Abstract: Background– Deranged glucose metabolism has deleterious cardiovascular and renal consequencies, predicted by disrupted circadian variation in blood pressure (BP). However, SGLT2 inhibitors (SGLTi), now veterinary-licensed, reduce cardiovascular risk in people and are renoprotective. The mechanism is unknown. We modelled natriuresis and glucosuria from SGLTi and assessed cardiovascular risk in rodents. Hypothesis– Combining natriuresis with glucosuria enhances circadian variation in BP. Animals– Sprague Dawley rats (n=16, 250-300g) were maintained on standard chow and water adlibitum (12-hour light cycle, 21±1ºC, 50% humidity). Diabetes mellitus (T1DM) was induced (35mg/kg streptozotocin, intraperitoneal) or rats received vehicle (n=8 both groups). Methods– BP was measured continuously for 2 weeks with radiotelemetry devices (DSI-HD-S10, distal aorta). After baseline (week 1), rats ate oral amiloride (ENaC antagonist, 1mg/kg q24) in week 2. Data (mesor±SD) were assessed by cosinor analysis and 2-way repeated-measures ANOVA. Results– There were complete data from 5 controls and 6 T1DM rats. Sinusoidal variation in systolic BP (127±8mmHg) and heart rate occurred in all rats. Amiloride did not modify systolic mesor but increased amplitude and dip by ~25% to 5.5±1.2mmHg and 4.7±0.5%. Diastolic BP (87±3mmHg) was unaffected. T1DM reduced heart rate by ~40beats/min to 340.8±34.2beats/min, while amiloride reduced it in controls and T1DM rats by ~20 beats/min without changing amplitude or dip (40.3±7.4beats/min,11.2±1.9%). Conclusions and Clinical Importance– Natriuresis by ENaC blockade reduced heart rate and enhanced circadian variation in BP, regardless of diabetic status. Contrary to our hypothesis, natriuresis from SGLT2i, rather than natriuresis/glucosuria combined, may offer cardiovascular benefits in small animals.
