapht]-1-yl) propionic acid (S18886) (antagonist of thromboxane A 2 /prostaglandins H 2 -receptors) and reversed to relaxation by indomethacin (inhibitor of cyclooxygenase). The latter relaxation was inhibited by charybdotoxin plus apamin, suggesting a role of endothelium-dependent hyperpolarizing factor (EDHF). This EDHF-mediated component was augmented slightly in arteries from STZ-rats. In mesenteric arteries, relaxations to acetylcholine were only partially inhibited by L-NAME, and the L-NAMEresistant component was abolished by charybdotoxin plus apamin. In the mesenteric arteries from STZ-rats, L-NAME-sensitive relaxations to acetylcholine were reduced and the EDHFcomponent was augmented. These findings demonstrate a marked heterogeneity in endothelium-dependent responses in rat arteries and their differential adaptation in the course of type I diabetes. In particular, the EDHF-mediated component not only compensates for the reduced bioavailability of nitric oxide in the femoral and mesenteric artery but also counteracts the augmented endothelium-dependent contractions in the former.The endothelial cells release both endothelium-derived relaxing factors and endothelium-derived contracting factors (EDCFs), which control the tone of the underlying smooth muscle. Endothelium-derived relaxing factors include NO, prostacyclin, and several endothelium-derived hyperpolarizing factors (EDHFs). Different vascular beds, exposed to varying local and neurohumoral influences, exhibit a marked heterogeneity in vascular responsiveness (Vanhoutte, 1978;Lü scher and Vanhoutte, 1990;Feletou and Vanhoutte, 2006). NO is a major contributor to endothelium-dependent relaxations in large conduit arteries, whereas endothelium-derived hyperpolarizing factor(s) play a predominant role in small arteries (Nagao et al., 1992;Shimokawa et al., 1996). Diabetes mellitus is characterized by hyperglycemia resulting from a defective secretion and/or action of insulin. Data on the impairment of endothelial function caused by type I diabetes are controversial. Thus, in blood vessels from...

Sex differences in mesenteric endothelial function of streptozotocin-induced diabetic rats: a shift in the relative importance of EDRFs

“…Specifically, in diabetic animals evidence suggests both increased and decreased EDHF-mediated response (29). There are reports of increased EDHF activity in the mesenteric arteries of diabetic animals (64,75), and it has been proposed that EDHF may serve as a backup vasodilator in situations associated with an altered bioavailability of NO (8,52). Nevertheless, a decrease in EDHF-mediated response has also been reported in the mesenteric and renal arteries (17,28,49,95).…”

“…Wigg et al (95) reported a preserved NO-dependent response, but an impaired EDHF-dependent response in femoral and mesenteric arteries. On the other hand, Shi et al (75) described a reduced NO-mediated response and an enhanced EDHF-mediated response in mesenteric arteries of diabetic rats. Finally, Leo et al (45) reported both impaired NO-and EDHF-mediated relaxation in the same arteries.…”

Oxygen‐derived free radicals mediate endothelium‐dependent contractions in femoral arteries of rats with streptozotocin‐induced diabetes

“…The effect of STZ-induced diabetes on nitric oxidemediated vasodilatation is still controversial; it has been reported as normal in the aorta (Head et al, 1987;Harris and MacLeod, 1988;Mulhern and Docherty, 1989), mesenteric artery (Harris and MacLeod, 1988) and femoral artery (Wigg et al, 2001), as blunted in aorta (Pieper et al, 1997;Vallejo et al, 2000), mesenteric artery (Heygate et al, 1995;Vallejo et al, 2000;Shi et al, 2007) and femoral artery (Shi et al, 2006) or augmented in aorta (Altan et al, 1989). The production of vasoconstrictor prostaglandins is augmented in diabetic animals (aorta , renal artery (Pflueger et al, 1999) and femoral artery (Shi et al, 2007)).…”

Obesity Up-Regulates Intermediate Conductance Calcium-Activated Potassium Channels and Myoendothelial Gap Junctions to Maintain Endothelial Vasodilator Function

“…Altered endothelial function is associated with animal models of type I diabetes (Shi et al, 2006), type II diabetes (Park et al, 2008), pulmonary hypertension (Kemp et al, 1995), hypercholesterolemia (Brandes et al, 1997), heart failure (Katz and Krum, 2001), and aging (Gaubert et al, 2007), where NO activity is reduced, and K Ca -mediated EDH is preserved or up-regulated to maintain overall vasodilation. The disease-related effects of endothelium-dependent vasodilation in diet-induced obesity are unknown.…”