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Acute SGLT2 Inhibition and the Pressure Natriuresis Response in Rats with Type 1 Diabetes
Author(s) -
Bailey Matthew A,
Costello Hannah M,
Stewart Kevin,
Binnie David,
Culshaw Geoffrey C,
Webb David J
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.569.10
Subject(s) - natriuresis , endocrinology , medicine , chemistry , renal sodium reabsorption , dapagliflozin , diuresis , reabsorption , mean arterial pressure , renal function , blood pressure , type 2 diabetes , kidney , diabetes mellitus , heart rate
Increasing blood pressure (BP) induces natriuresis due to downregulation of sodium transport in the proximal tubule. This pressure natriuresis (PN) response influences long‐term BP. Type‐1 diabetic (T1DM) patients show enhanced tubular sodium reabsorption and high BP. We have found that tubular sodium reabsorption is not modulated by BP in T1DM rats. The molecular mechanism of impaired PN is unknown but the sodium‐glucose cotransporter SGLT2 is a plausible candidate and inhibitors acutely induce diuresis in T1DM rats. This study tested the hypothesis that SGLT2 inhibition with dapagliflozin would improve the acute PN response in T1DM rats. T1DM was induced in male Sprague‐Dawley rats by streptozotocin (30–45mg/kg IP; plasma glucose 13.3–>35mmol). After 3 weeks rats were anaesthetised with Inactin (120mg/kg, IP). The jugular vein was cannulated and isotonic saline (containing FITC‐inulin and p‐amino hippurate for measurement of glomerular filtration rate (GFR) and renal plasma flow (RPF)) was infused. Rats were randomly allocated to receive either dapagliflozin (50mg/kg; n=7) or saline vehicle (n=7) and after an equilibration period and baseline urine collection, BP was increased by sequential arterial ligation of first the coeliac and mesenteric arteries and then the distal aorta and the natriuretic response was measured. Experiments were performed under a single blind and rats were euthanised by an overdose of anaesthetic. Data are mean +SD and comparisons were made by 2‐way ANOVA. GFR and RPF were not different between treatment groups and were unaffected by the experimentally‐induced rise in BP, consistent with autoregulation. In vehicle‐treated rats, incremental rises in BP increased urine flow rate from a baseline of 6 ± 3 to a peak of 51 ± 28μl/min/gkw (P<0.01), sodium excretion from 1.7 ± 0.5 to 16.7 ± 1.4 μmol/min/gkw (P<0.01) and fractional sodium excretion from 0.2 ± 7.6 to 5.4 ± 4.5% (P<0.01). The dapaglifozin‐treated rats responded to increasing pressure with a diuresis and natriuresis but the peak absolute (3.8 ± 4.1μmol/min/gkw; P=0.010) and fractional (15.2 ± 8.0%; P=0.018) sodium excretion were significantly lower than in the vehicle‐ group. Dapagliflozin increased urinary glucose excretion from 0.1 ± 0.2 to 0.4 ± 0.2μmol/min/gkw: glucose excretion was not modified by increasing BP in either group. Although dapagliflozin increased urine flow and glucose excretion at steady‐state BP, it did not enhance the acute PN response in T1DM rats. Thus, impaired PN in T1DM does not reflect increased SGLT2 activity. Support or Funding Information British Heart Foundation studentship FS/16/54/32730 & Kidney Research UK Project Grant RP2/2014 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .