Study of the in vivo and in vitro cardiovascular effects of (+)‐glaucine and N‐carbethoxysecoglaucine in rats

Abstract

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 vitro functional evaluation of isolaureline, dicentrine and glaucine enantiomers at 5‐HT2 and α1 receptors

“…Both ( R )‐ and ( S )‐glaucine ( 3b ) were also observed to act as antagonists at α 1 receptors, in line with previous studies on ( S )‐glaucine . However, they behaved very differently to the other test compounds at 5‐HT 2 receptors: ( S )‐glaucine acted as a partial agonist (Figure a), whereas ( R )‐glaucine appeared to enhance the response obtained in the presence of serotonin (in antagonism testing), particularly at the 5‐HT 2A receptor, suggesting that it may act as a positive allosteric modulator (Figure b).…”

Study of the in vivo and in vitro cardiovascular effects of a hydralazine‐like vasodilator agent (HPS‐10) in normotensive rats

“…Before specific experimental protocols were initiated, aortae were equilibrated at a resting tension of 1 g for at least 1 h during which the physiological solution was replaced every 10 min. The absence of acetylcholine (1 μM) vasorelaxant action in aortic rings precontracted with NA (10 μM) and a simple haematoxylin‐eosine staining technique were used to verify the removal of endothelial cells and the integrity of underlying smooth muscle (Orallo et al , 1995).…”

Molecular Modes of Action of Defensive Secondary Metabolites

“…partial α 2 agonist Roquebert and Grenie (1986), Buckingham (1996) Glaucine Aporphine Many Monimiaceae, Berberidaceae, Annonaceae, Lauraceae, Ranunculaccae, Papaveraceae α 1A,2 antagonist Orallo et al (1993Orallo et al ( , 1995, Madrero et al (1996) Gramine Indole Poaceae, Fabaceae, Aceraceae…”