Study of the in vivo and in vitro cardiovascular effects of (+)-glaucine and N-carbethoxysecoglaucine in rats.
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-1, p.o.) and anaesthetized normotensive rats (5 mg kg-1, i.v.). Furthermore, this compound showed no activity in the experiments carried out on rat isolated aorta [contractility and 45Ca2+ influx assays (5 microM)] and did not modify the rate and force of contraction in rat isolated atria (5 microM). 3. In conscious normotensive rats, oral administration of (+)-glaucine (25 mg kg-1) did not modify either systolic arterial pressure or heart rate. 4. In anaesthetized normotensive rats, (+)-glaucine (5 mg kg-1, 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-1, i.v.) did not modify the cardiovascular effects induced by noradrenaline (NA) (5 micrograms kg-1) and 5-hydroxytryptamine (5-HT) (300 micrograms kg-1) but markedly inhibited those induced by nicotine (200 micrograms kg-1). 5. In isolated intact aorta of rat, (+)-glaucine (0.15-5 microM) 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 Ca(2+)-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 microM) 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 microM) did not modify the basal uptake of 45Ca2+ but strongly inhibited the influx of 45Ca2+ induced by NA, 5-HT and K+.8. (+)-Glaucine (5microM) 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-1) may be due, at least in part, to a ganglioplexic effect; (b) the vasorelaxant action of ( + )-glaucine (0.15-5 microM) in rat isolated aorta can be attributed to an alpha1-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.
Orallo
F
F
Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Spain.
Fernández Alzueta
A
A
Campos-Toimil
M
M
Calleja
J M
JM
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001060:Aporphines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002319:Cardiovascular System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D010616:Phenanthrenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D013997:Time Factors
D001060:Aporphines; C094623:N-carbethoxysecoglaucine; D010276:Parasympatholytics; D010616:Phenanthrenes; D012701:Serotonin; D009538:Nicotine; C005004:glaucine; D002118:Calcium; D009638:Norepinephrine