DIRECT VASODILATORY EFFECTS OF SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITORS (SGLT2is) AND THE UNDERLYING MOLECULAR MECHANISMS IN RESISTANCE MESENTERIC ARTERIES

Abstract

Sodium glucose co-transporter 2 inhibitors (SGLT2is) are a novel class of oral glucose-lowering drugs. In the USA, the FDA has authorized canagliflozin (Cana), dapagliflozin (Dapa), empagliflozin (Empa), ertugliflozin (Ertu), and bexagliflozin (Bexa) for use to treat type 2 diabetic mellitus (T2DM). Recent cardiovascular outcome trials (CVOTs) indicated cardio-reno protection due to SGLT2is' blood pressure (BP)-lowering effects. Even though numerous long-term processes have been implicated to lower BP, issues still remain to explain the immediate BP-lowering effects of SGLT2is as revealed in recent CVOTs trials. One plausible mechanism may be direct modulation of contractility of resistance arteries which regulate peripheral resistance (R) and thus, blood pressure. Hence, we investigated SGLT2is Empa, Dapa, and Cana's ability to relax resistance mesenteric arteries and the underlying molecular mechanism (s). Pressurized arterial myography and pharmacological inhibitors were utilized to study the direct effect of SGLT2is on the contractility of freshly isolated, resistant mesenteric arteries from rats. We discovered that acute administration of SGLT2is (Empa, Dapa, and Cana) causes concentration-dependent vasodilation in myogenic and phenylephrine (PE)-preconstricted resistant mesenteric arteries, irrespective of SGLT2 inhibition. SGLT2is-evoked vasodilation was blocked by non-selective inhibition of smooth muscle cell voltage-gated K+ (KV) channels. However, the SGLT2is' KV channel specificity varies as Empa targeted KV1.5 and KV7, Dapa targeted KV7, and Cana targeted KV1.5, KV2.1, and KV7. In contrast, KV1.3, ATP-sensitive K+ (KATP) channels, SERCA pump, and small-, intermediate-, and large-conductance Ca2+-activated K+ channels (SKCa, IKCa, and BKCa) did not reduce SGLT2is-induced vasodilation. Furthermore, vasodilation was unaffected by NO-sGC-PKG and prostacyclin (PGI2) inhibition. Besides, SGLT2is-evoked vasodilation was unchanged by endothelium denudation. Overall, our results suggest that the vasodilatory action of SGLT2is like Empa, Dapa, and Cana may be independent of SGLT2 inhibition and mediated by its action on other molecular targets such as smooth muscle cell KV channels with varying specificity. Our findings reveal for the first time SGLT2is' direct vasodilatory activity in resistance arteries, which may explain their blood pressure lowering effects as demonstrated in CVOTs studies and their cardio-reno protective effects. The reported vasodilatory effects may lower blood pressure in vivo, but more research is needed.