Abstract
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 × 10 - 6, 3 × 10 - 5, 3 × 10 - 4, 9 × 10 - 4 and 1.5 × 10 - 3 M) inhibited in a concentration-dependent manner the contractions induced by phenylephrine (1 μM), KCl (80 mM) and KCl (30 mM), [IC50 = (0.4 ± 0.1, 2.4 ± 0.4 and 3 ± 0.4) × 10 - 4 M, respectively). The effect of reticuline on phenylephrine-induced contractions was attenuated by removal of the vascular endothelium [IC50 = (2.5 ± 0.7) × 10 - 4 M]. Similar results were obtained after pretreatment of the rings with L-NAME 100 μM [IC50 = (1.3 ± 0.1) × 10 - 4 M], L-NAME 300 μM [IC50 = (3 ± 0.3) × 10 - 4 M] or atropine 1 μM [IC50 = (1.2 ± 0.2) × 10 - 4 M]. On the other hand, the effect of reticuline on phenylephrine-induced contractions was not affected by indomethacin 1 μM [IC50 = (0.7 ± 0.3) × 10 - 4 M]. Reticuline (3 × 10 - 6, 3 × 10 - 5, 3 × 10 - 4, 9 × 10 - 4 and 1.5 × 10 - 3 M) antagonized CaCl2-induced contractions, and also inhibited the intracellular calcium dependent transient contractions induced by norepinephrine (1 μM), 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 Ca2+ channel blockade and/or 3) inhibition of Ca2+ release from norepinephrine-sensitive intracellular stores.
Key words
Reticuline - hypotension - cardiovascular - vasodilation -
Ocotea duckei
- Lauraceae
References
-
1 Van Den Berg M E. Plantas medicinais na Amazônia - Contribuição ao seu conhecimento sistemático. Conselho Nacional de Desenvolvimento Científico e Tecnológico - Programa de Trópicos Unidos 1982: p 223
-
2
Martin M L, Diaz M T, Montero M J, Prieto P, Roman L S, Cortes D.
Antispasmodic activity of benzylisoquinoline alkaloids analogous to papaverine.
Planta Med.
1993;
59 (suppl 1)
63-7
-
3
Morais L CSL, Barbosa-Filho J M, Almeida R N.
Central depressant effects of reticuline extracted from Ocotea duckei in rats and mice.
J Ethnopharmacol.
1998;
62 (suppl 1)
57-61
-
4
Watanabe H, Ikeda M, Qatanabe K, Kikuchi T.
Effects on central dopaminergic systems of D-coclaurine and D-reticuline, extracted from Magnolia salicifolia
.
Planta Med.
1981;
42
213-22
-
5
Martin M L, Sagredo J A, Morais J M, Montero J, Sanchez MT San Roman L.
Uterine inhibitory effect of reticuline. J Pharm.
Pharmacol.
1988;
40
801-2
-
6
Kimura I, Kimura M, Yoshizadi M, Yanada K, Kadota S, Kikuchi T.
Neuromuscular blocking action of alkaloids from a Japanese crude drug ”SHIN-1” (Flos Magnoliae) in frog skeletal muscle.
Planta Med.
1983;
48
43-7
-
7
Nakaoji K, Nayeshiro H, Tanahashi T.
Norreticuline and reticuline as possible new agents for hair growth acceleration.
Biol Pharm Bull.
1997;
20 (suppl 5)
586-8
-
8
Smith T L, Hutchins P M.
Anesthetic effects on hemodynamics of spontaneously hypertensive and Wistar-Kyoto rats.
Am J Physiol.
1980;
238
H539-44
-
9
Altura B M, Altura B T.
Differential effects of substrate on drug-induced contractions of rabbit aorta.
Am J Physiol.
1970;
219
1698-705
-
10
Sakata K, Karaki H.
Effects of a novel smooth muscle relaxant, KT-362, on contraction on cytosolic Ca2+ level in the rat aorta.
Br J Pharmacol.
1991;
102
174-8
-
11
Moncada S, Palmer R MJ, Higgs E A.
Nitric oxide: Physiology, pathophysiology and pharmacology.
Pharmacol Rev.
1991;
43
109-42
-
12
Furchgott R F.
Role of the endothelium in responses of vascular smooth muscle.
Circ Res.
1983;
53
557-73
-
13
Vanhoutte P M, Boulanger C M, Mombouli J V.
Endothelium-derived relaxing factors and converting enzyme inhibition.
Am J Cardiol.
1995;
76
3E-12E
-
14
Brunning T A, Hendricks M GC, Chang P C, Kuypers E AP, Van Zwieten P A.
In vivo characterization of vasodilating muscarinic receptors in humans.
Circ Res.
1994;
74
912-9
-
15
Moncada S, Higgs E A.
The L-arginine-nitric oxide pathway.
N Engl J Med.
1993;
29
2002-12
-
16
Nelson M T, Patlak J B, Worley J F, Standen N B.
Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone.
Am J Physiol (1 Pt 1).
1990;
259
C3-C18
-
17
Karaki H, Weiss G B.
Calcium release in smooth muscle.
Life Sci.
1988;
42
111-22
-
18
Karaki H, Ozaki H, Hori M, Mitsui-Saito M, Amano K, Harada K, Miyamoto S, Nakazawa H, Won K J, Sato K.
Calcium movements, distribution, and functions in smooth muscle.
Pharmacol Rev.
1997;
49 (suppl 2)
157-230
-
19
Bootman M D, Berridge M J.
The elemental principles of calcium signaling.
Cell.
1995;
83 (suppl 5)
675-8
Prof. Isac Almeida Medeiros
Laboratório de Tecnologia Farmacêutica
Universidade Federal da Paraíba
Caixa Postal 5009
58051-970 João Pessoa, PB
Brazil
Fax: +55-832167511 or 832167365
Email: isacmed@uol.com.br
