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Investigations of the dual contractile/relaxant properties showed by antioquine in rat aorta
Author(s) -
Ivorra M. Dolores,
Lugnier Claire,
Catret Maria,
Anselmi Elsa,
Cortes Diego,
D'Ocon Pilar
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13598.x
Subject(s) - prazosin , nitrendipine , extracellular , nifedipine , contraction (grammar) , diltiazem , chemistry , phenylephrine , calcium , muscle contraction , papaverine , contractility , aorta , verapamil , endocrinology , medicine , biochemistry , antagonist , biology , receptor , organic chemistry , blood pressure
1 In the present study we assessed the activity of antioquine, a bisbenzyltetrahydroisoquinoline alkaloid isolated from Pseudoxandra sclerocarpa , by examining its effects on the contractile activity of rat isolated aorta, specific binding of [ 3 H]‐(+)‐ cis ‐diltiazem, [ 3 H]‐nitrendipine and [ 3 H]‐prazosin to cerebral cortical membranes and the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta. 2 Contractions in rat aorta induced by high concentrations of KCl (80 m m ) and noradrenaline (1 μ m ) were inhibited by antioquine in a concentration‐dependent manner (0.1 μ m – 300 μ m ). The alkaloid appeared more potent against KCl‐induced contractions. This inhibitory effect was observed at both 37°C and 25°C. 3 Paradoxically, at the highest concentration tested (300 μ m ) antioquine induced a contractile response of similar magnitude in the presence and absence of extracellular calcium, at 37°C. This activity was greatly attenuated at 25°C. Antioquine‐induced contractions were not inhibited by prazosin (0.1 μ m ), nifedipine (1 μ m ) or diltiazem (100 μ m ). On the contrary, prazosin and nifedipine slightly increased the contractions in the presence of extracellular calcium. Papaverine (100 μ m ) partially inhibited the contractile response to antioquine both in the presence and absence of extracellular calcium. 4 At 25°C, in Ca 2+ ‐free solution, antioquine (300 μ m ) did not modify the contractile response (phasic and tonic) evoked by noradrenaline, but increased the phasic contraction induced by caffeine. At 37°C, the contraction elicited by antioquine made it impossible to observe the noradrenaline‐induced one. 5 Antioquine showed affinity for the [ 3 H]‐prazosin binding site and for the [ 3 H]‐(+)‐ cis ‐diltiazem binding site of the Ca 2+ ‐channel receptor complex, but had no effect at the dihydropyridine binding site in rat cerebral cortex. 6 Antioquine weakly inhibited some PDE forms isolated from bovine aorta: a CaM‐PDE (PDE I) which preferentially hydrolyzes cyclic GMP and is activated by calmodulin, and a rolipram‐sensitive cyclic AMP‐PDE (PDE IV) which hydrolyzed cyclic AMP. Antioquine did not exert any inhibitory effect on the other forms of PDE, a cyclic GMP selective form (PDE V) and a low K m cyclic AMP‐PDE that is inhibited by cyclic GMP (CGI‐PDE, PDE III). 7 The present work provides evidence that antioquine has properties both as a calcium entry blocker (possibly through the benzodiazepine recognition site in the calcium channel) and as a contractile agent. Its mechanism of action as a contractile agent is not related to Ca 2+ ‐entry and is hypothetically similar to that of calyculin‐A or okadaic acid. The possible involvement of α‐adrenoceptors in this paradoxical effect cannot be excluded. The rigidity of the molecule provides an interesting model for analyzing this contractile mechanism and the intracellular processes involved.