8-Oxo-9-Dihydromakomakine Isolated from <i>Aristotelia chilensis</i> Induces Vasodilation in Rat Aorta: Role of the Extracellular Calcium Influx

• Main Authors: Fredi Cifuentes, Javier Palacios, Adrián Paredes, Chukwuemeka R. Nwokocha, Cristian Paz
• Format: Article
• Language: English
• Published: MDPI AG 2018-11-01
• Series: Molecules
• Subjects: <i>Aristotelia chilensis</i> Molina Stuntz; vascular activity; endothelium-independent; indole alkaloid; 8-oxo-9-dihydromakomakine; voltage-dependent calcium channels
• Online Access: https://www.mdpi.com/1420-3049/23/11/3050

8-Oxo-9-dihydromakomakine is a tetracyclic indole alkaloid extracted from leaves of the Chilean tree <i>Aristotelia chilensis</i>. The present study investigated the effects of this alkaloid on vascular response in tissues isolated from aortic segments obtained from normotensive rats. Our results showed that 8-oxo-9-dihydromakomakine induced a dose-dependent relaxation of aortic rings pre-contracted with phenylephrine (PE; 10^&#8722;6 M). The vasorelaxation induced by 8-oxo-9-dihydromakomakine in rat aortic rings is independent of endothelium. The pre-incubation of aortic rings with 8-oxo-9-dehydromakomakine (10^&#8722;4 M) significantly reduced the contractile response to KCl (<i>p</i> &lt; 0.001) more than PE (<i>p</i> &lt; 0.05). The highest dose of 8-oxo-9-dehydromakomakine (10^&#8722;4 M) drastically reduced the contraction to KCl (6&#183;10^&#8722;2 M), but after that, PE (10^&#8722;6 M) caused contraction (<i>p</i> &lt; 0.05) in the same aortic rings. The addition of 8-oxo-9-dihydromakomakine (10^&#8722;5 M) decreased the contractile response to tetraethylammonium (a voltage-dependent potassium channels blocker; TEA; 5 &#215; 10^&#8722;3 M; <i>p</i> &lt; 0.01) and BaCl₂ (a non-selective inward rectifier potassium channel blocker; 5 &#215; 10^&#8722;3 M; <i>p</i> &lt; 0.001) in rat aorta. 8-oxo-9-dihydromakomakine (10^&#8722;5 M) decreased the contractile response to PE in rat aorta in the presence or absence of ouabain (an inhibitor of Na,K-ATPase; 10^&#8722;3 M; <i>p</i> &lt; 0.05). These results could indicate that 8-oxo-9-dihydromakomakine partially reduces plasma membrane depolarization-induced contraction. In aortic rings depolarized by PE, 8-oxo-9-dihydromakomakine inhibited the contraction induced by the influx of extracellular Ca²⁺ in a Ca²⁺ free solution (<i>p</i> &lt; 0.01). 8-oxo-9-dihydromakomakine reduced the contractile response to agonists of voltage-dependent calcium channels type L (Bay K6844; 10^&#8722;8 M; <i>p</i> &lt; 0.01), likely decreasing the influx of extracellular Ca²⁺ through the voltage-dependent calcium channels. This study provides the first qualitative analysis indicating that traditional folk medicine <i>Aristotelia chilensis</i> may be protective in the treatment of cardiovascular pathologies.