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. Endot oxin has been implicated as the causative agent in Gram-negative sepsis, bu t similar abnormalities are encountered in Gram-positive sepsis. We investi gated the influence of the major exotoxin of Staphylococcus aureus, staphyl ococcal alpha-toxin, in isolated perfused rat hearts. Methods and Results-alpha-Toxin 0.25 to 1 mu g/mL caused a dose-dependent i ncrease 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 thro mboxane A(2) and prostacyclin into the coronary effluent. The release of cr eatine kinase, lactate dehydrogenase, potassium, and lactate did not surpas s control heart values, and leukotrienes were also not detected. Indomethac in, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban fully blocked the alpha-toxin-induced coronary vasoconstrictor response an d the decrease in left ventricular developed pressure and dP/dt(max) wherea s the lipoxygenase inhibitor nordihydroguaiaretic acid, the platelet activa ting factor antagonist WEB 2086, and the alpha-adrenergic antagonist phento lamine were entirely ineffective. Inhibition of nitric oxide synthase even enhanced the alpha-toxin-induced increase in coronary perfusion pressure an d the loss in myocardial performance. Conclusions-Purified staphylococcal alpha-toxin provokes coronary vasoconst riction and loss in myocardial contractility. The responses appear to be la rgely attributable to the generation of thromboxane and are even enhanced w hen the endogenous nitric oxide synthesis is blacked. Bacterial exotoxins, such as staphylococcal a-toxin, may thus be implicated in the loss of cardi ac performance encountered in Gram-positive septic shock.