Effect of chronic endothelin receptor antagonism on cerebrovascular function in type 2 diabetes

Abstract

Diabetes increases the risk of stroke and contributes to poor clinical outcomes in this patient population. Myogenic tone of the cerebral vasculature, including basilar arteries, plays a key role in controlling cerebral blood flow. Increased myogenic tone is ameliorated with ET receptor antagonism in Type 1 diabetes. However, the role of endothelin-1 (ET-1) and its receptors in cerebrovascular dysfunction in Type 2 diabetes, a common comorbidity in stroke patients, remains poorly elucidated. Therefore, we hypothesized that 1) cerebrovascular dysfunction occurs in the Goto-Kakizaki (GK) model of Type 2 diabetes, and 2) pharmacological antagonism of ETA receptors ameliorates, while ETB receptor blockade augments vascular dysfunction. GK or control rats were treated with antagonists to either ETA (atrasentan, 5 mg.kg(-1).day(-1)) or ETB (A-192621, 15 or 30 mg.kg(-1).day(-1)) receptors for 4 wk and vascular function of basilar arteries was assessed using a wire myograph. GK rats exhibited increased sensitivity to ET-1. ET(A) receptor antagonism caused a rightward shift, indicating decreased sensitivity in diabetes, while it increased sensitivity to ET-1 in control rats. Endothelium-dependent relaxation was impaired in diabetes. ETA receptor blockade restored relaxation to control values in the GK animals with no significant effect in Wistar rats and ETB blockade with 30 mg.kg(-1).day(-1) A-192621 caused paradoxical constriction in diabetes. These studies demonstrate that cerebrovascular dysfunction occurs and may contribute to altered regulation of myogenic tone and cerebral blood flow in diabetes. While ETA receptors mediate vascular dysfunction, ETB receptors display differential effects. These results underscore the importance of ETA/ETB receptor balance and interactions in cerebrovascular dysfunction in diabetes.

Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes

“…GK rats were originally derived from selective breeding of glucose intolerant Wistar rats, which serve as the control for this model (Cheng et al, 2001;Standaert et al, 2004). They are neither hyperlipidemic nor hypertensive, allowing the opportunity to determine hyperglycemia effects in a spontaneous model of diabetes (Cheng et al, 2001;Elgebaly et al, 2008;Harris et al, 2008;Sachidanandam et al, 2008). Metabolic parameters summarized in Table 1 demonstrated that hyperglycemia was markedly augmented with the high-fat diet in the diabetic group and correlated with the long-term glucose control depicted by HbA1C levels.…”

Increased Contractility to Noradrenaline and Normal Endothelial Function in Mesenteric Small Arteries from the Goto-Kakizaki Rat Model of Type 2 Diabetes

“…However, studies of the endothelial-dependent relaxation of other vascular beds from the GK rat show a variance in the response between different vascular beds from the same model. In the superior mesenteric arteries from GK rats, the ACh-mediated relaxation appears to be attenuated [15,19,20], as well as in aortic segments [27,34] and in the basilar arteries [23,35].The reduction we find in the maximal tension of GK arteries in the presence of indomethacin could indicate that a vasoconstricting prostaglandin might also be of importance, as previously reported by Kimura et al [30]. However, the effect of indomethacin was not significantly different between the two groups, and the difference in contraction persisted after indomethacin treatment, making it unlikely that the prostaglandin pathway is a major mechanism explaining the different contractility.…”

Carotid Artery Stenosis is Exacerbated in Spontaneously Obese Model Rats with Diabetes

“…In the present analysis, metabolic correction with insulin notably reversed the enhanced endothelial function in the diabetic model rats, which may be due to the downregulation of endothelial nitric oxide synthase (eNOS)/heme oxygenase (HO)-1 9) . Insulin administration also resulted in intimal hyperplasia, particularly subendothelial thickening with the potential to impede the diffusion of nitric oxide into smooth muscle required to induce relaxation 10) . Intimal hyperplasia is also induced by insulin in rats with type 1 diabetes after balloon injury and may be responsible for accelerated carotid artery stenosis in humans.…”

“…Intimal hyperplasia is also induced by insulin in rats with type 1 diabetes after balloon injury and may be responsible for accelerated carotid artery stenosis in humans. Therefore, metabolic correction with insulin may lead to unintentional hyperinsulinemia and intimal hyperplasia that may be detrimental to the endothelial function and promote vascular atherosclerosis 10,11) . In this study, intimal thickening was more pronounced in the OLETF rats than the LETO rats.…”