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Inotropic and chronotropic effects of N 6 ‐substituted derivatives of cyclic AMP as assessed in guinea‐pig isolated right atria and papillary muscle
Author(s) -
Kawada Tomie,
Yoshida Yutaka,
Imai Shoichi
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.tb11963.x
Subject(s) - chronotropic , inotrope , papillary muscle , guinea pig , adenosine , chemistry , medicine , potency , endocrinology , ventricle , biochemistry , heart rate , in vitro , blood pressure
1 The inotropic and chronotropic actions of N 6 ‐substituted adenosine 3″:5″‐cyclic monophosphate (cyclic AMP) derivatives (N 6 ‐R cyclic AMPs) were studied in guinea‐pig isolated right atrial preparations and in the papillary muscle preparations from guinea‐pig right ventricle. 2 All the N 6 ‐R cyclic AMPs except N 6 ‐C 14 H 29 produced positive inotropic effects in papillary muscle. The C 5 H 11 , C 6 H 13 , C 7 H 15 , C 8 H 17 and C 9 H 19 compounds were the most potent as inotropic agents, the potency being lower with compounds having longer or shorter N 6 ‐side chains than these. 3 In right atria N 6 ‐C 2 H 5 ‐C 7 H 15 cyclic AMPs produced negative chronotropic effects. However, after treatment of the preparations with 8‐phenyltheophylline the negative chronotropic effects were either much attenuated or abolished, indicating the involvement of adenosine receptors. 4 All the N 6 ‐R cyclic AMPs except N 6 ‐C 14 H 29 were more potent activators of bovine myocardial protein kinase than cyclic AMP. The partition coefficients between octanol and an aqueous phase of N 6 ‐R cyclic AMPs became greater as the numbers of carbon atoms increased, and there appeared to be a relationship between partition coefficient and inotropic potency. It was concluded that membrane penetrativeness rather than potency as activators of protein kinase determined the potencies of N 6 ‐R cyclic AMPs as positive inotropic agents. 5 Derivatives such as N 6 ‐C 7 H 15 cyclic AMP, which have positive inotropic activity without any marked negative chronotropic effect, may be useful as cardiotonic agents in heart failure.