Ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppressing nicotinic acetylcholine receptor-ion channels in cultured bovine adrenal medullary cells

Abstract

Ikarisoside A is a natural flavonol glycoside derived from plants of the genus Epimedium, which have been used in Traditional Chinese Medicine as tonics, antirheumatics, and aphrodisiacs. Here, we report the effects of ikarisoside A and three other flavonol glycosides on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that ikarisoside A (1-100 μM), but not icariin, epimedin C, or epimedoside A, concentration-dependently inhibited the secretion of catecholamines induced by acetylcholine, a physiological secretagogue and agonist of nicotinic acetylcholine receptors. Ikarisoside A had little effect on catecholamine secretion induced by veratridine and 56 mM K(+). Ikarisoside A (1-100 μM) also inhibited (22)Na(+) influx and (45)Ca(2+) influx induced by acetylcholine in a concentration-dependent manner similar to that of catecholamine secretion. In Xenopus oocytes expressing α3β4 nicotinic acetylcholine receptors, ikarisoside A (0.1-100 μM) directly inhibited the current evoked by acetylcholine. It also suppressed (14)C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine at 1-100 μM and 10-100 μM, respectively. The present findings suggest that ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.

The Pharmacological Effects of Herbs on Catecholamine Signaling

“…We observed that ikarisoside A (1-100 μM) concentration dependently inhibited the secretion of catecholamines induced by ACh (0.3 m) (Figure 2A), but not the secretion of catecholamines induced by veratridine and 56 mK + [10]. Ikarisoside A also suppressed the 22 Na + influx and 45 Ca 2+ influx induced by ACh in a concentrationdependent manner similar to that of catecholamine secretion (Figure 2B, C) [10] . Ikarisoside A is a flavonol glycoside with one rhamnose at the 3 position in the chemical structure.…”

“…Adrenal medullary cells derived from embryonic neural crests are functionally homologous to sympathetic postganglionic neurons [2,10]. Our research demonstrated that in cultured bovine adrenal medullary cells, at least three distinct types of ionic channels participate in catecholamine secretion, including nicotinic acetylcholine receptor (nAChR)-ion channels, voltage-dependent Na + channels, and voltage-dependent Ca 2+ channels [2,11].…”

“…Ikarisoside A is a natural flavonol glycoside derived from plants of the genus Epimedium, which have been used in traditional Chinese medicine as tonics, antirheumatics, and aphrodisiacs [10,23,24], and is used as a tonic supplement in Japan. Ikarisoside A has antioxidant and anti-inflammatory effects [23] and antiosteoporosis effects [10,25]. Icariin, another flavonoid in the genus Epimedium, has an anti-stress effect in the forced swimming test in mice [26].…”

“…In the human body, the most abundant catecholamines are adrenaline, noradrenaline, and dopamine, all of which are produced from phenylalanine and/or tyrosine. Catecholamines are biosynthesized mainly in the adrenal medulla, the postganglionic fibers of the sympathetic nervous system, and the central nervous system [2,9,10]. Catecholamines play very important roles in aspects of the cardiovascular system such as heart rate and blood pressure, blood glucose levels, and the general functions of the central and peripheral sympathetic nervous system [9].…”

“…Our research demonstrated that in cultured bovine adrenal medullary cells, at least three distinct types of ionic channels participate in catecholamine secretion, including nicotinic acetylcholine receptor (nAChR)-ion channels, voltage-dependent Na + channels, and voltage-dependent Ca 2+ channels [2,11]. In these cells, the Na + influx induced by acetylcholine (ACh) via nAChR-ion channels or by veratridine via voltage-dependent Na + channels is a prerequisite for Ca 2+ influx via the activation of voltage-dependent Ca 2+ channels and subsequent catecholamine secretion; in contrast, high K + directly gates voltage-dependent Ca 2+ channels to increase the Ca 2+ influx without increasing the 22 Na + influx [10,11] (Figure 1). ACh-induced Ca 2+ influx is also a prerequisite for the stimulation of catecholamine synthesis associated with the activation of tyrosine hydroxylase [2,[12][13][14][15].…”