Pharmacological Effects of (+)-Nantenine, an Alkaloid Isolated From Platycapnos spicata, in Several Rat Isolated Tissues

Abstract

In this work, the potential activity of (+)-nantenine (a natural aporphin alkaloid) in several rat isolated tissues was studied. In rat isolated intact aorta, (+)-nantenine (0.05 - 0.5 μM) competitively antagonized with almost equal effectiveness the contractions produced by phenylephrine (PE) and 5-hydroxytryptamine (5-HT) in normal Krebs solution. However, at higher concentrations (2 μM), the alkaloid also reduced the maximal effect induced by these two agonists. In depolarizing Ca²⁺-free high KCl 50 mM solution, (+)-nantenine (1.5 - 6 μM) inhibited, in a non-competitive way, the increase in tension evoked by Ca²⁺ with depression of the maximum response. On the other hand, (+)-nantenine (3 - 30 μM) did not affect the contractile effect caused by okadaic acid (OA, 1 μM) while, however, this alkaloid totally relaxed, in a concentration-dependent fashion, the contractions produced by phorbol 12-myristate 13-acetate (PMA, 1 μM) in endothelium-containing rat aortic rings. (+)-Nantenine (1 - 30 μM) reversed and competitively antagonized the inhibitory action induced by B-HT 920 in electrically-stimulated rat vas deferens. In isolated rat atria, (+)-nantenine (3 - 10 μM) diminished the contraction frequency. (+)-Nantenine (3 μM) significantly reduced the depolarization (voltage)-activated transient (T-type) and sustained (long-lasting, L-type) barium inward currents [I _Ba(T) and I _Ba(L)] recorded in whole cell-clamped rat aortic myocytes. These results indicate that the pharmacological effects of (+)-nantenine observed at concentrations lower than 1 μM can be attributed to α₁-adrenergic and 5-HT_2A receptor blocking properties whereas at higher concentrations (> 1 μM) the pharmacological activity of this natural compound may be also due to a decrease of Ca²⁺ influx through transmembrane calcium channels (calcium antagonist activity), to an inhibition of PKC actions and/or to an α₂-adrenoceptor blockade.

Abbreviations

5-HT:5-hydroxytryptamine

I _Ba(L):sustained (L type) voltage-activated barium inward current

I _Ba(T):transient (T type) voltage-activated barium inward current

IP₃:inositol 1,4,5-trisphosphate

I-V:current-voltage

K_ATP:ATP-sensitive K⁺ channels

K_Ca:large conductance Ca²⁺-activated K⁺ channels

OA :okadaic acid

PMA:phorbol 12-myristate 13-acetate

PE: phenylephrine

TEA :tetraethylammonium

V_h: holding potential

α-Adrenoceptor antagonism - calcium antagonist activity - rat aorta - PKC effects - rat vas deferens - 5-HT_2A receptor - rat atria - (+)-nantenine

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