Vasodilatory and antihypertensive effects of sotagliflozin: Ex vivo evaluation in isolated rat aortic rings and an in vivo assessment in spontaneously hypertensive rats

Sotagliflozin, a dual SGLT1/2 inhibitor, is noted for its cardioprotective and antihypertensive effects, yet its direct vascular action remains unclear. This study investigated its ex vivo vasodilatory effects in isolated rat thoracic aorta and in vivo antihypertensive effects in non-diabetic Spontaneously Hypertensive rats (SHRs), with subchronic safety assessment. Aortic rings were pre-contracted with phenylephrine or potassium chloride, and underlying mechanisms were studied using pathway-specific inhibitors against matched vehicle controls. Blood pressure and heart rate were measured weekly over 28 days of oral treatment, and safety assessed through body weight, organ weight, biochemistry and hematology. Sotagliflozin induced a concentration-dependent, predominantly endothelium-dependent vasodilation. Cyclooxygenase-derived prostanoid signaling coupled to the AC/cAMP/PKA axis contributed most consistently. In contrast, attenuation by L-NAME and ODQ was surmounted at higher concentrations, indicating a supplementary role for the NO/sGC/cGMP pathway. Vasodilation persisted under KCl-induced depolarization and was unaffected by potassium channel blockers, arguing against a requirement for potassium channel-mediated hyperpolarization. Sotagliflozin also blunted vasoconstriction mediated by voltage-operated calcium channels and inositol triphosphate receptors. In vivo, 200 mg/kg significantly reduced systolic blood pressure relative to baseline and vehicle control, comparably to propranolol and without reflex tachycardia, whereas diastolic and mean arterial pressures were unaltered. Body and organ weights were unaffected, serum uric acid was lower at 50 and 100 mg/kg, urea was higher at the upper doses, and hematology was unremarkable. These findings indicate that sotagliflozin exerts direct vasodilatory activity in the rat thoracic aorta and lowers systolic blood pressure at supratherapeutic doses, warranting further investigation.