Insulin sensitivity and big ET-1 conversion to ET-1 after ET_A- or ET_B-receptor blockade in humans

Abstract

Ahlborg, Gunvor, and Jonas Lindströ m. Insulin sensitivity and big ET-1 conversion to ET-1 after ETA-or ETBreceptor blockade in humans. J Appl Physiol 93: 2112-2121, 2002. First published September 6, 2002 10.1152/japplphysiol.00477.2002-Cardiovascular diseases are characterized by insulin resistance and elevated endothelin (ET)-1 levels. Furthermore, ET-1 induces insulin resistance. To elucidate this mechanism, six healthy subjects were studied during a hyperinsulinemic euglycemic clamp during infusion of (the ET-1 precursor) big ET-1 alone or after ETA-or ETB-receptor blockade. Insulin levels rose after big ET-1 with or without the ETB antagonist BQ-788 (P Ͻ 0.05) but were unchanged after the ETA antagonist BQ-123 ϩ big ET-1. Infused glucose divided by insulin fell after big ET-1 with or without BQ-788 (P Ͻ 0.05). Insulin and infused glucose divided by insulin values were normalized by ETA blockade. Mean arterial blood pressure rose during big ET-1 with or without BQ-788 (P Ͻ 0.001) but was unchanged after BQ-123. Skeletal muscle, splanchnic, and renal blood flow responses to big ET-1 were abolished by BQ-123. ET-1 levels rose after big ET-1 (P Ͻ 0.01) in a similar way after BQ-123 or BQ-788, despite higher elimination capacity after ETA blockade. In conclusion, ET-1-induced reduction in insulin sensitivity and clearance as well as splanchnic and renal vasoconstriction are ETA mediated. ETA-receptor stimulation seems to inhibit the conversion of big ET-1 to ET-1. skeletal muscle; splanchnic blood flow; renal blood flow; mean arterial blood pressure ENDOTHELIN (ET)-1 WAS CHARACTERIZED as well as the gene encoding for the prepropeptide cloned by Yanagisawa et al. (42). ET-1 belongs to a family of vasoactive peptides and is synthesized by the endothelium from its inactive precursor, big ET-1. Vascular endothelial cells secrete both ET-1 and big ET-1 (35). Both peptides are detected in plasma from healthy individuals and increase during, e.g., myocardial infarction (30). The potent and prolonged vasoconstriction in the splanchnic, renal, and pulmonary vascular beds has previously been demonstrated in healthy young individuals during systemic infusion of both ET-1 (39, 40) or its precursor big ET-1 (3, 4). Both big ET-1 and ET-1 are efficiently eliminated in the splanchnic, renal, and skeletal muscle vascular beds (4, 21, 39, 40), and ET-1 is eliminated in the pulmonary circulation as well (40). At a given arterial ET-1 level, the vascular responses to infused big ET-1 are more pronounced than to ET-1 infusion (3, 4), indicating that locally synthesized ET-1 reaches more vascular smooth muscle ET-1 receptors than ET-1 taken up from the blood.The vascular responses can be explained by the presence of two different ET-receptor subtypes: ET A and ET B (8, 34). ET A and ET B are found on vascular smooth muscle cells where both mediate contraction (12, 15), whereas only ET B receptors are located on the endothelial cells and stimulate the production of the vasodilators prostacyclin (16) and nitric oxide (NO) (16,28). ...

Dual Endothelin Receptor Blockade Acutely Improves Insulin Sensitivity in Obese Patients With Insulin Resistance and Coronary Artery Disease

“…Furthermore, chronic selective ET A receptor antagonism improves insulin sensitivity and reduces hyperinsulinemia in animal models (23). We have shown that ET A receptor blockade improves, while selective ET B receptor blockade impairs, insulin sensitivity during infusion of the ET-1 precursor big ET-1 in healthy humans (14). In the present study, insulin sensitivity improved only after dual ET A ϩET B receptor blockade but not following selective ET A receptor blockade, indicating that the ET B receptor plays a different role in health and disease.…”

“…Splanchnic blood flow (SBF) and renal blood flow (RBF) were determined by the constant infusions of cardiogreen, PAH, and the hematocrit, as previously described (12). In a previous study, hepatic and renal vein catheters were introduced to ascertain that fractional uptake, F (equal to the arteriovenous difference divided by the arterial concentration), of cardiogreen and PAH were not influenced by the infusion of the ET-1 blockers (17) or the clamp procedure (14). As there was no change in the F values, a constant F value of 0.8 for cardiogreen and 0.9 for PAH was used in the present study.…”

“…The notion that ET-1 modulates insulin sensitivity was supported by the demonstration that ET-1 reduces insulin sensitivity in healthy volunteers (13). Furthermore, the ET-1 precursor, big ET-1, reduces insulin sensitivity via an action mediated by the ET A receptor in healthy subjects (14). However, no study has investigated whether endogenous ET-1 contributes to reduced insulin sensitivity in patients with insulin resistance.…”

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

“…Some studies have also reported a decrease in flow to the skeletal muscle, but findings are inconsistent [12,[15][16][17]. Both acute and chronic infusion of endothelin-1 in vivo results in hyperinsulinaemia and insulin resistance [18], two traits of the obese Zucker rat that are abolished by treatment with endothelin A blockers [19,20].…”

Inhibitor of NF B pathway JSH 23 inhibit oxidative stress generated by endothelin 1 ET 1

“…Increased levels of ET-1 reduces blood flow in skeletal muscle [12] and inhibition ET A receptor improve blood flow to active skeletal muscle [13]. In addition, elevated ET-1 levels lead to NADPH oxidase activation and superoxide formation via ET A receptors, resulting in excessive ROS production and endothelial dysfunction [14].…”