The effects of endothelin‐1 and N<sup>G</sup>‐nitro‐<scp>l</scp>‐arginine methyl ester on regional haemodynamics in conscious rats with streptozotocin‐induced diabetes mellitus

Kiff, Rachel J.; Gardiner, Sheila M.; Compton, A.M.; Bennett, T.

doi:10.1111/j.1476-5381.1991.tb09787.x

Cited by 90 publications

(54 citation statements)

References 60 publications

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“…Thus, for renal and mesenteric vascular beds, where flow is increased by diabetes, ET-mediated vasoconstriction was increased. However, in the hindlimb circulation, where flow decreases with diabetes, the vasoconstrictor response was relatively muted [50]. The data for sciatic nerve agree with the latter finding, as the effects of BQ-123 suggest that there would already be much greater local ET production and vasoconstriction with diabetes.…”

Section: Discussionsupporting

confidence: 80%

“…Diabetic vessels have reduced ET sensitivity [44-461, perhaps caused by a down-regulation of receptors [47,48] or transduction mechanisms [49] in response to chronic exposure. Regional blood flow patterns for bolus ET injection are altered by diabetes in conscious rats [10,50] but the changes are complex, suggesting tissue heterogeneity. Thus, for renal and mesenteric vascular beds, where flow is increased by diabetes, ET-mediated vasoconstriction was increased.…”

Section: Discussionmentioning

confidence: 99%

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The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

1994

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Summary Abnormal vascular endothelium function may contribute to the reduced nerve perfusion implicated in the aetiology of neuropathy in diabetes mellitus. The aim was to test the hypothesis that a powerful vasoconstrictor, endothelin-1, could be involved in nerve dysfunction in streptozotocin-diabetic rats. After 6 weeks of untreated diabetes, rats were implanted with osmotic minipumps which continuously delivered the endothelin-1 antagonist, BQ-123, to the circulation via a jugular vein cannula. Sciatic motor conduction velocity, monitored serially, was increased after 4 days, treatment (p = 0.028), and reached asymptote by 9-11 days (p = 0.0001), when the degree of amelioration was approximately 60 % of the initial diabetic deficit. Treatment of non-diabetic rats for 13 days with BQ-123 had no significant effect on motor conduction velocity. Sensory saphenous nerve conduction velocity was measured acutely after 20 days, BQ-123 treatment. The amelioration of a sensory deficit was approximately 80 % (p < 0.001); the resultant conduction velocity value was not significantly different from that of a non-diabetic control group. After 20 days, treatment, sciatic nutritive endoneurial blood flow was measured by microelectrode polarography and hydrogen clearance. A 48 % deficit with untreated diabetes (p < 0.001) was 64 % ameliorated by BQ-123 treatment (p < 0.001). In non-diabetic rats, BQ-123 treatment had no effect on blood flow. We conclude that endothelin-1 does not seem to be involved in the control of nerve blood flow in non-diabetic rats; however, it makes a major contribution to the perfusion deficit in experimental diabetes. This has deleterious consequences for nerve conduction, and it is possible that endothelin-1 receptor blockade may have therapeutic potential in diabetic patients. [Diabetologia (1994[Diabetologia ( ) 37: 1209[Diabetologia ( -1215

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

1994

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“…Previous studies from our own laboratory have shown lower HR and reduced systolic blood pressure in conscious STZ-induced diabetic rats (44). However, a few studies from other laboratories have reported unchanged (5,6,24) or increased blood pressure in diabetic rats (22). Although the reasons for these discrepancies are not very clear, it is likely that differences in the duration of diabetes, use of anesthetics, and varied techniques employed for measurement of blood pressure may have contributed to the disparities in the observed results (25).…”

Section: Discussionmentioning

confidence: 67%

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

Nagareddy¹,

Xia²,

McNeill³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

138

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(MABP) and heart rate (HR), endothelial dysfunction, and attenuated pressor responses to vasoactive agents. We investigated whether these abnormalities are due to diabetes-associated activation of inducible nitric oxide synthase (iNOS). In addition, the effect of the duration of diabetes on these abnormalities was also evaluated. Diabetes was induced by administration of 60 mg/kg STZ via the tail vein. One, 3, 9, or 12 wk after STZ injection, MABP, HR, and endothelial function were measured in conscious unrestrained rats. Pressor response curves to bolus doses of methoxamine (MTX) and angiotensin II (ANG II) were constructed in the presence of N- [3(aminomethyl)benzyl]-acetamidine, dihydrochloride (1400W), a specific inhibitor of iNOS. Depressed MABP and HR and impairment of endothelial function were observed as early as 3 wk after induction of diabetes. Acute inhibition of iNOS with 1400W (3 mg/kg iv) restored the attenuated pressor responses to both MTX and ANG II without affecting the basal MABP and HR. Immunohistochemical and Western analysis blot studies in cardiovascular tissues revealed decreased expression of endothelial nitric oxide synthase (eNOS) concomitant with increased expression of iNOS and nitrotyrosine with the progression of diabetes. Our findings suggest that induction of iNOS in cardiovascular tissues is dependent on the duration of diabetes and contributes significantly to the depressed pressor responses to vasoactive agents and potentially to endothelial dysfunction. inducible nitric oxide synthase; nitric oxide; cardiovascular abnormalities CHRONIC HYPERGLYCEMIA has been shown to directly affect the composition and structure of cardiac, vascular, and renal tissues, the progressive modification of which results in a deranged cardiovascular homeostasis (8). Cardiovascular depression, characterized by depressed mean arterial blood pressure (MABP), heart rate (HR), and attenuated pressor responses to vasoactive agents is one of the most notable manifestations of this derangement, particularly in animal models of Type 1 diabetes. Although the exact mechanisms by which diabetes contributes to cardiovascular depression are currently unknown, it is likely that hyperglycemia may initiate this abnormality through the activation of protein kinase C, increased activity of the polyol pathway, formation of nonenzymatic advanced glycosylation end products, oxidative stress, and/or possibly by induction of nitric oxide (NO) synthase (NOS) (19,42).The role of NO in the regulation of hemodynamics under hyperglycemic conditions has been controversial. Despite an impairment of endothelial function and reduced bioavailability of endothelium-derived NO, streptozotocin (STZ)-induced diabetic rats are not hypertensive but instead are normotensive or hypotensive (9,14,18,20,23,31,39,44). In addition, an increased dependence on a functional NO system at the onset of diabetes has been reported to prevent the development of hypertension in STZ diabetic rats (12). It has been suggested that increased NO synthesis m...

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“…Furthermore, it is not known what the effect would be on ET-1 responses of bathing solutions appropriately adjusted for the differences in the composition of the extracellular fluid (including osmolality) of control and STZtreated rats. Indeed, no such comparative in vitro studies with adjusted bathing solutions have been performed (Kiff et al, 1991a). Also, changes in aortic endothelial cell function may not reflect changes in other vascular beds.…”

Section: Discussionmentioning

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

British J Pharmacology

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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.

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The effects of endothelin‐1 and N^G‐nitro‐l‐arginine methyl ester on regional haemodynamics in conscious rats with streptozotocin‐induced diabetes mellitus

Cited by 90 publications

References 60 publications

The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

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

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The effects of endothelin‐1 and NG‐nitro‐l‐arginine methyl ester on regional haemodynamics in conscious rats with streptozotocin‐induced diabetes mellitus

Cited by 90 publications

References 60 publications

The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

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

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The effects of endothelin‐1 and N^G‐nitro‐l‐arginine methyl ester on regional haemodynamics in conscious rats with streptozotocin‐induced diabetes mellitus

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