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

¹ Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet, Stockholm, Sweden
² Department of Medicine, Division of Cardiology, Karolinska Institutet, Stockholm, Sweden

Address correspondence and reprint requests to John Pernow, Department of Cardiology, Karolinska University Hospital, Solna, S-171 76 Stockholm, Sweden. E-mail: john.pernow{at}ki.se

OBJECTIVE—Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may inhibit glucose uptake. The objective of the study was to investigate if ET (selective ET_A and dual ET_A+ET_B) receptor blockade improves insulin sensitivity in patients with insulin resistance and coronary artery disease.

RESEARCH DESIGN AND METHODS—Seven patients (aged 58 ± 2 years) with insulin resistance and coronary artery disease completed three hyperinsulinemic-euglycemic clamp protocols: a control clamp (saline infusion), during ET_A receptor blockade (BQ123), and during combined ET_A (BQ123) and ET_B receptor blockade (BQ788). Splanchnic blood flow (SBF) and renal blood flow (RBF) were determined by infusions of cardiogreen and p-aminohippurate.

RESULTS—Total-body glucose uptake (M) differed between the clamp protocols with the highest value in the BQ123+BQ788 clamp (P < 0.05). The M value corrected by insulin was higher in the BQ123+BQ788 than in the control clamp (P < 0.01) or the BQ123 clamp (P < 0.05). There was no difference between the control clamp and the BQ123 clamp. Mean arterial pressure did not change during the control clamp, whereas it decreased during both the BQ123 (P < 0.01) and BQ123+BQ788 (P < 0.05) clamps. RBF increased and renal vascular resistance decreased in the BQ123+BQ788 clamp (P < 0.05) but not in the BQ123 clamp. There was no change in SBF in either clamp.

CONCLUSIONS—Dual ET_A+ET_B receptor blockade acutely enhances insulin sensitivity in patients with insulin resistance and coronary artery disease, indicating an important role for endogenous ET-1.

Abbreviations: ET, endothelin • MAP, mean arterial blood pressure • PAH, p-aminohippurate • RBF, renal blood flow • SBF, splanchnic blood flow

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