Clinical and experimental evidence has shown that myocardial ischemia activates cardiac spinal afferents that mediate sympathoexcitatory reflex responses. During myocardial ischemia thromboxane A₂ (TxA₂) is released in large quantities by activated platelets in the coronary circulation of patients with coronary artery disease. We hypothesized that endogenous TxA₂ contributes to sympathoexcitatory reflexes during myocardial ischemia through stimulation of TxA₂/prostaglandin endoperoxide receptors (TP) receptors. Regional myocardial ischemia was induced by occlusion of a diagonal branch of left anterior descending coronary artery of anaesthetized cats. Hemodynamic parameters and renal sympathetic nerve activity were recorded after sinoaortic denervation and bilateral vagotomy. Regional myocardial ischemia evoked significant increases in mean blood pressure (122±10 vs. 139±12 mmHg, before vs. ischemia), aortic flow (153±18 vs. 167±20 ml/min), dP/dt40 (2736±252 vs. 2926±281 mmHg/s), systemic vascular resistance (0.6±0.1 vs. 0.9±0.12 PRU) and renal sympathetic nerve activity by 22%. The reflex nature of the excitatory responses was confirmed by observing its disappearance after blockade of cardiac nerve transmission with intrapericardial 2% procaine treatment. Moreover, application of U46619 (2.5-10 µg), a TxA₂ mimetic, on the heart caused graded increases in mean arterial pressure and renal nerve activity, responses that were abolished three min after local blockade of cardiac neural transmission with intrapericardial procaine. BM13,177 (30 mg/kg, IV), a selective TP receptor antagonist, eliminated the reflex responses to U46619 and significantly attenuated the excitatory responses during brief (5 min) regional myocardial ischemia. The sympathoexcitatory reflex responses to U46619 were unchanged by blockade of histamine H₁ receptors with pyrilamine and serotonin 5-HT₃ receptors with tropisetron, indicating specificity of this TP receptor agonist. These data indicate that endogenous TxA₂ participates in myocardial ischemia-mediated sympathoexcitatory reflex responses through a TP receptor mechanism.