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

Research output: Contribution to journalArticle

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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
Externally publishedYes

Fingerprint

Isoproterenol
Endotoxins
Nitric Oxide Synthase
Dexamethasone
Protein Isoforms
Ventricular Pressure
Perfusion
Adrenergic Receptors
Arginine
Nitric Oxide Synthase Type II
Septic Shock
Nitric Oxide
Western Blotting
Head
Pressure
Antibodies

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Depression of the inotropic action of isoprenaline by nitric oxide synthase induction in rat isolated hearts. / Sun, Xiaolu; Wei, Shan; Szabo, Csaba; Dusting, Gregory J.

In: European Journal of Pharmacology, Vol. 320, No. 1, 05.02.1997, p. 29-35.

Research output: Contribution to journalArticle

Sun, Xiaolu ; Wei, Shan ; Szabo, Csaba ; Dusting, Gregory J. / Depression of the inotropic action of isoprenaline by nitric oxide synthase induction in rat isolated hearts. In: European Journal of Pharmacology. 1997 ; Vol. 320, No. 1. pp. 29-35.
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N2 - 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).

AB - 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).

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