Staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility in perfused rat hearts: role of thromboxane generation.
BACKGROUND
Cardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, in isolated perfused rat hearts.


RESULTS
Alpha-toxin 0.25 to 1 microg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dt(max)), dropping to a minimum of <60% of control. These changes were accompanied by a liberation of thromboxane A(2) and prostacyclin into the coronary effluent. The release of creatine kinase, lactate dehydrogenase, potassium, and lactate did not surpass control heart values, and leukotrienes were also not detected. Indomethacin, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban fully blocked the alpha-toxin-induced coronary vasoconstrictor response and the decrease in left ventricular developed pressure and dP/dt(max), whereas the lipoxygenase inhibitor nordihydroguaiaretic acid, the platelet activating factor antagonist WEB 2086, and the alpha-adrenergic antagonist phentolamine were entirely ineffective. Inhibition of nitric oxide synthase even enhanced the alpha-toxin-induced increase in coronary perfusion pressure and the loss in myocardial performance.


CONCLUSIONS
Purified staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility. The responses appear to be largely attributable to the generation of thromboxane and are even enhanced when the endogenous nitric oxide synthesis is blocked. Bacterial exotoxins, such as staphylococcal alpha-toxin, may thus be implicated in the loss of cardiac performance encountered in Gram-positive septic shock.
Sibelius
U
U
Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
Grandel
U
U
Buerke
M
M
Mueller
D
D
Kiss
L
L
Kraemer
H J
HJ
Braun-Dullaeus
R
R
Haberbosch
W
W
Seeger
W
W
Grimminger
F
F
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology*; D004487:Edema; D011464:Epoprostenol / Q000378:metabolism*; D005098:Exotoxins / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006460:Hemolysin Proteins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007773:Lactates / Q000378:metabolism; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D010477:Perfusion; D010648:Phenylacetates / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011188:Potassium / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013211:Staphylococcus aureus; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D001381:Azepines; D001427:Bacterial Toxins; D005098:Exotoxins; D006460:Hemolysin Proteins; D007773:Lactates; D010648:Phenylacetates; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D014230:Triazoles; C021091:staphylococcal alpha-toxin; C052518:WEB 2086; D013928:Thromboxane A2; D009637:Masoprocol; D011464:Epoprostenol; D007770:L-Lactate Dehydrogenase; D001241:Aspirin; D011188:Potassium; C051762:daltroban; D007213:Indomethacin