Cocaine enhances susceptibility to endotoxemic shock in a subset of rats.
OBJECTIVE
We hypothesized that the sympathomimetic cocaine may alter cardiovascular and inflammatory responses and enhance susceptibility to endotoxemia due to innate differences in patterns of sympathetic and cardiovascular responsiveness.


METHODS
Prospective study.


METHODS
Experimental animal laboratory.


METHODS
Fifty-six conscious, instrumented albino rats.


METHODS
Rats were instrumented for determination of arterial pressure and intravenous drug administration and, in some rats, for cardiac output. After recovery, rats were given cocaine (5 mg/kg i.v., twice daily with 4-6 trials) to identify one of two hemodynamic response patterns: a) an increase in systemic vascular resistance with cardiac depression (vascular responders) or b) smaller increases in systemic vascular resistance and no change or an increase in cardiac output (mixed responders). At least 1 month after characterizing response patterns to cocaine, animals were pretreated with cocaine (5 mg/kg i.v.) or an equivalent bolus of vehicle (0.9% saline) while recording hemodynamics. Five minutes later, Escherichia coli lipopolysaccharide (serotype O55:B5, 20 mg/kg i.v.) was administered for 15 mins.


RESULTS
Hemodynamic responses, pupillary diameter, and serum cytokines were determined at several time points. Lipopolysaccharide administration (5-40 mg/kg) without cocaine produced dose-dependent depressor responses with recovery typically within 2 hrs. Although 87% of rats survived a single 20 mg/kg dose of lipopolysaccharide when given alone, pretreatment of vascular responders with cocaine before lipopolysaccharide resulted in greater increases in systemic vascular resistance and pupillary mydriasis and lethality in five of six vascular responders, whereas only one of six mixed responders died. Pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.1 mg/kg i.v.) before cocaine and lipopolysaccharide attenuated hemodynamic responses and improved survival among vascular responders. Serum interleukin-6 and interleukin-10 were elevated in rats treated with cocaine and lipopolysaccharide compared with rats treated with lipopolysaccharide alone, whereas serum tumor necrosis factor-alpha was reduced by cocaine pretreatment. Moreover, serum interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 were elevated in nonsurvivors compared with survivors after cocaine and lipopolysaccharide administration.


CONCLUSIONS
We conclude that cocaine enhances susceptibility and worsens outcome from endotoxic shock by augmenting sympathetic activity, particularly in vascular responders, and that alpha-adrenoceptors mediate the altered inflammatory responses.
Knuepfer
Mark M
MM
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, MO 63104, USA. Knuepfmm@slu.edu
Bloodgood
Tracy A
TA
Matuschak
George M
GM
Lechner
Andrew J
AJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000503:physiopathology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012680:Sensitivity and Specificity; D012772:Shock, Septic / Q000503:physiopathology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D003042:Cocaine