Injury of arterial endothelial cells in diabetic, sucrose-fed and aged rats

1 The effect of short-and long-term streptozotocin (STZ)-induced diabetes (12 and 52 weeks) on the vascular response to phenylephrine was examined in the isolated thoracic aorta with and without intact endothelium from diabetic, age matched control rats and diabetic rats treated with insulin. 2 Twelve weeks after induction of diabetes, aortae with intact endothelium demonstrated no changes either in sensitivity (defined as pD2) or contractility (defined as the maximal developed tension per aortic tissue wet weight) to phenylephrine. 3 In contrast, 52 weeks after induction of diabetes, aortae, with intact endothelium demonstrated an increased sensitivity to phenylephrine while contractility to phenylephrine was not changed. Insulin treatment partially corrected the increased sensitivity to phenylephrine observed in diabetic rat aorta. 4 Removal of endothelium abolished the difference in phenylephrine sensitivity between diabetic and control aortae at 52 weeks. 5 Pretreatment of intact aortae with methylene blue, an inhibitor of endothelium-derived relaxing factor (EDRF), abolished the difference in phenylephrine sensitivity between control and diabetic rat aortae at 52 weeks, while pretreatment with indomethacin, an inhibitor of cyclo-oxygenase, had no effect. These results suggest that decreases in production or release of EDRF might be responsible for the increased vascular sensitivity to phenylephrine observed in long-term STZ diabetic rats. 6 Acetylcholine-induced relaxation, which is EDRF-dependent, was less in diabetic rat aortae with intact endothelium at 52 weeks, but not at 12 weeks. These results further support the theory that decreases in capacity of the endothelium to synthesize or release EDRF may occur in long-term STZ diabetic rats.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endothelium‐dependent increase in vascular sensitivity to phenylephrine in long‐term streptozotocin diabetic rat aorta

Chang

Stevens

1992

“…In animal models of diabetes there is histological evidence (Arbogast et al, 1984) that vascular endothelium is abnor- ' Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Endothelial function in the isolated perfused mesentery and aortae of rats with streptozotocin‐induced diabetes: effect of treatment with the aldose reductase inhibitor, ponalrestat

Taylor¹,

Wickenden

Mirrlees

et al. 1994

1 Noradrenaline sensitivity and relaxation to acetylcholine were investigated in the isolated perfused mesentery and in aortic rings of control and streptozotocin (STZ)-induced (50 mg kg-') diabetic Charles River rats. 2 In addition, noradrenaline sensitivity and acetylcholine relaxation were similarly assessed in streptozotocin-induced diabetic rats treated from the time of onset of diabetes with the aldose reductase inhibitor, ponalrestat (100 mg kg-' day-'). 3 The untreated diabetic rats (2-10 weeks after injection of STZ) demonstrated enhanced vascular sensitivity to n6radrenaline in the perfused mesenteric arterial tree, compared with age matched controls (pECm [-log

“…It appears that damage to the vascular endothelium may be an early pathological process in some of the diabetes patients (Bierman & Brunzell, 1978;Dolgov et al, 1982). Vascular function abnormalities, as manifested by haemodynamic changes (Pugliese et al, 1991) as well as increased vascular permeability (Parving, 1976;Pugliese et al, 1989), and changes in vascular structure (Arbogast et al, 1984), develop early in human diabetes and in animal models of this disease (Cameron & Cotter, 1992;Tomlinson et al, 1992). Vascular function abnormalities are also re¯ected by decreased synthesis of prostacyclin and nitric oxide (Durante et al, 1988;McVeigh et al, 1992) and increased levels of circulating endothelin (Takahashi et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Dobesilate enhances endothelial nitric oxide synthase‐activity in macro‐ and microvascular endothelial cells

Suschek

Kolb²,

Kolb-Bachofen

1997

1 Dobesilate is used for normalizing vascular dysfunction in a number of diseases. In search for an eect on endothelial NO production, macrovascular endothelial cells from rat aorta, microvascular endothelial cells from rat exocrine pancreatic tissue, and capillary endothelial cells from rat islets, were cultured in the presence or absence of Mg-Dobesilate. The activity of constitutive nitric oxide synthase (ecNOS) in resident cells as well as of inducible nitric oxide synthase (iNOS) in cytokine-activated cells was measured indirectly by recording the citrulline concentrations in culture supernatants. 2 In each of the dierent endothelial cells Mg-Dobesilate incubation (0.25 ± 1 mM) for 24 h led to a signi®cant and concentration-dependent increase in ecNOS-activities. With cytokine-activated endothelial cell cultures only moderate eects were seen with little or no concentration-dependency. Addition of the NOS-inhibitor N G -monomethyl-L-arginine led to a signi®cant suppression of citrulline formation in all cultures as an evidence for the enzyme speci®city of these eects. 3 iNOS-and ecNOS-speci®c reverse transcription and semi-quantitative polymerase chain reaction (RT ± PCR) with RNA from resident or cytokine-activated endothelial cells gave no evidence for an increase in NOS-speci®c mRNA after Mg-Dobesilate-treatment. Furthermore, Dobesilate-mediated enhancement of NO synthesis in resting endothelial cells was not due to iNOS induction in these cells, as no iNOS-speci®c signal was found by RT ± PCR.