HIV-1 infection has been associated with cardiomyopathy in a subset of patients. In order to determine whether HIV-1 alters myocardial function or the myocardial response to stress, transgenic mice that express the HIV-1 protein Tat were used. Heart function was assessed using the isolated working heart preparation. Response to infection was assessed by measuring heart function at various times after endotoxin administration. Since cytokines are implicated in myocardial dysfunction, plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) and myocardial mRNA and protein levels of TNF-alpha and IL-6 were determined. Tat by itself did not cause myocardial dysfunction; however, 4 h after endotoxin, myocardial function was more severely compromised in the Tat mice than in control mice. Plasma TNF-alpha levels were elevated at 2 h and higher in the control group but myocardial levels were similar in the two groups. Plasma IL-6 was increased but myocardial levels were different only at 24 h at which time myocardial function was no longer depressed. Tat expression, by itself, did not impair intrinsic myocardial function but did increase myocardial injury induced by endotoxin. Although cytokines are associated with dysfunction, TNF-alpha and IL-6 were probably not responsible for the exaggerated dysfunction in Tat mice receiving endotoxin.