Inotropic and chronotropic effects of N⁶‐substituted derivatives of cyclic AMP as assessed in guinea‐pig isolated right atria and papillary muscle

Abstract

1 The inotropic and chronotropic actions of N6-substituted adenosine 3': 5'-cyclic monophosphate (cyclic AMP) derivatives (N6-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 N6-R cyclic AMPs except N6-C14H29 produced positive inotropic effects in papillary muscle. The C5Hl1, C6H13, C7H1,_ C8Hl7 and CgH19 compounds were the most potent as inotropic agents, the potency being lower with compounds having longer or shorter N6-side chains than these.3 In right atria N6-C2H5-C7H1s 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 N6-R cyclic AMPs except N6-C14H29 were more potent activators of bovine myocardial protein kinase than cyclic AMP. The partition coefficients between octanol and an aqueous phase of N6-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 N6-R cyclic AMPs as positive inotropic agents.5 Derivatives such as N6-C7HA, cyclic AMP, which have positive inotropic activity without any marked negative chronotropic effect, may be useful as cardiotonic agents in heart failure.

Positive Inotropic and Chronotropic Effects of 8-Substituted Derivatives of Cyclic AMP and Activation of Protein Kinase A

“…Determination of protein kinase A activity The assay of protein kinase activity based on the phosphorylation of histone was carried out essentially as described by Miyamoto et al (14), and the experimental conditions were similar to those described previously (15). Briefly, the activation of the bovine myocar dial protein kinase A was assessed in a 0.1-ml incubation mixture containing 50 ,umoles HEPES (pH 7.0), 5 ,u moles MgC12, 10 ,u g his tone, 0.1 nmoles y-32P-ATP, 2 ,ug protein kinase enzyme and various concentrations (5 X 104-2.5 X 10-5M) of the cyclic AMP or 8-R cAMPs.…”

Isolation of mutants with improved production of cAMP from Microbacterium sp. no. 205 (ATCC21376)

“…Medical application of derivatives of cyclic adenosine Y,5'-monophosphate (cAMP) as cardiotonic agents (Kawada et al 1989) has recently given good results. Improved production of cAMP would therefore be desirable and microbial production has attracted special attention because it is simple and economical.…”