Diabetic state, high plasma insulin and angiotensin II combine to augment endothelin‐1‐induced vasoconstriction via ET_A receptors and ERK

Abstract

Background and purpose: Mechanisms associated with the enhanced contractile response to endothelin-1 in hyperinsulinaemic diabetes have been examined using the rat aorta. Functions for angiotensin II, endothelin-1 receptor expression and extracellular signal-regulated kinase (ERK) have been investigated. Experimental approach: Streptozotocin-induced diabetic rats were infused with angiotensin II or, following insulin treatment, were treated with losartan, an angiotensin II receptor antagonist. Contractions of aortic strips with or without endothelium, in response to endothelin-1 and angiotensin II, were examined in vitro. Aortic ET A receptors and ERK/MEK expression were measured by western blotting. Key results: Insulin-treated diabetic rats exhibited increases in plasma insulin, angiotensin II and endothelin-1. The systolic blood pressure and endothelin-1-induced contractile responses in aortae in vitro were enhanced in insulin-treated diabetic rats and blunted by chronic losartan administration. LY294002 (phosphatidylinositol 3-kinase inhibitor) and/or PD98059 (MEK inhibitor) diminished the enhanced contractile response to endothelin-1 in aortae from insulin-treated diabetic rats. ET A and ET B receptors, ERK-1/2 and MEK-1/2 protein expression and endothelin-1-stimulated ERK phosphorylation were all increased in aortae from insulin-treated diabetic rats. Such increases were blunted by chronic losartan administration. Endothelin-1-induced contraction was significantly higher in aortae from angiotensin II-infused diabetic rats. angiotensin II-infusion increased ERK phosphorylation, but the expression of endothelin receptors and ERK/MEK proteins remained unchanged. Conclusions and implications: These results suggest that the combination of high plasma angiotensin II and insulin with a diabetic state induced enhancement of endothelin-1-induced vasoconstriction, ET A receptor expression and ERK expression/ activity in the aorta. Losartan improved both the diabetes-related abnormalites and the diabetic hypertension.

Losartan Normalizes Endothelium-Derived Hyperpolarizing Factor–Mediated Relaxation by Activating Ca2+-Activated K+ Channels in Mesenteric Artery From Type 2 Diabetic GK Rat

“…We (32,33) and others (34) have previously reported that the above losartan dosage regimen has beneficial effects on vascular functions in a number of disease models in rats. Moreover, in a very recent study, again using the above losartan dosage regimen, we noted that Ang II-mediated contraction was largely suppressed in mesenteric arteries obtained from losartan-treated GK or Wistar rats (35).…”

Effect of Long-Term Diabetes on Serotonin-Mediated Contraction in Carotid Arteries from Streptozotocin-Induced Diabetic Male and Female Rats

“…Experimental type 1 diabetic rats were induced with a single intravenous injection of STZ (65 mg/kg dissolved in citrate buffer), as described previously. [22][23][24] As a control, age-matched rats were injected with citrate buffer alone. All animals were given a standard laboratory diet and water ad libitum until the rats were 31 or 32 weeks old (viz.…”

Examining the Role of Insulin in the Regulation of Cardiovascular Health

“…In addition to this well-described stimulation of NO synthesis by insulin, insulin also stimulates synthesis of the vasoconstrictor, endothelin-1 (ET-1), which can dominate under certain circumstances [20]. The molecular mechanisms by which insulin stimulates NO and ET-1 synthesis are discussed further below.…”