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Selective inhibition of cAMP phosphodiesterase III activity by the cardiotonic agent saterinone in guinea pig myocardium.
Arzneimittelforschung. 1988 Sep; 38(9):1293-8.A

Abstract

The effects of saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy] phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) on force of contraction, beating frequency, and on phosphodiesterase (PDE) activity were investigated in isolated preparations from guinea pig hearts. The effects of 3-isobutyl-1-methylxanthine (IBMX) and milrinone were studied for comparison. Saterinone exerted a concentration-dependent (1-30 mumol/l) positive inotropic effect (EC50 = 9.1 mumol/l) in guinea pig papillary muscles. The drug was more potent in increasing force of contraction than was milrinone, but its efficacy was only half as great as that of milrinone. Also IBMX revealed an about 4-fold greater positive inotropic efficacy than saterinone. This study provides functional evidence that the positive inotropic effect of saterinone is at least partially due to a cyclic adenosine monophosphate (cAMP)-dependent mechanism because carbachol antagonized the increase in force of contraction completely. In order to elucidate a possible mechanism of action of saterinone its effects on cardiac cAMP PDE activity were investigated. Saterinone selectively and potently inhibited the isoenzyme III of PDE (IC50 = 0.06 mumol/l). The mean IC50-values for the inhibition of PDE I and II were 323-fold greater. Thus, saterinone proved to be a selective inhibitor of "low-Km, cAMP specific" PDE III. Saterinone revealed only a moderate positive chronotropic effect. The beating frequency of guinea pig spontaneously beating right auricles was augmented by 26.4% at most, that is half as much as the effect of isoprenaline at a similarly effective positive inotropic concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Fed. Rep. of Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

2852013

Citation

Brunkhorst, D, et al. "Selective Inhibition of cAMP Phosphodiesterase III Activity By the Cardiotonic Agent Saterinone in Guinea Pig Myocardium." Arzneimittel-Forschung, vol. 38, no. 9, 1988, pp. 1293-8.
Brunkhorst D, von der Leyen H, Meyer W, et al. Selective inhibition of cAMP phosphodiesterase III activity by the cardiotonic agent saterinone in guinea pig myocardium. Arzneimittelforschung. 1988;38(9):1293-8.
Brunkhorst, D., von der Leyen, H., Meyer, W., Schmidt-Schumacher, C., & Scholz, H. (1988). Selective inhibition of cAMP phosphodiesterase III activity by the cardiotonic agent saterinone in guinea pig myocardium. Arzneimittel-Forschung, 38(9), 1293-8.
Brunkhorst D, et al. Selective Inhibition of cAMP Phosphodiesterase III Activity By the Cardiotonic Agent Saterinone in Guinea Pig Myocardium. Arzneimittelforschung. 1988;38(9):1293-8. PubMed PMID: 2852013.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective inhibition of cAMP phosphodiesterase III activity by the cardiotonic agent saterinone in guinea pig myocardium. AU - Brunkhorst,D, AU - von der Leyen,H, AU - Meyer,W, AU - Schmidt-Schumacher,C, AU - Scholz,H, PY - 1988/9/1/pubmed PY - 1988/9/1/medline PY - 1988/9/1/entrez SP - 1293 EP - 8 JF - Arzneimittel-Forschung JO - Arzneimittelforschung VL - 38 IS - 9 N2 - The effects of saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy] phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) on force of contraction, beating frequency, and on phosphodiesterase (PDE) activity were investigated in isolated preparations from guinea pig hearts. The effects of 3-isobutyl-1-methylxanthine (IBMX) and milrinone were studied for comparison. Saterinone exerted a concentration-dependent (1-30 mumol/l) positive inotropic effect (EC50 = 9.1 mumol/l) in guinea pig papillary muscles. The drug was more potent in increasing force of contraction than was milrinone, but its efficacy was only half as great as that of milrinone. Also IBMX revealed an about 4-fold greater positive inotropic efficacy than saterinone. This study provides functional evidence that the positive inotropic effect of saterinone is at least partially due to a cyclic adenosine monophosphate (cAMP)-dependent mechanism because carbachol antagonized the increase in force of contraction completely. In order to elucidate a possible mechanism of action of saterinone its effects on cardiac cAMP PDE activity were investigated. Saterinone selectively and potently inhibited the isoenzyme III of PDE (IC50 = 0.06 mumol/l). The mean IC50-values for the inhibition of PDE I and II were 323-fold greater. Thus, saterinone proved to be a selective inhibitor of "low-Km, cAMP specific" PDE III. Saterinone revealed only a moderate positive chronotropic effect. The beating frequency of guinea pig spontaneously beating right auricles was augmented by 26.4% at most, that is half as much as the effect of isoprenaline at a similarly effective positive inotropic concentration.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0004-4172 UR - https://www.unboundmedicine.com/medline/citation/2852013/Selective_inhibition_of_cAMP_phosphodiesterase_III_activity_by_the_cardiotonic_agent_saterinone_in_guinea_pig_myocardium_ DB - PRIME DP - Unbound Medicine ER -