Tetrahydrofurfuryl Nitrate: A New Organic Nitrate Induces Hypotension and Vasorelaxation Without Vascular Tolerance Induction

The development of new organic nitrates is still relevant due to the clinical limitations of their use. Tetrahydrofurfuryl nitrate (NTHF) is a new organic nitrate obtained through a synthetic route of sugarcane. The aim of this research was to investigate the cardiovascular effects promoted by NTHF in rats. Isolated vascular smooth muscle cells (VSMC) were incubated with a specific probe and were analyzed in a flow cytometer to measure the NO concentration after NTHF treatment. Rat superior mesenteric rings were isolated and used for isometric tension recordings and the evaluation of the vasorelaxant activity induced by NTHF. For the in vivo study, polyethylene catheters were implanted into the abdominal aorta and inferior vena cava of the rats (weighing 250–300 g). NTHF increased NO levels in rat VSMCs. In anesthetized rats, NTHF induced hypotension and bradycardia after intravenous administration. These effects were attenuated after the administration of a sGC inhibitor, methylene blue. In the phenylephrine pre-contracted superior mesenteric artery of rats, NTHF (1 pM–10 μM) induced concentration-dependent vasodilatation in both the intact and removed endothelium. Furthermore, in the presence of NO° scavenging (C-PTIO and HDX) or ODQ, a sGC inhibitor, the vasorelaxation induced by NTHF was decreased. NTHF tolerance was evaluated in mesenteric artery rings previously exposed with isolated concentrations of the new organic nitrate. The vasorelaxant effect was not modified by exposure to nitrate. These results demonstrated that NTHF induced hypotension and bradycardia in vivo and a vasorelaxant effect with the participation of the NO-sGC-PKG pathway and triggering calcium-activated K+ channels without vascular tolerance induction.