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Cardiovascular Research 2002 56(2):225-234; doi:10.1016/S0008-6363(02)00543-6
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Sepsis causes presynaptic histamine H3 and {alpha}2-adrenergic dysfunction in canine myocardium

Zao-Qin Cheng, Deepak Bose, Han Jacobs, R Bruce Light and Steven N Mink*

University of Mannitoba, Departments of Medicine, Pharmacology and Therapeutics, Anesthesiology, and Biochemistry and Molecular Biology, Winnipeg, Manitoba, Canada

minksn{at}cc.umanitoba.ca

* Corresponding author. MD Health Sciences Center, GF-221 700 William Ave Winnipeg, Manitoba R3E-0Z3, Canada. Tel.: +1-204-787-2914; fax: +1-204-787-1932.

Objective: Histamine H3 receptors and {alpha}2-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 {alpha}2-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 {alpha}2-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 {alpha}2-adrenoceptors and tested whether H3 activation would attenuate the {alpha}2-agonist and {alpha}2-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 {alpha}2-agonist and {alpha}2-antagonist effects on adrenergic activation as compared with nonseptic plasma. Conclusion: We conclude that presynaptic sympathetic dysfunction may contribute to cardiovascular collapse in sepsis.

KEYWORDS Adrenergic (ant)agonists; Autonomic nervous system; Contractile function; G-proteins, Septic shock


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