Free arachidonic versus eicosapentaenoic acid differentially influences the potency of bacterial exotoxins to provoke myocardial depression in isolated rat hearts.
OBJECTIVE
Staphylococcal alpha-toxin and Escherichia coli hemolysin (ECH) evoke cardiac dysfunction in isolated rat hearts by provoking myocardial synthesis of arachidonic acid-derived thromboxane A2 or the cysteinyl-leukotrienes, LTC4, LTD4, and LTE4, respectively. We investigated whether low doses of either toxin, which fail to induce cardiac depression by themselves, induce cardiac dysfunction when combined with free arachidonic acid.


METHODS
Prospective, experimental study.


METHODS
Research laboratory at a university hospital.


METHODS
Isolated hearts from male Wistar rats.


METHODS
Hearts were perfused with low doses of ECH or alpha-toxin in the absence or presence of arachidonic acid or the alternative eicosanoid precursor eicosapentaenoic acid (EPA).


RESULTS
Application of low-dose ECH with arachidonic acid increased coronary perfusion pressure, depressed left ventricular contractile function, provoked electrical instability, and induced a release of creatine kinase concomitant with the liberation of LTC4, LTD4, and LTE4 into the perfusate. All events were abolished when formation of cysteinyl-leukotrienes was blocked by the 5-lipoxygenase activity inhibitor MK-886, targeting 5-lipoxygenase activating protein. In the presence of arachidonic acid, low doses of alpha-toxin caused an increase in cerebral perfusion pressure and a decline of contractile performance, attributable to the release of thromboxane A2, as both events were mitigated by the cyclooxygenase-inhibitor indomethacin. High doses of ECH caused cardiac dysfunction even in the absence of arachidonic acid. However, in the presence of EPA, the cardiodepressant effect of ECH was blunted. Release of EPA-derived LTE5 at the expense of arachidonic acid-derived LTC4, LTD4, and LTE4 was noted in these hearts.


CONCLUSIONS
The potency of the bacterial exotoxins ECH and alpha-toxin to cause coronary vasoconstriction and myocardial depression is dependent on the availability of free arachidonic acid and may be influenced by supplying omega-3 fatty acids as alternative lipid precursors.
Grandel
Ulrich
U
Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
Benkelmann
Robin
R
Buerke
Michael
M
Kiss
Ladislau
L
Hattar
Katja
K
Mayer
Konstantin
K
Heep
Martina
M
Seeger
Werner
W
Grimminger
Friedrich
F
Sibelius
Ulf
U
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001427:Bacterial Toxins; D004195:Disease Models, Animal; D004347:Drug Interactions; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005098:Exotoxins; D007213:Indomethacin / Q000494:pharmacology; D015289:Leukotrienes / Q000032:analysis; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D011336:Probability; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D001427:Bacterial Toxins; D005098:Exotoxins; D015289:Leukotrienes; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid; D007213:Indomethacin