N-Salicyloyltryptamine, an N-Benzoyltryptamine Analogue, Induces Vasorelaxation through Activation of the NO/sGC Pathway and Reduction of Calcium Influx.

Benzoyltryptamine analogues act as neuroprotective and spasmolytic agents on smooth muscles. In this study, we investigated the ability of N-salicyloyltryptamine (STP) to produce vasorelaxation and determined its underlying mechanisms of action. Isolated rat mesenteric arteries with and without functional endothelium were studied in an isometric contraction system in the presence or absence of pharmacological inhibitors. Amperometric experiments were used to measure the nitric oxide (NO) levels in CD31+ cells using flow cytometry. GH3 cells were used to measure Ca2+ currents using the whole cell patch clamp technique. STP caused endothelium-dependent and -independent relaxation in mesenteric rings. The endothelial-dependent relaxations in response to STP were markedly reduced by L-NAME (endothelial NO synthase-eNOS-inhibitor), jHydroxocobalamin (NO scavenger, 30 µM) and ODQ (soluble Guanylyl Cyclase-sGC-inhibitor, 10 µM), but were not affected by the inhibition of the formation of vasoactive prostanoids. These results were reinforced by the increased NO levels observed in the amperometric experiments with freshly dispersed CD31+ cells. The endothelium-independent effect appeared to involve the inhibition of voltage-gated Ca2+ channels, due to the inhibition of the concentration-response Ca2+ curves in depolarizing solution, the increased relaxation in rings that were pre-incubated with high extracellular KCl (80 mM), and the inhibition of macroscopic Ca2+ currents. The present findings show that the activation of the NO/sGC/cGMP pathway and the inhibition of gated-voltage Ca2+ channels are the mechanisms underlying the effect of STP on mesenteric arteries.

The ent-15α-Acetoxykaur-16-en-19-oic Acid Relaxes Rat Artery Mesenteric Superior via Endothelium-Dependent and Endothelium-Independent Mechanisms.

The objective of the study was to investigate the mechanism of the relaxant activity of the ent-15α-acetoxykaur-16-en-19-oic acid (KA-acetoxy). In rat mesenteric artery rings, KA-acetoxy induced a concentration-dependent relaxation in vessels precontracted with phenylephrine. In the absence of endothelium, the vasorelaxation was significantly shifted to the right without reduction of the maximum effect. Endothelium-dependent relaxation was significantly attenuated by pretreatment with L-NAME, an inhibitor of the NO-synthase (NOS), indomethacin, an inhibitor of the cyclooxygenase, L-NAME + indomethacin, atropine, a nonselective antagonist of the muscarinic receptors, ODQ, selective inhibitor of the guanylyl cyclase enzyme, or hydroxocobalamin, a nitric oxide scavenger. The relaxation was completely reversed in the presence of L-NAME + 1 mM L-arginine or L-arginine, an NO precursor. Diterpene-induced relaxation was not affected by TEA, a nonselective inhibitor of K+ channels. The KA-acetoxy antagonized CaCl(2)-induced contractions in a concentration-dependent manner and also inhibited an 80 mM KCl-induced contraction. The KA-acetoxy did not interfere with Ca(2+) release from intracellular stores. The vasorelaxant induced by KA-acetoxy seems to involve the inhibition of the Ca(2+) influx and also, at least in part, by endothelial muscarinic receptors activation, NO and PGI(2) release.

Calcium channel blockade as a target for the cardiovascular effects induced by the 8 (17), 12E, 14-labdatrien-18-oic acid (labdane-302).

The cardiovascular effects induced by labdane-302, a diterpene isolated from the stems of Xylopia langsdorffianna St. Hill and Tull, were evaluated in male Wistar rats. In normotensive, conscious animals, labdane-302 produced dose-dependent hypotension and tachycardia. These effects were significantly attenuated after pre-treatment with L-NAME (20 mg/kg, i.v.). In isolated mesenteric artery rings, labdane-302 (10(-10)-10(-4)M) elicited concentration-dependent relaxation of phenylephrine-induced contractions (IC50 = 5.4 +/- 1.4 microM). Endothelium removal, and pre-treatment with L-NAME (100 microM) or indomethacin (10 microM) caused significant reductions in sensitivity. Labdane-302 also caused concentration-dependent relaxation in arterial rings pre-contracted with high extracellular KCl (80 mM). In Ca2+-free depolarized preparations, labdane-302 inhibited contractions produced by cumulative increases in extracellular Ca2+ concentration. In GH3 cells, labdane-302 (100 microM) inhibited whole-cell L-type Ca2+ currents by approximately 50%. These results demonstrate that labdane-302 causes hypotension through peripheral vasodilation, mediated in part by NO and PGI2 and by blockade of Ca2+ entry through L-type Ca2+ channels.