title: Sepsis causes presynaptic histamine H3 and alpha2-adrenergic dysfunction in canine myocardium.
abstract: OBJECTIVE
  Histamine H3 receptors and alpha2-adrenoceptors are presynaptic receptors that modulate norepinephrine (NE) release from sympathetic nerves innervating the cardiovascular system. We previously showed that cardiac H3 receptors are activated in sepsis, and that this activation leads to a decrease in the adrenergic response (AR) [J. Appl. Physiol. 85 (1998) 1693-1701] H3-receptors and alpha2-receptors appear to be coupled to GTP binding regulatory proteins (G) that modulate transmitter release by reducing calcium current into the nerve terminals through neuronal calcium channels. There may also be interaction between H3-receptors and alpha2-receptors on AR that may occur either at the receptor or a more downstream level.
  
  
  METHODS
  In the present study, we examined the effect of septic plasma on AR in a canine ventricular preparation in which field stimulation was used to produce AR. We determined whether there was interaction between H(3)-receptors and alpha2-adrenoceptors and tested whether H3 activation would attenuate the alpha2-agonist and alpha2-antagonist effects of clonidine and yohimbine, respectively. We also determined whether the mechanism by which septic plasma decreases the adrenergic response involves inactivation of an inhibitory G protein and used pertussis toxin (PTX) to assess this effect.
  
  
  RESULTS
  We found that septic plasma attenuated AR produced by field stimulation, and that this decrease was mediated by a PTX sensitive inhibitory G protein. H3 activation also attenuated the alpha2-agonist and alpha2-antagonist effects on adrenergic activation as compared with nonseptic plasma.
  
  
  CONCLUSIONS
  We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis.
authors.affiliation: University of Mannitoba, Department of Medicine, Manitoba, Winnipeg, Canada.
authors.forename: Zao-Qin
authors.initials: ZQ
authors.lastname: Cheng
authors.forename: Deepak
authors.initials: D
authors.lastname: Bose
authors.forename: Han
authors.initials: H
authors.lastname: Jacobs
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Light
authors.forename: Steven N
authors.initials: SN
authors.lastname: Mink
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D046508:Culture Techniques; D004285:Dogs; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000294:innervation* / Q000503:physiopathology; D006632:Histamine / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D037342:Pertussis Toxin / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D018100:Receptors, Histamine H3 / Q000502:physiology*; D012772:Shock, Septic / Q000097:blood* / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D018100:Receptors, Histamine H3; D015016:Yohimbine; D006632:Histamine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D003000:Clonidine