Sepsis causes presynaptic histamine H3 and α2-adrenergic dysfunction in canine myocardium

Objective: Histamine H3 receptors and α2-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 α2-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 α2-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 H3-receptors and α2-adrenoceptors and tested whether H3 activation would attenuate the α2-agonist and α2-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 α2-agonist and α2-antagonist effects on adrenergic activation as compared with nonseptic plasma. Conclusion: We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis.