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


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
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.
Ross
R M
RM
Biochemistry, School of Medicine, University of Tasmania, Private Bag 58, Hobart, 7001, Australia.
Kolka
C M
CM
Rattigan
S
S
Clark
M G
MG
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D019332:Endothelin-1 / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology; D000078790:Insulin Secretion; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D001786:Blood Glucose; D019332:Endothelin-1; D007328:Insulin; D007329:Insulin Antagonists; D000493:Allopurinol