Altered paracrine effect of endothelin in blood vessels of the hyperinsulinemic, insulin resistant obese Zucker rat

Objective: Earlier, we reported that high insulin incubation in vitro leads to increased ETA receptor expression in cultured rat aortic smooth muscle cells (Diabetes 1998, 47: 934-944). Our later observation of enhanced endot helin-1 evoked vasoconstriction in aorta from the hyperinsulinemic obese Zu cker rat indicated that this interaction might also be relevant in vivo. To further examine the relationship between insulinemia and endothelin, we ch aracterized endothelin receptor expression and endothelin-1 peptide levels in vascular tissues and plasma from young and old obese Zucker rats. Method s: 12 and 40-week-old Zucker obese and lean rats were used. Plasma endothel in-1 levels and endothelin-1 peptide content in the mesenteric artery and i n the thoracic aorta were examined by radioimmunoassay. Messenger RNA level s of endothelin-1 peptide and ETA and ETB receptors were examined in the ao rtic and mesenteric vessels using RT-PCR. Results: Obese rats from both age groups had significantly higher plasma levels of insulin (4-10 fold), tota l cholesterol (2-3 fold), triglycerides (10-fold), and glucose (similar to 1.5 fold) than their lean counterparts. There was a trend toward worsening lipoproteinemia and glycemia, but improved insulinemia with age in the obes e rats. In association with these changes, obese rats exhibited attenuated endothelin-1 peptide and preproET-1 mRNA levels, but conversely elevated ET A and ETB receptor mRNA levels in both aortic and mesenteric vessels. Concl usion: These data suggest that vascular tissue from the metabolically dysre gulated obese Zucker rat exhibits attenuated endothelin-1 peptide productio n and elevated endothelin receptor levels. Since elevated insulin levels ha ve been linked to increased endothelin receptor expression, it is plausible that hyperinsulinemia upregulates endothelin receptors contributing to ele vated vasoconstrictor responses to endothelin-1 in this model of obesity an d hypertension. (C) 2000 Elsevier Science B.V. All rights reserved.