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

Abstract

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.

The effect of insulin treatment and of islet transplantation on the resistance artery function in the STZ‐induced diabetic rat

“…Another investigation of vascular 1988), isolated reactivity of both aortae and mesenteric arteries in chronic rfused kidneys experimental diabetes showed that the increased contractile response to noradrenaline was evident only in the untreated diabetics, whereas treatment with insulin completely prevented the increase (Macleod, 1985). Similar findings were reported in a long-term study of diabetes where the aortae from untreated diabetic rats showed an increased sensitivity to the agonist, phenylephrine, which was partially corrected in the insulintreated group (Chang & Stevens, 1992). In one study of resistance artery function, of similar experimental design to our study, evidence of enhanced contractility to noradrenaline was revealed in both untreated and insulin treated diabetic rats, and similarly, incubation with a nitric oxide synthase inhibitor (L-NAME) resulted in an increase in sensitivity to noradrenaline in the diabetic vessels (Taylor et al, 1994a).…”

Insulin and vanadate restore decreased plasma endothelin concentrations and exaggerated vascular responses to normal in the streptozotocin diabetic rat

“…Although our study suggests that STZ diabetes is associated with increases in vasoconstrictor responses to both ET-1 and MTX, other studies have shown both decreased [9,15,17] and increased [10,13] vasoconstrictor and vasodilator responses to ET-1 and both decreased [7,11] and increased [8,12,14] vasoconstrictor responses to a 1 adrenergic stimulation in STZ rats. This interstudy variation could result from differences in the vascular bed studied, the severity and duration of hyperglycaemia and differences in experimental procedures for measuring vasoconstriction [1].…”

“…Discrepancies in vivo may result from differences in the degree and duration of hyperglycaemia, the presence of diabetic complications, and possibly in the state of endothelial function in the model studied. It is possible that differences in endothelium derived relaxing factor (EDRF) production may contribute to these variations since its function declines in proportion to the duration of hyperglycaemia in STZ diabetes, and it is known to inhibit ET release [12,34]. Acetylcholine-evoked relaxation of aortic rings was intact in our study (data not shown), suggesting that EDRF production remained unaffected by STZ diabetes in this vascular smooth muscle preparation.…”

“…Later studies have shown that insulin infusion increases plasma ET concentrations in humans [25,26]. The increase in plasma ET after insulin treatment of diabetic rats in our study could be due to: a) the return to normal of hyperglycaemia and hyperlipidaemia resulting in restoration of ET production from EC [26], b) the return to normal of hyperglycaemia leading to restoration of EDRF mediated inhibition of ET release [12,34] or c) the direct effect of insulin on endothelial ET production [23,24] Fig. 3a±d.…”

Human α-defensin regulates smooth muscle cell contraction: a role for low-density lipoprotein receptor–related protein/α2-macroglobulin receptor

“…The thoracic aorta was removed, dissected free of fat and connective tissue, and cut into transverse rings 5 mm in length. 18,19 The rings were gently rotated on a stainless steel rod to remove the endothelium (denuded aorta). The tissues were kept in an oxygenated (95% O 2 , 5% CO 2 ) solution of Krebs-Henseleit (KH) buffer (144 mM NaCl, 5.9 mM KCl, 1.6 mM CaCl 2 , 1.2 mM MgSO 4 , 1.2 mM KH 2 PO 4 , 25 mM NaHCO 3 , and 11.1 mM D-glucose).…”