Sodium-glucose co-transporter 2 inhibition does not alter the pressure natriuretic response in Sprague Dawley rats

Hypertension is the single biggest risk factor for cardiovascular death and occurs when renal sodium excretion becomes less sensitive to increases in blood pressure (BP). Sodium-glucose co-transporter 2 inhibitors (SGLT2i) increase sodium and glucose excretion and show clinical promise in reducing cardiovascular risk, even in non-diabetics. We hypothesised that SGLT2i increases renal excretion of sodium when BP increases.
Sprague Dawley rats (350-450 g) were terminally anaesthetised (50 mg/kg thiopental ip) and injected with 1 mg/kg iv of SGLT2i, dapagliflozin (dapa, n=8), or 2% DMSO vehicle (n=8). BP (carotid artery) was increased by sequential ligation of the coeliac and cranial mesenteric arteries (step 1) followed by the distal aorta (step 2). Urine (tube cystotomy) and plasma were collected and fractional excretion of sodium (FENa), potassium, chloride, glucose, and glomerular filtration rate (GFR; FITC inulin clearance) were calculated. Data are presented as mean±standard deviation and were analysed by two-way ANOVA with Tukey’s multiple comparisons test.
Baseline BP and induced pressure ramps were similar between groups (baseline dapa 125.2±10.9 mmHg, vehicle 122.2±9.8 mmHg, p=0.996; step 1 dapa 17.4±9.0 mmHg, vehicle 22.7±6.8 mmHg, p=0.803; step 2 dapa 43.2±17.9 mmHg, vehicle 47.1±9.7 mmHg, p=0.904). GFR was also not different between groups at baseline (dapa 0.98±0.15 mL/min/g kidney weight [kw], vehicle 1.30±0.25 mL/min/g kw, p=0.25). GFR increased with BP and the response was similar in both groups (step 1: dapa 1.46±0.29 mL/min/g kw, vehicle 1.61±0.25 mL/min/g kw, p=0.25; step 2: dapa 2.13±0.33 mL/min/g kw, vehicle 2.32±0.57 mL/min/g kw, p=0.25). Urinary glucose excretion was higher in the dapa group compared to vehicle throughout the experiment (p<0.0001), despite similar plasma glucose (p=0.082). FENa increased ~40-fold in both groups (baseline: dapa 0.89±1.21%, vehicle 0.54±0.43%, p>0.999; step 1: dapa 9.07±4.20%, vehicle 10.81±4.12%, p=0.986; step 2: dapa 21.20±9.53%, vehicle 19.95±6.21%, p=0.997). Urine flow rate also increased markedly in both groups (baseline: dapa 12.14±9.637 μL/min/g kw, vehicle 4.74±3.36 μL/min/g kw, p=0.982; step 1: dapa 33.72±9.75 μL/min/g kw, vehicle 28.46±13.31 μL/min/g kw, p=0.996; step 2: dapa 77.30±32.92 μL/min/g kw, vehicle 91.86±35.67 μL/min/g kw, p=0.748). No significant differences were seen in potassium or chloride excretion between the groups (p=0.363 and p=0.277, respectively).
Acute increases in BP induces natriuresis and diuresis, reflecting diminished tubular sodium reabsorption. The response is unaffected by SGLT2 inhibition, despite glycosuria. This does not support an enhanced natriuretic response to increased BP as the mechanism underpinning reduced cardiovascular risk in non-diabetics receiving SGLT2i.