Depression of the inotropic action of isoprenaline by nitric oxide synthase induction in rat isolated hearts

Xiaolu Sun, Shan Wei, Csaba Szabo, Gregory J. Dusting

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    Abstract

    The mechanisms involved in myocardial dysfunction during septic shock are not well understood. We have investigated the effects of endotoxin and the role of nitric oxide (NO) in the β-adrenoceptor responsiveness of rat isolated, ejecting hearts perfused at 60 mmHg of head pressure. In vivo pretreatment with endotoxin (4 mg/kg, i.p., 3 h before heart isolation) significantly attenuated the inotropic response (increase in left ventricular developed pressure, LVP) to isoprenaline (0.15 μg) after 30 min equilibration and after a further 90 min of perfusion. The peak rate of LVP development (dP/dt(max)) in response to isoprenaline was reduced by endotoxin pretreatment, as was the increase of coronary flow. The depression of ventricular contraction was prevented by pretreatment with dexamethasone (1 mg/kg, i.p., 30 min before endotoxin), and was also restored by perfusion with N(G)-nitro-L-arginine (L-NA, 10 μM) for 60 min, but not by N(G)-nitro-D-arginine (D-NA, 10 μM). Mercaptoethylguanidine (MEG, 30 μM), a selective inhibitor of the inducible NO synthase (isoform 2), also reversed the depression of the isoprenaline response caused by endotoxin pretreatment. However, treatment with endotoxin, dexamethasone, L-NA, D-NA or MEG had minimal effects on the baseline parameters of LVP, dP/dt(max) and coronary flow, which all tended to decline over the 2 h perfusion period. Western blot analysis using an antibody to NO synthase (isoform 2, but not to isoform 3) revealed the induction of a protein corresponding to NO synthase 2 in the endotoxin-treated hearts but not in control hearts or those treated with dexamethasone or MEG. In summary, these results indicate that endotoxin depresses myocardial contractile function and reduces inotropic responsiveness to β-adrenoceptor activation. The effect of endotoxin on the inotropic response is mediated, at least in part, by products of an endogenous NO synthase that is suppressed by dexamethasone and a specific inhibitor of NO synthase (isoform 2).

    Original languageEnglish (US)
    Pages (from-to)29-35
    Number of pages7
    JournalEuropean Journal of Pharmacology
    Volume320
    Issue number1
    DOIs
    StatePublished - Feb 5 1997

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    Keywords

    • Dexamethasone
    • Endotoxin
    • Mercaptoethylguanidine
    • Myocardial contractility
    • Nitric oxide (NO) synthase
    • β-Adrenoceptor

    ASJC Scopus subject areas

    • Pharmacology

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