Influence of the endothelium on contractile responses of arteries from diabetic rats

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.

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

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

“…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.

“…In view of the observed increases in contractile responsiveness of arteries from diabetic rats to NA (MacLeod, 1985;Harris & MacLeod, 1988), it is possible that the phosphoinositide messenger system is augmented in these tissues. The present study was undertaken to investigate whether PKC-mediated contractile responses are altered in aortae and mesenteric arteries from male rats with STZ-induced diabetes of 12-14 weeks duration.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C‐mediated contractile responses of arteries from diabetic rats

Abebe

MacLeod

1990

1 The role of protein kinase C (PKC) in mediating enhanced contractile responses of aortae and mesenteric arteries from male rats with 12-14 week streptozotocin-induced diabetes to noradrenaline (NA) was investigated using the PKC activator, phorbol 12,13-dibutyrate (PDB), and the PKC inhibitor, staurosporine. 2 Maximum contractile responses of aortae and mesenteric arteries from diabetic rats to NA were significantly enhanced compared with responses of arteries from age-matched control animals. The maximum NA responses were increased by 59.6 + 7.9% in aortae and by 54.9 + 7.4% in mesenteric arteries from diabetic animals, compared to their respective controls. 3 Pretreatment of aortae and mesenteric arteries from both control and diabetic animals with staurosporine (5 x 10 -8M) caused marked inhibition of contractile responses to a maximum concentration of NA (10-5M in aortae; 3 x 10 5M in mesenteric arteries). In the presence of staurosporine, no difference was observed in the magnitude of contractile responses of arteries from control and diabetic rats to NA. 4 Maximum contractile responses of mesenteric arteries from diabetic rats to PDB were significantly increased (by 45.0 + 4.9%) compared to responses of arteries from control animals. In contrast, no significant difference was found in the magnitude of contractile responses of aortae from control and diabetic rats to PDB. 5 Staurosporine (5 x 10-8M) caused marked attenuation of contractile responses of arteries from control and diabetic rats to a maximum concentration of PDB (3 x 10-6 M). In the presence of staurosporine, the difference in magnitude of contractile responses of mesenteric arteries from control and diabetic rats to PDB was abolished. 6 Contractile responses of aortae and mesenteric arteries from control and diabetic rats to PDB were reduced in the absence of extracellular Ca2", and in the presence of the Ca2 + channel blockers, nifedipine (3 x 10-6 M) or verapamil (3 x 10-6 M). Under these conditions, no difference was found in the magnitude of contractile responses of mesenteric arteries from control and diabetic rats to PDB. 7 These data suggest that enhanced contractile responses of aortae and mesenteric arteries from streptozotocin-induced diabetic rats to NA may result, at least in part, from increased activation of PKC. In addition, increased activation of PKC-mediated processes, which are dependent on the presence of extracellular Ca2+, may further contribute to the enhanced contractile responses of diabetic mesenteric arteries to NA.