A Contrasting effect of the diabetic state upon the contractile responses of aortic preparations from the rat and rabbit

1,015

769

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of di erent animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to di er according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.

Section: Experimental and Clinical Evidence For The Presence Of Impaimentioning

confidence: 93%

Endothelial dysfunction in diabetes

Vriese

Verbeuren

Voorde

et al. 2000

1,015

769

“…Although other workers have found a small but significant, reduction of aortic weights in diabetes, the diabetes has been of longer duration, and wet rather than dry weights were quoted (Scarborough & Carrier, 1983;1984;Head et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…Mulhern & Docherty, 1989) or 2 g (e.g. Owen & Carrier, 1979;Scarborough & Carrier, 1983;Head et al, 1987;Harris & MacLeod, 1988). Such tensions probably do not approximate to those found in vivo (see below, and Mulvany & Halpern, 1977;Angus et al, 1986), and therefore the present study was designed to examine the responsiveness of aortic rings under a more physiological tension.…”

Section: Introductionmentioning

confidence: 99%

Attenuated responses to endothelin‐1, KCl and CaCl₂, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Fulton

Hodgson

Sikorski

et al. 1991

1 This study investigated the responsiveness to vasoconstrictor agents (including endothelin-1, ET-1) of aortic rings from rats with two-week streptozotocin (STZ, 60mgkg-', i.v.)-induced diabetes and vehicletreated control rats. The basal tension was 10g, which was estimated to be more physiological than the tension of 1-2 g that has been previously used for most studies of aortic rings from diabetic rats. 2 Maximum responses to ET-1 (0.13-18 nM), KCl (2-20mM) or CaCl2 (1OpM-10mM) were reduced in aortae from STZ-treated rats compared to those from control rats. Such reductions were still evident after removal of the endothelium. 3 Responses to noradrenaline (NA, 0.1 nM-26pM) of aortae from STZ-treated rats were not significantly different from responses of aortae of control rats.4 Removal of endothelium resulted in a significant reduction in the EC50 values for NA of rings from both STZ-treated rats (6.90 + 0.13 and 8.17 + 0.35 (-logM) with and without endothelium, respectively, n = 5) and control rats (6.90 + 0.15 and 8.37 + 0.44 (-logM) with and without endothelium, respectively, n= 5).5 In calcium-free medium (with 1 mm EGTA), responses to NA and ET-1 were reduced compared with those in normal Krebs solution and maximum responses were less in rings from STZ-treated compared with control rats. 6 Indomethacin (5,UM) did not prevent the reduced maximum responsiveness to ET-1 in rings from STZ-treated rats compared with those from controls. 7 This study indicates that changes in vascular responsiveness to ET-1, KCI and CaCl2 (but not NA) occur in aortae of two-week STZ-treated rats. The endothelium does not appear to play a major role in mediating changes in responsiveness to ET-1.

“…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

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.