The Roles of Endothelin Receptors in Pressure Natriuresis in Early Experimental Type 1 Diabetes Mellitus

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Abstract / Description of output

Introduction: Type 1 diabetes mellitus (T1DM) impairs pressure natriuresis by reducing renal medullary perfusion. Natriuresis, but not medullary perfusion, recovers with insulin. ETA receptor (ETAR) blockade lowers blood pressure (BP), ETB receptor (ETBR) blockade promotes sodium/water retention. Objective: We hypothesized that pressure natriuresis and medullary perfusion would recover in T1DM rats following ETAR blockade, while ETBR blockade would prevent recovery with insulin. Methods: Nondiabetic control (382.2±13.5 g, n=32), T1DM (332±14g, n=32) and T1DM+insulin (354.8±25.3 g, n=26) Sprague Dawley rats received iv vehicle, atrasentan (ETAR antagonist, 5 mg/kg), A-192621 (ETBR antagonist, 10mg/kg), or atrasentan+A-192621. Arterial ligation induced pressure natriuresis by increasing mean BP (~25 mm Hg). GFR, renal artery flow and cortical flux were autoregulated. Results: In non-diabetic controls, atrasentan reduced urine flow rate (38.6±6.2 to 15.7±4.9 μl/min/g kw, P=0.02), sodium excretion rate (UNaV, 16.7±1.4 to 1.7±0.5 μmol/min/g kw, P<0.01), fractional sodium excretion (FENa, 15.0±2.4 to 3.4±1.4%, P=0.044) and medullary flux (227.2±26.7 to 115.5±11.9 %, P<0.01). A-192621 increased UNaV (26.6±6.9 μmol/min/g kw, P=0.03) and FENa (21.6±3.4%, P=0.01) without increasing medullary flux. Combined antagonism suppressed UNaV (5.0±2.4μmol/min/g kw, P=0.03) and medullary flux (105.9±12.9 %, P<0.01). By contrast, suppression of natriuresis (4.1±1.1 μmol/min/g kw, P<0.01) and medullary flux (115.4±10.3 %, P<0.01) in T1DM rats was unaffected by atrasentan. Recovery of natriuresis (24.9±17.8 μmol/min/g kw) in T1DM+insulin rats was unaffected by A-192621 and was independent of medullary flux (112.2±6.8 %). Conclusions: Neither ETAR nor ETBR blockade enhances pressure natriuresis in T1DM or prevents recovery with insulin. Furthermore, when BP rises acutely, endothelin receptors have opposite effects to their putative roles - ETARs promote natriuresis, whereas ETBRs are antinatriuretic. Despite anti-hypertensive benefits, selective ETAR antagonists can promote sodium and water retention. Funding: Kidney Research UK, British Heart Foundation
Original languageEnglish
Publication statusPublished - 2017
EventET-15 : International Conference on Endothelin - Prague, Czech Republic
Duration: 4 Oct 20177 Oct 2018


Country/TerritoryCzech Republic


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