title: In vivo alpha-adrenergic responses and troponin I phosphorylation: anesthesia interactions.
abstract: The mechanisms by which alpha-adrenergic stimulation of the heart in vivo can cause contractile dysfunction are not well understood. We hypothesized that alpha-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 alpha-chloralose-urethane. With alpha-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 alpha-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 (alpha-chloralose-urethane) demonstrate that alpha-adrenergic-mediated force reduction is mediated through troponin I protein kinase C phosphorylation. beta-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.
authors.affiliation: Freeman Hospital, Dept of Cardiology, Newcastle upon Tyne NE7 7DN, UK. guy.macgowan@nuth.nhs.uk
authors.forename: Guy A
authors.initials: GA
authors.lastname: MacGowan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rager
authors.forename: Sanjeev G
authors.initials: SG
authors.lastname: Shroff
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mathier
mesh_terms: D000777:Anesthetics / Q000008:administration & dosage; D000818:Animals; D002698:Chloralose / Q000008:administration & dosage*; D000431:Ethanol / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D051379:Mice; D008822:Mice, Transgenic / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D019210:Troponin I / Q000172:deficiency*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
chemical_list: D000777:Anesthetics; D011942:Receptors, Adrenergic, alpha; D019210:Troponin I; C062527:tribromoethanol; D002698:Chloralose; D000431:Ethanol; D011493:Protein Kinase C