Acute blockade by endothelin-1 of haemodynamic insulin action in rats

Abstract

Aims/hypothesis Plasma levels of endothelin-1 are frequently elevated in patients with hypertension, obesity and type 2 diabetes. We hypothesise that this vasoconstrictor may prevent full perfusion of muscle, thereby limiting delivery of insulin and glucose and contributing to insulin resistance. Materials and methods The acute effects of endothelin-1 on insulin-mediated haemodynamic and metabolic effects were examined in rats in vivo. Endothelin-1 (50 pmol min −1 kg −1 for 2.5 h) was infused alone, or 30 min prior to a hyperinsulinaemic-euglycaemic insulin clamp (10 mU min −1 kg −1 for 2 h). Insulin clamps (10 or 15 mU min −1 kg −1 ) were performed after 30 min of saline infusion. Results Endothelin-1 infusion alone increased plasma endothelin-1 11-fold (p<0.05) and blood pressure by 20% (p<0.05). Endothelin-1 alone had no effect on femoral blood flow, capillary recruitment or glucose uptake, but endothelin-1 with 10 mU min −1 kg −1 insulin caused a decrease in insulin clearance from 0.35±0.6 to 0.19± 0.02 ml/min (p=0.02), resulting in significantly higher plasma insulin levels (10 mU min −1 kg −1 insulin: 2,120± 190 pmol/l; endothelin-1+10 mU min −1 kg −1 insulin: 4,740± 910 pmol/l), equivalent to 15 mU min −1 kg −1 insulin alone (4,920±190 pmol/l). The stimulatory effects of equivalent doses of insulin on femoral blood flow, capillary recruitment and glucose uptake were blocked by endothelin-1.Conclusions/interpretation Endothelin-1 blocks insulin's haemodynamic effects, particularly capillary recruitment, and is associated with decreased muscle glucose uptake and glucose infusion rate. These findings suggest that elevated endothelin-1 levels may contribute to insulin resistance of muscle by increasing vascular resistance and limiting insulin and glucose delivery.

Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity

“…Accordingly, we have recently found that insulin induces ET-1-dependent vasoconstriction in skeletal muscle arterioles of obese rats (Eringa et al 2007). Experimental studies in healthy rats have demonstrated that ET-1 infusion in vivo severely blunts the increased capillary recruitment and limb blood flow caused by insulin (Ross et al 2007).…”

“…Blood pressure is inversely related to insulin sensitivity and capillary recruitment, a consequence of reduced endotheliumdependent vasodilation at the pre-capillary level (Serne et al 1999). Infusion of ET-1 in vivo blunts capillary recruitment and limb blood flow caused by insulin (Ross et al 2007) and results in increased blood pressure and reduced muscle glucose uptake. In addition, insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by an imbalance between NO and ET-1 production (Potenza et al 2005).…”

Microvascular Dysfunction

“…Recent experimental studies in rats demonstrate that endothelin-1 infusion in vivo severely blunted the increased capillary recruitment and limb blood flow caused by insulin. 33 These effects of endothelin-1 were accompanied by increased blood pressure and reduced muscle glucose uptake. In addition, insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production.…”

Blueberry Tea Enhances Insulin Sensitivity by Augmenting Insulin-Mediated Metabolic and Microvascular Responses in Skeletal Muscle of High Fat Fed Rats

“…We have shown that acute defects in insulin-mediated microvascular recruitment can contribute to the development of muscle insulin resistance in vivo. Infusion of α-methyl serotonin [26], endothelin-1 [27], L-N G -Nitroarginine methyl ester [7,29,37], TNFα [38], Intralipid® plus heparin [39] and glucosamine [40] in healthy animals attenuate insulin-mediated microvascular recruitment and insulin-mediated muscle glucose uptake. In addition, chronic models of insulin resistance including the high fat-fed rat (36% fat wt/ wt) [3], and obese Zucker rat [41] display marked attenuation in insulin-mediated microvascular recruitment and muscle glucose uptake.…”

“…Microvascular perfusion in muscle was assessed from metabolism of exogenously infused 1-methyl xanthine (1-MX; Sigma Aldrich, St. Louis, MO, USA) as previously published [3,6,8,14,[25][26][27][28][29]. Briefly, a bolus of allopurinol (10μmol/kg; Sigma Aldrich) was given 5 min prior to 1-MX infusion to partially inhibit the activity of xanthine oxidase and ensure a constant saturating arterial level of 1-MX.…”