Host defense responses to endotoxemia vary in individuals. Cocaine use further compromises responses to microbial infections in some humans, although the factors responsible for individual predisposition to septic shock in the context of drug abuse is particularly complex and poorly understood. It appears that multiple factors interact to determine individual responsiveness including autonomic regulation of the acute inflammatory responses. This proposal is based on the premise that cocaine will enhance the predisposition to septic shock more readily in some individuals than others. We propose that divergent vascular responsivity to cocaine plays a pivotal role in the induction of cardiovascular dysfunction, including the septic shock syndrome from Gram-negative infectious agents. The effects of the sympathomimetic, cocaine, are potentially on both cardiovascular derangements and on pathogen-induced cytokine gene expression, thereby reducing survival during endotoxemia. In our model of cocaine-induced cardiomyopathies and hypertension in conscious rats, cocaine evokes substantial increases in systemic vascular resistance (SysVR) and renal sysmpathetic nerve activity concurrent with reductions in cardiac output (CO) in animals designated vascular responders. In contrast, mixed responders have smaller increases in SysVR and increases in CO. Our evidence suggests that differences between vascular and mixed responders depend on divergent CNS-mediated sympathetic responses to cocaine. We hypothesize that the excessive sympathetic responsiveness to cocaine and endotoxemia noted in vascular responders results in life-threatening shock due to either a greater loss in receptor sensitivity or to enhanced expression of pro-inflammatory cytokines. This proposal will reveal the causes of alterations in the prognosis of endotoxemia after acute and chronic cocaine use. First, we will verify that acute cocaine pretreatment differentially affects cardiovascular responses, cytokine expression and lethality in rats exposed to Gram-negative endotoxemia. We will utilize lipopolysaccharide (LPS) as a self-limiting model of Gram-negative inflammation. Second, we will determine the contribution of peripheral adrenergic receptors and the sympathetic nervous system that are responsible for variations in individual sensitivity to LPS-induced endotoxemia in animals exposed to cocaine. Third, we will determine the role of specific peripheral autacoids in mediating variable hemodynamic and cytokine responses to LPS. We will assess proinflammatory cytokine synthesis and levels in the plasma, liver, spleen and lungs and block the actions of IL-1B and TNF-alpha. Fourth, we will examine the effects of chronic exposure to cocaine on patterns of autonomic regulation and cytokine expression to acute endotoxemia. Finally, we will study the potential contribution of autonomic and cytokine responsiveness to susceptibility to endotoxemia in rats exposed to repeated cocaine. These studies will provide novel insights into the pathogenesis of cardiovascular dysfunction during infection-related inflammation and clarify the role of the sympathetic nervous system in modulating vascular tone and cytokine responsivity. This information will contribute to our understanding of predisposing factors to the incidence and severity of septic shock in humans and the mechanisms by which cocaine use affects this process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013256-03
Application #
6634302
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (05))
Program Officer
Thadani, Pushpa
Project Start
2001-04-01
Project End
2006-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
3
Fiscal Year
2003
Total Cost
$291,070
Indirect Cost
Name
Saint Louis University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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