Acute myocardial ischemia and subsequent reperfusion result in biochemical and ionic changes in cardiac myocytes which cause contracture of the muscle and a reduced contractile force. Whether changes observed in single myocytes isolated from ischaemic ventricles are a direct consequence of the acute insult, or develop more slowly due to subsequent alterations in load and neurohumoural environment, is controversial. Myocytes from ischemic hearts have a similar contraction amplitude to those from non-failing hearts at physiological or maximally activating levels of ca2+. This could be partly due to the method of cell selection, or could represent the detection of a population of myocytes that have recovered from the original insult. However, there are significant decreases in the velocities of contraction and, particularly, relaxation in myocytes from the ischaemic heart. These resemble alterations caused by anoxia/reperfusion, but similar changes have also been observed in non-ischaemic causes of heart failure. Responses of beta-adrenoceptor stimulation are reduced in single cells from the failing heart, and a post-receptor defect has also been detected. Treatment with pertussis toxin, which reduces the activity of the inhibitory guanine-nucleotide binding protein (Gi) was able to restore beta-adrenoceptor responses to normal. The hypothesis that alterations in the beta-adrenoceptor/Gi/cAMP pathway represent the response of the myocyte to continued exposure to noradrenaline, because of the high sympathetic drive in these patients, is supported by the strong parallels observed with catecholamine-treated animals, and by the fact that non-ischemic aetiologies exhibit similar desensitization. It is concluded that the surviving myocytes in an ischaemic heart are damaged by the neurohumoral alterations that represent the body's attempt to restore cardiac output.