Experiments were conducted in the anesthetized rabbit to investigate mechanisms for arrhythmias that occur following left atrial injection of the thromboxane A₂ (TXA₂) mimetic, U46619. Arrhythmias were primarily of ventricular origin, dose dependent in frequency, and TXA₂ receptor mediated. The response was receptor specific since arrhythmias were absent following pretreatment with a TXA₂ receptor antagonist (SQ29548) and did not occur in response to another prostaglandin, PGF₂. Alterations in coronary blood flow were unlikely the cause of these arrhythmias since coronary blood flow (as measured with florescent microspheres) was unchanged following U46619 and there were no observable changes in the ECG - ST segment. In addition, arrhythmias did not occur following administration of another vasoconstrictor (phenylephrine). The potential involvement of autonomic cardiac efferent nerves in these arrhythmias was also investigated since TXA₂ has been shown to stimulate peripheral nerves. Pretreatment of animals with the -adrenergic receptor antagonist (propranolol) did not reduce the frequency of these arrhythmias. Pretreatment with atropine or bilateral vagotomy resulted in an increased frequency of arrhythmias suggesting that parasympathetic nerves may actually inhibit the arrhythmogenic activity of TXA₂. These experiments demonstrate that left atrial injection of U46619 elicits arrhythmias via a mechanism independent of a significant reduction in coronary blood flow or activation of the sympathetic nervous system. It is possible that TXA₂ may have a direct effect on the electrical activity of the heart in vivo which provides significant implications for cardiac events where TXA₂ is increased, e.g., following myocardial ischemia or administration of cyclooxygenase-2 inhibitors.