Sodium-glucose cotransporter 2 inhibition does not improve the acute pressure natriuresis response in rats with type 1 diabetes.

NEW FINDINGS: What is the central question of this study? Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk in patients with both diabetic and non-diabetic kidney disease: can SGLT2 inhibition improve renal pressure natriuresis (PN), an important mechanism for long-term blood pressure control, which is impaired in type 1 diabetes mellitus (T1DM)? What is the main finding and its importance? The SGLT2 inhibitor dapagliflozin did not enhance the acute in vivo PN response in either healthy or T1DM Sprague-Dawley rats. The data suggest that the mechanism underpinning the clinical benefits of SGLT2 inhibitors on health is unlikely to be due to an enhanced natriuretic response to increased blood pressure. ABSTRACT: Type 1 diabetes mellitus (T1DM) leads to serious complications including premature cardiovascular and kidney disease. Hypertension contributes importantly to these adverse outcomes. The renal pressure natriuresis (PN) response, a key regulator of blood pressure (BP), is impaired in rats with T1DM as tubular sodium reabsorption fails to down-regulate with increasing BP. We hypothesised that sodium-glucose cotransporter 2 (SGLT2) inhibitors, which reduce cardiovascular risk in kidney disease, would augment the PN response in T1DM rats. Non-diabetic or T1DM (35-50 mg/kg streptozotocin i.p.) adult male Sprague-Dawley rats were anaesthetised (thiopental 50 mg/kg i.p.) and randomised to receive either dapagliflozin (1 mg/kg i.v.) or vehicle. Baseline sodium excretion was measured and then BP was increased by sequential arterial ligations to induce the PN response. In non-diabetic animals, the natriuretic and diuretic responses to increasing BP were not augmented by dapagliflozin. Dapagliflozin induced glycosuria, but this was not influenced by BP. In T1DM rats the PN response was impaired. Dapagliflozin again increased urinary glucose excretion but did not enhance PN. Inhibition of SGLT2 does not enhance the PN response in rats, either with or without T1DM. SGLT2 makes only a minor contribution to tubular sodium reabsorption and does not contribute to the impaired PN response in T1DM.

Assessment of left atrial volume in dogs: comparisons of two-dimensional and real-time three-dimensional echocardiography with ECG-gated multidetector computed tomography angiography.

INTRODUCTION: We hypothesized that real-time three-dimensional echocardiography (RT-3DE) was superior to two-dimensional echocardiography for the estimation of left atrial volume (LAV), using electrocardiographic (ECG)-gated multidetector computed tomography angiography (MDCTA) as a volumetric gold standard. The aim was to compare maximum LAV (LAVmax) and minimum LAV (LAVmin) measured by biplane area-length method (ALM), biplane method of disk (MOD) and RT-3DE with 64-slice ECG-gated MDCTA in dogs ANIMALS: The study included twenty dogs, anaesthetized for various diagnostic purposes and without evidence of cardiovascular disease. METHODS: Left atrial volume was estimated by ALM, MOD and RT-3DE following ECG-gated MDCTA. The results were compared with LAV from MDCTA and correlations were performed. The limits of agreement (LoA) between methods were evaluated using Bland-Altman analysis and intraclass correlations. Coefficients of variation were calculated. RESULTS: Area-length method (r = 0.79 and 0.72), MOD (r = 0.81 and 0.70) and RT-3DE (r = 0.94 and 0.82) correlated with MDCTA for LAVmax and LAVmin, respectively (all p < 0.05). Biases for LAVmax (-0.96 mL, 95% LoA: -5.6 to 3.7) and LAVmin (-0.67 mL, 95% LoA: -5.4 - 4.1) were minimal with RT-3DE, reflecting a slight underestimation. Conversely, MOD (LAVmaxbias = 3.19 mL, 95% LoA: -5.7 - 12.1; LAVminbias = 1.96 mL, 95% LoA: -4.6 - 8.5) and ALM (LAVmaxbias = 4.05, 95% LoA: -5.7 - 13.8; LAVminbias = 2.80 mL, 95% LoA: -3.9 - 9.5) suggested LAV overestimation. Intraobserver and interobserver variability were adequate. CONCLUSIONS: Real-time three-dimensional echocardiography is a non-invasive, accurate and feasible method with superior accuracy to two-dimensional methods.

Impaired pressure natriuresis and non-dipping blood pressure in rats with early type 1 diabetes mellitus.

KEY POINTS: Type 1 diabetes mellitus increases cardiovascular risk; hypertension amplifies this risk, while pressure natriuresis regulates long-term blood pressure. We induced type 1 diabetes in rats by streptozotocin injection and demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, tubular sodium reabsorption was not downregulated, and proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected. Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance, but did not restore medullary blood flow. Radiotelemetry showed that diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced. Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes, and this impairment could be a target for preventing hypertension in type 1 diabetes. ABSTRACT: Type 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague-Dawley rats were injected with streptozotocin (30-45 mg/kg) or citrate vehicle. After 3 weeks, pressure natriuresis was induced by serial arterial ligation. In non-diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P < 0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P < 0.01). Mechanistically, normal lithium clearance suggested that distal tubule sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. Radiotelemetry showed that T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non-diabetic controls (P < 0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.

Expression of urocortin peptides in canine myocardium and plasma.

Urocortin (Ucn) peptides are the endogenous ligands for the corticotropin-releasing factor type 2 receptor (CRFR2). They have potentially important roles in cardiovascular physiology in health and disease, and show promise as therapeutics for congestive heart failure. Analysis of canine heart tissue showed mRNA expression of Ucn 1, Ucn 3 and CRFR2 in all heart chambers. Immunohistochemistry also demonstrated Ucns 1 and 3 expression in cardiomyocytes. To assess the potential usefulness of circulating Ucns as markers of heart disease, plasma samples from 45 dogs with cardiac disease and 15 controls were analysed by radioimmunoassay. Both Ucns 1 and 3 were measurable but the presence of cardiac disease did not alter their concentrations. Therefore, whilst Ucns are expressed in canine myocardium (where they may play a role in the endogenous neurohumoral response to cardiac disease or failure) they do not appear to be sensitive biomarkers of cardiac disease in our canine patient population.