SGLT2 inhibition potentiates the cardiovascular, renal, and metabolic effects of sGC stimulation in hypertensive rats with prolonged exposure to high-fat diet

Abstract

Prolonged high fat diet (HFD) accelerates the cardiovascular, renal and metabolic dysfunction in hypertensive rats with altered renal development (ARDev). Soluble guanylate cyclase (sGC) stimulation or sodium-glucose cotransporter 2 (SGLT2) inhibition may improve cardiovascular, renal, and metabolic function in settings of hypertension and obesity. This study examined whether six weeks treatment with an SGLT2 inhibitor (EMPAGLIFLOZIN, 7 mg/kg/day) enhances the cardiovascular, renal and metabolic effects of a sGC stimulator (PRALICIGUAT, 10 mg/kg/day) in hypertensive rats with ARDev and prolonged exposure to HFD. Arterial pressure (AP), renal vascular resistance (RVR), fat abdominal volume (FAV), insulin resistance, leptin and triglycerides levels and intrarenal infiltration of inflammatory cells were higher, but cardiac output and creatinine clearance were lower in hypertensive rats (n=15) than in normotensive rats (n=7). PRALICIGUAT administration (n=10) to hypertensive rats reduced (P<0.05) AP, FAV, plasma concentrations of leptin and triglycerides, and increased (P<0.05) cardiac output and creatinine clearance. EMPAGLIFLOZIN administration (n=8) only increased (P<0.05) glucosuria and creatinine clearance, and decreased (P<0.05) plasma leptin and triglycerides concentrations in hypertensive rats. Simultaneous administration of PRALICIGUAT and EMPAGLIFLOZIN (n=10) accelerated the decrease in AP, improved glucose tolerance, reduced (P<0.05) incremental body weight gain, and decreased (P<0.05) insulin resistance index, RVR and the infiltration of T-CD3 lymphocytes in renal cortex and renal medulla. In summary, the combined administration of PRALICIGUAT and EMPAGLIFLOZIN leads to a greater improvement of the cardiovascular, renal and metabolic dysfunction secondary to prolonged exposure to HFD in hypertensive rats with ARDev than the treatment with either PRALICIGUAT or EMPAGLIFLOZIN alone.

Endothelin type A receptor blockade increases renoprotection in congestive heart failure combined with chronic kidney disease: Studies in 5/6 nephrectomized rats with aorto-caval fistula

“…Admittedly, the method does not allow accurate measurements of diastolic BP and mean arterial pressure, in contrast to radiotelemetry which, however, could not be implemented in long-term studies in large groups of 5/6 NX + ACF animals. Nevertheless, as repeatedly shown, this method provides valuable information regarding the role of BP in mediating cardiovascular and renal effects of various treatment regimens in rats [48]. While being aware of this methodological limitation, we have demonstrated in preliminary experiments that the tail-cuff method and radiotelemetry provided similar results in 5/6 NX rats [41,45].…”

New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure

“…In clinical trials, the 24 h ambulatory blood pressure shows a slight reduction among people suffering from nocturnal hypertension, diabetes, or salt sensitivity with the application of SGLT2i, thereby lowering the incidence of heart failure and the tolls of cardiovascular mortality ( 49 ). Such an efficacy may be achieved by regulating renal HIF-1α, impairing inflammation and oxidative stress ( 50 ), regulating the function of the paraventricular nucleus of the hypothalamus (PVN) ( 51 ), and sGC pathways ( 52 ). A meta-analysis of 43 RCT studies reveals that under SGLT2i treatment, patients' systolic blood pressure (SBP) decreases by a mean of 2.46 mmHg and diastolic blood pressure (DBP) by a mean of 1.46 mmHg ( 25 , 53 ), while another meta-analysis confirms that SGLT2i significantly reduced 24 h dynamic SBP and dynamic DBP, and such an effect is concluded as SGLT2i-like effect ( 54 ).…”