Boldine, an Alkaloid from Peumus boldus Molina, Induces Endothelium-Dependent Vasodilation in the Perfused Rat Kidney: Involvement of Nitric Oxide and Small-Conductance Ca2+-Activated K+ Channel

Abstract

Boldine, 2,9-dihydroxy-1,10-dimethoxyaporphine, is the main alkaloid found in the leaves and bark of Peumus boldus Molina. In recent years, boldine has demonstrated several pharmacological properties that benefit endothelial function, blood pressure control, and reduce damage in kidney diseases. However, the renal vasodilator effects and mechanisms remain unknown. Herein, perfused rat kidneys were used to study the ability of boldine to induce vasodilation of renal arteries. For that, left kidney preparations with and without functional endothelium were contracted with phenylephrine and received 10-300 nmol boldine injections. The preparations were then perfused for 15 min with phenylephrine plus L-NAME, indomethacin, KCl, tetraethylammonium, glibenclamide, apamin, charybdotoxin, or iberiotoxin. In 30, 100, and 300 nmol doses, boldine induced a dose-and endothelium-dependent relaxing effect on the renal vascular bed. No vasodilator effects were observed in preparations lacking functional endothelium. While the inhibition of the cyclooxygenase enzyme through the addition of indomethacin did not cause any change in the vasodilating action of boldine, the nonselective nitric oxide synthase inhibitor L-NAME fully precluded the vasodilatory action of boldine at all doses tested. The perfusion with KCl or tetraethylammonium (nonselective K⁺ channels blocker) also abolished the vasodilatory effect of boldine, indicating the participation of K⁺ channels in the renal action of boldine. The perfusion with glibenclamide (selective ATP-sensitive K⁺ channels blocker), iberiotoxin (selective high-conductance Ca²⁺-activated K⁺ channel blocker), and charybdotoxin (selective high- and intermediate-conductance Ca²⁺-activated K⁺ channel blocker) did not modify the vasodilatory action of boldine. On the other hand, the perfusion with apamin (selective small-conductance Ca²⁺-activated K⁺ channel blocker) completely prevented the vasodilatory action of boldine at all doses tested. Together, the present study showed the renal vasodilatory properties of boldine, an effect dependent on the generation of nitric oxide and the opening of a small-conductance Ca²⁺-activated K⁺ channel.