Myocardial ischemia-mediated excitatory reflexes: a new function for thromboxane A₂?

Abstract

Fu LW, Phan A, Longhurst JC. Myocardial ischemia-mediated excitatory reflexes: a new function for thromboxane A 2? Am J Physiol Heart Circ Physiol 295: H2530 -H2540, 2008. First published October 24, 2008 doi:10.1152/ajpheart.00790.2008.-Clinical and experimental evidence has shown that myocardial ischemia activates cardiac spinal afferents that mediate sympathoexcitatory reflex responses. During myocardial ischemia, thromboxane A 2 (TxA2) is released in large quantities by activated platelets in the coronary circulation of patients with coronary artery disease. We hypothesized that endogenous TxA 2 contributes to sympathoexcitatory reflexes during myocardial ischemia through stimulation of TxA2/prostaglandin endoperoxide (TP) receptors. Regional myocardial ischemia was induced by occlusion of a diagonal branch of left anterior descending coronary artery of anesthetized 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 Ϯ 10 vs. 139 Ϯ 12 mmHg, before vs. ischemia), aortic flow (153 Ϯ 18 vs. 167 Ϯ 20 ml/min), first derivative of left ventricular pressure at 40-mmHg developed pressure (2,736 Ϯ 252 vs. 2,926 Ϯ 281 mmHg/s), systemic vascular resistance (0.6 Ϯ 0.1 vs. 0.9 Ϯ 0.12 peripheral resistance units), 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 U-46619 (2.5-10 g), a TxA2 mimetic, on the heart caused graded increases in mean arterial pressure and renal nerve activity, responses that were abolished 3 min after local blockade of cardiac neural transmission with intrapericardial procaine. BM 13,177 (30 mg/kg iv), a selective TP receptor antagonist, eliminated the reflex responses to U-46619 and significantly attenuated the excitatory responses during brief (5 min) regional myocardial ischemia. The sympathoexcitatory reflex responses to U-46619 were unchanged by blockade of histamine H 1 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. sympathetic nerves; U-46619; BM 13,177 CLINICAL OBSERVATIONS INDICATE that angina pectoris can be accompanied by either hypertension and tachycardia, hypotension and bradycardia, or hypotension and tachycardia (19,20,30). The latter response very likely is mediated by the baroreceptor-induced reflex chronotropic response to the hypertension. The former two responses more likely are caused by cardiogenic reflexes. In fact, myocardial ischemia is a powerful stimulus that can activate both vagal and sympathetic (spinal) cardiac sensory nerve fibers. Excitation of cardiac vagal afferents le...

Blockade of the TP receptor attenuates the exercise pressor reflex in decerebrated rats with chronic femoral artery occlusion

“…The exercise pressor reflex was evoked by electrical stimulation of the cut peripheral ends of the left L 4 and L5 ventral roots (1-3 times motor threshold, 0.1-ms pulse duration, 40 Hz) for 30 s. TP receptors in the left hindlimb were blocked by injecting daltroban (80 g), a TP receptor antagonist, into the arterial supply of the left hindlimb (8,47). Before injection, the balloon occluder on the abdominal aorta and inferior vena cava was inflated to trap the injectate within the circulation of the left hindlimb.…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…10) causes arrhythmia (Wacker et al, 2009). TP receptors are also located on afferent sympathetic nerve endings in the heart and may participate in the sympathoexcitatory reflex that occurs during myocardial ischemia (Fu et al, 2008).…”

Ionotropic glutamate receptors in the external lateral parabrachial nucleus participate in processing cardiac sympathoexcitatory reflexes

“…Microinjection of Kyn into the elPBN reversibly attenuated BK-induced reflex responses in four vagus intact animals. These data are the first to show that NMDA and AMPA ionotropic glutamate receptors in the elPBN play an important role in processing cardiac excitatory reflex responses.2-amino-5-phosphonopentanoic acid; 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzol(F)quinoxaline; bradykinin; renal sympathetic nerve activity ACTIVATION OF CARDIAC SPINAL (sympathetic) sensory nerve endings during myocardial ischemia by ischemic metabolites, such as thromboxane A 2 and bradykinin (BK), evokes sympathoexcitatory reflex responses, including hypertension and tachyarrhythmias as well as increases in sympathetic outflow (11,12,14,21,53). Clinical and experimental studies (13,35,52,60) have demonstrated that these reflexes significantly contribute to the development of lethal ventricular arrhythmias and heart failure, ultimately increasing morbidity and mortality of patients.…”