Calcium influx inhibition is involved in the hypotensive and vasorelaxant effects induced by yangambin.

The pharmacological effects on the cardiovascular system of yangambin, a lignan isolated from Ocotea duckei Vattimo (Lauraceae), were studied in rats using combined functional and biochemical approaches. In non-anaesthetized rats, yangambin (1, 5, 10, 20, 30 mg/kg, i.v.) induced hypotension (-3.5 ± 0.2; -7.1 ± 0.8; -8.9 ± 1.3; -14 ± 2.3, -25.5% ± 2.6%, respectively) accompanied by tachycardia (5.9 ± 0.5; 5.9 ± 1.6; 8.8 ± 1.4; 11.6, 18.8% ± 3.4%, respectively). In isolated rat atria, yangambin (0.1 µM-1 mM) had very slight negative inotropic (Emax = 35.6% ± 6.4%) and chronotropic effects (Emax = 10.2% ± 2.9%). In endothelium-intact rat mesenteric artery, yangambin (0.1 µM-1 mM) induced concentration-dependent relaxation (pD2 = 4.5 ± 0.06) of contractions induced by phenylephrine and this effect was not affected by removal of the endothelium. Interestingly, like nifedipine, the relaxant effect induced by yangambin was more potent on the contractile response induced by KCl 80 mM (pD2 = 4.8 ± 0.05) when compared to that induced by phenylephrine. Furthermore, yangambin inhibited CaCl2-induced contractions in a concentration-dependent manner. This lignan also induced relaxation (pD2 = 4.0 ± 0.04) of isolated arteries pre-contracted with S(-)-Bay K 8644. In fura-2/AM-loaded myocytes of rat mesenteric arteries, yangambin inhibited the Ca2+ signal evoked by KCl 60 mM. In conclusion, these results suggest that the hypotensive effect of yangambin is probably due to a peripheral vasodilatation that involves, at least, the inhibition the Ca2+ influx through voltage-gated Ca2+ channels.

Cardiovascular effects induced by reticuline in normotensive rats.

The cardiovascular effects of reticuline, isolated in a pure form from the stem of Ocotea duckei Vattimo, were studied in rats by using a combined in vivo and in vitro approach. In normotensive rats, reticuline (5, 10 and 20 mg/kg, i. v., randomly) injections produced an intense hypotension. This hypotensive response was attenuated after either, L-NAME (20 mg/kg, i. v.), a nitric oxide (NO) synthase inhibitor, or atropine (2 mg/kg, i. v.), a muscarinic receptor antagonist. In isolated rat aortic rings with intact endothelium, reticuline (3 x 10 ( - 6), 3 x 10 ( - 5), 3 x 10 ( - 4), 9 x 10 ( - 4) and 1.5 x 10 ( - 3) M) inhibited in a concentration-dependent manner the contractions induced by phenylephrine (1 microM), KCl (80 mM) and KCl (30 mM), [IC (50) = (0.4 +/- 0.1, 2.4 +/- 0.4 and 3 +/- 0.4) x 10 ( - 4) M, respectively). The effect of reticuline on phenylephrine-induced contractions was attenuated by removal of the vascular endothelium [IC (50) = (2.5 +/- 0.7) x 10 ( - 4) M]. Similar results were obtained after pretreatment of the rings with L-NAME 100 microM [IC (50) = (1.3 +/- 0.1) x 10 ( - 4) M], L-NAME 300 microM [IC (50) = (3 +/- 0.3) x 10 ( - 4) M] or atropine 1 microM [IC (50) = (1.2 +/- 0.2) x 10 ( - 4) M]. On the other hand, the effect of reticuline on phenylephrine-induced contractions was not affected by indomethacin 1 microM [IC (50) = (0.7 +/- 0.3) x 10 ( - 4) M]. Reticuline (3 x 10 ( - 6), 3 x 10 ( - 5), 3 x 10 ( - 4), 9 x 10 ( - 4) and 1.5 x 10 ( - 3) M) antagonized CaCl (2)-induced contractions, and also inhibited the intracellular calcium dependent transient contractions induced by norepinephrine (1 microM), but not those induced by caffeine (20 mM). These results suggest that the hypotensive effect of reticuline is probably due to a peripheral vasodilation in consequence of: 1) muscarinic stimulation and NOS activation in the vascular endothelium, 2) voltage-dependent Ca (2+) channel blockade and/or 3) inhibition of Ca (2+) release from norepinephrine-sensitive intracellular stores.