Insulin increases endothelin-1-evoked intracellular free calcium responses by increased ET(A) receptor expression in rat aortic smooth muscle cells
| Autor: | Thomas W. Wilson, Venkat Gopalakrishnan, J. R. Mcneill, Rob L Hopfner, R. V. Hasnadka |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Endothelin Receptor Antagonists
Male Agonist Vasopressin medicine.medical_specialty Vascular smooth muscle Transcription Genetic medicine.drug_class Endocrinology Diabetes and Metabolism Receptor expression medicine.medical_treatment Biology Muscle Smooth Vascular Rats Sprague-Dawley Piperidines Internal medicine Internal Medicine medicine Animals Insulin Obesity RNA Messenger Receptor Aorta Cells Cultured Endothelin-1 Receptors Endothelin Endothelins Drug Synergism Rats Inbred Strains Receptor Endothelin A Receptor Endothelin B Endothelin 1 Peptide Fragments Rats Rats Zucker Up-Regulation Kinetics Endocrinology Gene Expression Regulation Calcium medicine.symptom Oligopeptides Vasoconstriction |
| Zdroj: | Diabetes. 47:937-944 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/diabetes.47.6.937 |
| Popis: | While insulin is known to promote vascular smooth muscle (VSM) relaxation, it also enhances endothelin-1 (ET-1) secretion and action in conditions such as NIDDM and hypertension. We examined the effect of insulin pretreatment on intracellular free calcium ([Ca2+]i) responses to ET-1 in cultured aortic smooth muscle cells (ASMCs) isolated from Sprague-Dawley (SD) rats and measured ET(A) receptor characteristics and ET-1-evoked tension responses in aorta obtained from insulin-resistant, hyperinsulinemic Zucker-obese (ZO) and control Zucker-lean (ZL) rats. Pretreatment of rat ASMCs with insulin (10 nmol/l for 24 h) failed to affect basal [Ca2+]i levels but led to a significant increase in peak [Ca2+]i response (1.7-fold; P < 0.01) to ET-1. The responses to IRL-1620 (an ET(B) selective agonist), ANG II, and vasopressin remained unaffected. ET-1-evoked peak [Ca2+]i responses were significantly attenuated by the inclusion of the ET(A) antagonist, BQ123, in both groups. The ET(B) antagonist, BQ788, abolished [Ca2+]i responses to IRL-1620 but failed to affect the exaggerated [Ca2+]i responses to ET-1. Saturation binding studies revealed a twofold increase (P < 0.01) in maximal number of binding sites labeled by 125I-labeled ET-1 in insulin-pretreated cells and no significant differences in sites labeled by 125I-labeled IRL-1620 between control and treatment groups. Northern blot analysis revealed an increase in ET(A) mRNA levels after insulin pretreatment for 20 h, an effect that was blocked by genistein, actinomycin D, and cycloheximide. Maximal tension development to ET-1 was significantly greater (P < 0.01), and microsomal binding studies using [3H]BQ-123 revealed a twofold higher number of ET(A) specific binding sites (P < 0.01) in aorta from ZO rats compared with that of ZL rats. These data suggest that insulin exaggerates ET-1-evoked peak [Ca2+]i responses via increased vascular ET(A) receptor expression, which may contribute to enhanced vasoconstriction observed in hyperinsulinemic states. |
| Databáze: | OpenAIRE |
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