Comparison of effects of diabetes mellitus on an EDHF-dependent and an EDHF-independent artery

Wigg, Susan J; Tare, Marianne; Tonta, Mary A; O’Brien, Richard C; Meredith, Ian T.; Parkington, Helena C.

doi:10.1152/ajpheart.2001.281.1.h232

Cited by 115 publications

(151 citation statements)

References 18 publications

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“…Consistent with previous studies (Wigg et al, 2001;Sandow et al, 2002), endothelium-dependent vasodilation in normal adult rat saphenous artery is NO-mediated, with the response to ACh being blocked by L-NAME and ODQ. The present results demonstrate that the contribution of NO is significantly impaired in obese rat saphenous artery, which is compensated for by the appearance of IK Ca and MEGJmediated activity, to maintain endothelium-dependent vasodilation.…”

Section: Discussionsupporting

confidence: 91%

“…In adult rat saphenous artery, endothelium-dependent vasodilation is entirely NO-mediated (Wigg et al, 2001;Sandow et al, 2002Sandow et al, , 2004. The inability of an EDH to be transferred to the adjacent smooth muscle is caused by the lack of sufficient MEGJs in this bed to facilitate current/ion transfer between the cell layers (Sandow et al, 2002(Sandow et al, , 2004, which contrasts with the saphenous artery of juvenile rat, where MEGJ-dependent EDH is down-regulated after development (Sandow et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Chadha

Haddock²,

Howitt³

et al. 2010

J Pharmacol Exp Ther

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The mechanisms involved in altered endothelial function in obesity-related cardiovascular disease are poorly understood. This study investigates the effect of chronic obesity on endothelium-dependent vasodilation and the relative contribution of nitric oxide (NO), calcium-activated potassium channels (K Ca ), and myoendothelial gap junctions (MEGJs) in the rat saphenous artery. Obesity was induced by feeding rats a cafeteriastyle diet (ϳ30 kJ as fat) for 16 to 20 weeks, with this model reflecting human dietary obesity etiology. Age-and sexmatched controls received standard chow (ϳ12 kJ as fat). Endothelium-dependent vasodilation was characterized in saphenous arteries by using pressure myography with pharmacological intervention, Western blotting, immunohistochemistry, and ultrastructural techniques. In saphenous artery from control, acetylcholine (ACh)-mediated endothelium-dependent vasodilation was blocked by NO synthase and soluble guanylate cyclase inhibition, whereas in obese rats, the ACh response was less sensitive to such inhibition. Conversely, the intermediate conductance K Ca (IK Ca ) blocker 1-[(2-chlorophenyl)diphenyl-methyl]-1H pyrazole attenuates ACh-mediated dilation in obese, but not control, vessels. In a similar manner, putative gap junction block with carbenoxolone increased the pEC 50 for ACh in arteries from obese, but not control, rats. IK1 protein and MEGJ expression was up-regulated in the arteries of obese rats, an observation absent in control. Addition of the small conductance K Ca blocker apamin had no effect on ACh-mediated dilation in either control or obese rat vessels, consistent with unaltered SK3 expression. Up-regulation of distinct IK Caand gap junction-mediated pathways at myoendothelial microdomain sites, key mechanisms for endothelial-derived hyperpolarization-type activity, maintains endothelium-dependent vasodilation in diet-induced obese rat saphenous artery. Plasticity of myoendothelial coupling mechanisms represents a significant potential target for therapeutic intervention.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

Chadha

Haddock²,

Howitt³

et al. 2010

J Pharmacol Exp Ther

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“…Gap junction pathways in retinal arteries [45] and gap junction activity in mesenteric arteries [24] from STZ-induced diabetic rats have been shown to be reduced, and Ding et al [46] demonstrated that Cx37 mRNA expression was reduced in small mesenteric arteries from STZ-induced diabetic apoEdeficient mice compared with nondiabetic apoE-deficient control mice. Furthermore, we have shown a decrease in gap junction activity in isolated renal arteries from the female 25-week-old OZRs, associated with decreases in connexin 40 protein levels and Cx40 mRNA expression (E. J Young and J. J Reid, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…Cell cultures exposed to high glucose levels have been used to study gap junctions and specific connexins in isolation, with results showing attenuation of gap junction activity in bovine aortic endothelial and smooth muscle cells [22,23]. Furthermore, investigations using animal models of type 1 diabetes have shown attenuation of EDHF-mediated responses [24] and gap junction activity in mesenteric [25] arteries from streptozotocin (STZ)-induced diabetic rats. To our knowledge, no studies in insulin-resistant or type 2 diabetic animal models have studied changes in gap junction and connexin activity.…”

