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In vivo -adrenergic responses and troponin I phosphorylation: anesthesia interactions

¹Cardiovascular Institute and ²Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania; ³Department of Cardiology at the Freeman Hospital and ⁴University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom

Submitted 2 September 2004 ; accepted in final form 29 November 2004

The mechanisms by which -adrenergic stimulation of the heart in vivo can cause contractile dysfunction are not well understood. We hypothesized that -adrenergic-mediated contractile dysfunction is mediated through protein kinase C phosphorylation of troponin I, which in in vitro experiments has been shown to reduce actomyosin Mg-ATPase activity. We studied pressure-volume loops in transgenic mice expressing mutant troponin I lacking protein kinase C phosphorylation sites and hypothesized altered responses to phenylephrine. As anesthesia agents can produce markedly different effects on contractility, we studied two agents: avertin and -chloralose-urethane. With -chloralose-urethane, at baseline, there were no contractile abnormalities in the troponin I mutants. Phenylephrine produced a 50% reduction in end-systolic elastance in wild-type controls, although a 9% increase in troponin I mutants (P < 0.05). Avertin was associated with reduced contractility compared with -chloralose-urethane. Avertin anesthesia, at baseline, produced a reduction in end-systolic elastance by 31% in the troponin I mutants compared with wild-type (P < 0.05), and this resulted in further marked systolic and diastolic dysfunction with phenylephrine in the troponin I mutants. Dobutamine produced no significant difference in the contractile phenotype of the transgenic mice with either anesthetic regimen. In conclusion, these data (-chloralose-urethane) demonstrate that -adrenergic-mediated force reduction is mediated through troponin I protein kinase C phosphorylation. -Adrenergic responses are not mediated through this pathway. Altering the myofilament force-calcium relationship may result in in vivo increased sensitivity to negative inotropy. Thus choice of a negative inotropic anesthetic agent (avertin) with phenylephrine can lead to profound contractile dysfunction.

protein kinase C; ventricular function

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