1 Effects of the aporphinoid alkaloid, (+)-glaucine, on rat vas deferens were investigated. inhibited Ca2+-induced contractions with depression of the maximal response at higher doses and with a pD'2 value of 3.65. Furthermore, (+)-glaucine (50 IM) did not modify basal 45Ca uptake but strongly inhibited the influx of 45Ca induced by K+. 7 These results suggest that (+)-glaucine has non-selective a,-and M2-adrenoceptor blocking properties. At higher doses, (+)-glaucine shows calcium antagonist activity which may be responsible, at least in part, for the inhibition of the contractions induced by Ca2+ in calcium-free high-potassium medium. (+ )-

1 The cardiovascular and vasorelaxant effects of (+)-glaucine and of a semisynthetic derivative (N-carbethoxysecoglaucine) were studied in rats. 2 N-carbethoxysecoglaucine did not modify either systolic arterial pressure or heart rate values in conscious (25 mg kg-', p.o.) and anaesthetized normotensive rats (5 mg kg ', i.v.) 3 In conscious normotensive rats, oral administration of (+)-glaucine (25 mg kg-') did not modify either systolic arterial pressure or heart rate.4 In anaesthetized normotensive rats, (+)-glaucine (5 mg kg-', i.v.) produced a remarkable fall in mean arterial pressure (MAP) accompanied by a significant decrease in heart rate. In the same preparation, (+ )-glaucine (5 mg kg-', i.v.) did not modify the cardiovascular effects induced by noradrenaline (NA) (5 Ag kg-') and 5-hydroxytryptamine (5-HT) (300 1tg kg-') but markedly inhibited those induced by nicotine (200 Ig kg-').5 In isolated intact aorta of rat, (+)-glaucine (0.15-5tiM) competitively inhibited the contractions induced by NA (with a pA2 value of 7.14) and non-competitively those induced by 5-HT (in normal Krebs solution) and Ca2+ (in depolarizing Ca2+-free high-K+ 50 mM solution), with depression of the maximal response and with pD2' values of 5.56 and 5.26, respectively. 6 In experiments in Ca2+-free medium, (+)-glaucine (3 JAM) inhibited the contractions induced by NA and had no effect on either 5-HT-or caffeine-induced contractions. 7 Furthermore, in the experiments with radioactive Ca2+, (+)-glaucine (3 JAM) did not modify the basal uptake of 45Ca2+ but strongly inhibited the influx of 45Ca2+ induced by NA, 5-HT and K+. 8 (+)-Glaucine (5JM) had no effect on rate and force of contraction in rat isolated atria. 9 These results indicate that: (a) the cardiovascular effects (hypotension and bradycardia) of (+)-glaucine in anaesthetized normotensive rats (5 mg kg-') may be due, at least in part, to a ganglioplexic effect; (b) the vasorelaxant action of ( + )-glaucine (0.15-5 JM) in rat isolated aorta can be attributed to an a,-adrenoceptor blocking property (which may explain its inhibition of noradrenaline-induced 45Ca2+ influx and contractions in normal Krebs solution and noradrenaline-induced contractions in Ca2+-free medium) and to a Ca2+-antagonist activity (which may be responsible, at least in part, for the inhibition of 45Ca2+ uptake induced by NA, 5-HT and K+ and the contractions induced by both NA and 5-HT in normal Krebs solution and by Ca2+ in Ca2+-free high-K+ medium) and (c) there is no correlation between the mechanisms of action observed for (+ )-glaucine in vivo and in vitro, which suggests that the vasorelaxant activity of this alkaloid does not contribute to its hypotensive activity.

In this work, the potential vasorelaxant activity of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, was studied for the first time in rat aorta. (+)-Nantenine (3 - 30 microM) totally relaxed, in a concentration-dependent manner and with almost equal effectiveness, the contractions induced by noradrenaline (NA) or by a high KCl concentration (60 mM) in intact rat aortic rings. Mechanical removal of endothelium and/or pretreatment of aorta rings with glibenclamide (10 microM) or tetraethylammonium (TEA, 2 mM) did not significantly modify the vasorelaxant effects of this aporphine alkaloid. In the experiments in Ca(2+)-free medium, (+)-nantenine (10 microM) had no effect on caffeine-induced contractions. Furthermore, in the studies with radiolabelled Ca(2+), (+)-nantenine (3 - 30 microM) did not modify the basal uptake of (45)Ca(2+) but decreased, in a concentration-dependent fashion, the influx of (45)Ca(2+) induced by NA and KCl in endothelium-containing and endothelium-denuded rat aortic rings. In addition, (+)-nantenine (3 - 30 microM) was ineffective to scavenge superoxide anion (O(2) (-)) radicals generated by the hypoxanthine (HX)-xanthine oxidase (XO) system and/or to inhibit XO activity. These results indicate that: a) the vasorelaxant effects of (+)-nantenine in rat aorta are due, at least in part, to a blockage of Ca(2+) influx through transmembrane calcium channels, b) the activation of ATP-sensitive K(+) channels (K(ATP)) and large conductance Ca(2+)-activated K(+) channels (K(Ca)) present in smooth muscle cells, the presence (integrity) of endothelial system, an inhibitory action on XO enzymatic activity and/or O(2)(-) radicals scavenging properties are not involved in the vascular effects of (+)-nantenine in rat aorta described above.

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In order to clarify the mechanism of hypotensive activity of platelet activating factor (PAF), the effects of this drug on blood pressure in anaesthetized normotensive rats, on KCl- and noradrenaline-induced 45Ca uptake and contractile responses in rat aorta rings with and without endothelium were studied. PAF (3 micrograms kg-1, i.v.) showed long-lasting hypotensive effects in anaesthetized normotensive rats accompanied by a significant increase in heart rate. PAF (0.1-10 microM) did not relax the contractions induced by noradrenaline (10 microM) or K+ (60 mM) in rubbed or intact rat aorta. PAF did not affect the basal uptake of 45Ca2+ nor that induced by the two vasoconstrictor agents. In experiments in a calcium free medium, PAF (10 microM) had no effect on the noradrenaline- (10 microM) induced contractions. These results suggest that the hypotensive activity of PAF in normotensive anaesthetized rats is not due to a direct effect on rubbed and intact rat aorta rings (acting within the cell or blocking Ca2+ influx through L-type transmembrane calcium channels).