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Reversal of the cardiotonic and action‐potential prolonging effects of DPI 201–106 by BDF 8784, a methyl‐indol derivative
Author(s) -
Armah Benjamin I.,
Pfeifer Thomas,
Ravens Ursula
Publication year - 1989
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.1476-5381.1989.tb11888.x
Subject(s) - inotrope , chemistry , indole test , derivative (finance) , tetrodotoxin , pharmacology , stereochemistry , medicine , endocrinology , financial economics , economics
1 We studied the interaction of the cardiotonic compound DPI 201–106 (4‐[3′‐(4″‐benzhydryl‐1′‐piperazinyl)−2′‐hydroxypropoxy]‐1H‐indole‐2‐carbonitrile; DPI) and its derivative BDF 8784 (2‐methyl‐4‐[3′‐(4″‐benzhydryl‐1”‐piperazinyl)−2′‐hydroxypropoxy]‐1H‐indole; BDF) in isolated right ventricular papillary muscles of guinea‐pig heart. 2 In contrast to the cardiotonic DPI, the methyl‐indole derivative lacked a positive inotropic effect and even caused negative inotropic effects in concentrations above 1 μ m . At 10 μ m BDF significantly reduced the force of contraction and dV / dt max' but did not affect action potential duration (APD). 3 Pretreatment of papillary muscles with BDF prevented the positive inotropic action of DPI in a concentration‐dependent, but non‐competitive fashion. At 10 μ m , BDF prevented the inotropic effect of racemic DPI and shortened the DPI‐induced prolongation of action potential duration. BDF similarly affected the inotropic and APD‐prolonging effects of the sea anemone polypeptide ATX II. 4 In cardiac myocytes, DPI induced a tetrodotoxin (TTX)‐sensitive, slowly inactivating inward current. The slow decay of this current was enhanced by BDF. In cells pretreated with BDF, DPI was not effective. BDF alone depressed the sodium and the calcium current. 5 In conclusion, the non‐inotropic methyl‐indole derivative BDF interacts with DPI non‐competitively at the sodium channels to abolish the inotropic and APD‐prolonging effects of DPI, emphasizing the importance of the substituent in position 2 of the indole moiety for this effect.