Section: Introductionmentioning

confidence: 99%

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

et al. 2008

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Aims/hypothesis The objective of this study was to examine the effect of insulin resistance on endothelium-derived hyperpolarising factor (EDHF) and small mesenteric artery endothelial function using 25-week-old insulin-resistant obese Zucker rats (OZRs) and lean littermate control rats (LZRs). The involvement of gap junctions and their connexin subunits in the EDHF relaxation response was also assessed. Methods Mesenteric arteries were evaluated using the following assays: (1) endothelial function by pressure myography, with internal diameter recorded using video microscopy; (2) connexin protein levels by western blotting; and (3) Cx mRNA expression by real-time PCR. Results Relaxations in response to acetylcholine were significantly smaller in mesenteric arteries from the OZRs than the LZRs, whereas there was no difference in relaxations in response to levcromakalim. Responses to acetylcholine were not altered by nitric oxide inhibitors, but were abolished by charybdotoxin in combination with apamin, which blocked the EDHF component of the response. 40 Gap27 significantly attenuated the response to acetylcholine in the LZRs, but had no effect in the OZRs. Connexin 40 protein and Cx40 mRNA levels in mesenteric vascular homogenates were significantly smaller in the OZRs than in the LZRs, with no difference in connexin 43 or Cx43 mRNA levels. Conclusions/interpretation These findings demonstrate that endothelial dysfunction in mesenteric arteries from the insulin-resistant OZRs can be attributed to a defect in EDHF. The results also suggest that the defective EDHF is at least partly related to an impairment of connexin 40-associated gap junctions, through a decrease in connexin 40 protein and Cx40 mRNA expression in the OZRs.

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“…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)).…”

Section: Introductionmentioning

confidence: 99%

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

Shi

Man

et al. 2007

British J Pharmacology

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Background and purpose:The present experiments were designed to study the contribution of oxygen-derived free radicals to endothelium-dependent contractions in femoral arteries of rats with streptozotocin-induced diabetes. Experimental approach: Rings with and without endothelium were suspended in organ chambers for isometric tension recording. The production of oxygen-derived free radicals in the endothelium was measured with 2 0 ,7 0 -dichlorodihydrofluorescein diacetate using confocal microscopy. The presence of protein was measured by western blotting. Key results: In the presence of L-NAME, the calcium ionophore A23187 induced larger endothelium-dependent contractions in femoral arteries from diabetic rats. Tiron, catalase, deferoxamine and MnTMPyP, but not superoxide dismutase reduced the response, suggesting that oxygen-derived free radicals are involved in the endothelium-dependent contraction. In the presence of L-NAME, A23187 increased the fluorescence signal in femoral arteries from streptozotocin-treated, but not in those from control rats, confirming that the production of oxygen-derived free radicals contributes to the enhanced endotheliumdependent contractions in diabetes. Exogenous H 2 O 2 caused contractions in femoral arterial rings without endothelium which were reduced by deferoxamine, indicating that hydroxyl radicals contract vascular smooth muscle and thus could be an endothelium-derived contracting factor in diabetes. The reduced presence of Mn-SOD and the decreased activity of catalase in femoral arteries from streptozotocin-treated rats demonstrated the presence of a redox abnormality in arteries from rats with diabetes. Conclusions and implications: These findings suggest that the redox abnormality resulting from diabetes increases oxidative stress which facilitates and/or causes endothelium-dependent contractions.

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Comparison of effects of diabetes mellitus on an EDHF-dependent and an EDHF-independent artery

Cited by 115 publications

References 18 publications

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

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

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

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

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