title: Undiscovered role of endogenous thromboxane A2 in activation of cardiac sympathetic afferents during ischaemia.
abstract: Myocardial ischaemia activates blood platelets, which in turn stimulate cardiac sympathetic afferents, leading to chest pain and sympathoexcitatory reflex cardiovascular responses. Previous studies have shown that activated platelets stimulate ischaemically sensitive cardiac sympathetic afferents, and that thromboxane A(2) (TxA(2)) is one of the mediators released from activated platelets during myocardial ischaemia. The present study tested the hypothesis that endogenous TxA(2) stimulates cardiac afferents during ischaemia through direct activation of TxA(2) (TP) receptors coupled with the phospholipase C-protein kinase C (PLC-PKC) cellular pathway. Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) in anaesthetized cats. Single fields of 39 afferents (conduction velocity = 0.27-3.65 m s(-1)) were identified in the left or right ventricle initially with mechanical stimulation and confirmed with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 39 cardiac afferents (8 Adelta-, 31 C-fibres) and the responses of these 39 afferents to chemical stimuli were further studied in the following four protocols. In the first protocol, 2.5, 5 and 10 microg of the TxA(2) mimetic, U46619, injected into the left atrium (LA), stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BM13,177, a selective TxA(2) receptor antagonist, abolished the responses of six afferents to 5 microg of U46619 injected into the left atrium and attenuated the ischaemia-related increase in activity of seven other afferents by 44%. In contrast, cardiac afferents, in the absence of TP receptor blockade responded consistently to repeated administration of U46619 (n = 6) and to recurrent myocardial ischaemia (n = 7). In the fourth protocol, administration of PKC-(19-36), a selective PKC inhibitor, attenuated the responses of six other cardiac afferents to U46619 by 38%. Finally, using an immunohistochemical staining approach, we observed that TP receptors were expressed in cardiac sensory neurons in thoracic dorsal root ganglia. Taken together, these data indicate that endogenous TxA(2) contributes to the activation of cardiac afferents during myocardial ischaemia through direct stimulation of TP receptors probably located in the cardiac sensory nervous system and that the stimulating effect of TxA(2) on cardiac afferents is dependent, at least in part, upon the PLC-PKC cellular pathway.
authors.affiliation: Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA. lwfu@uci.edu
authors.forename: Liang-Wu
authors.initials: LW
authors.lastname: Fu
authors.forename: Zhi-Ling
authors.initials: ZL
authors.lastname: Guo
authors.forename: John C
authors.initials: JC
authors.lastname: Longhurst
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000320:Adrenergic Fibers / Q000502:physiology*; D000344:Afferent Pathways / Q000502:physiology*; D000818:Animals; D002415:Cats; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000294:innervation*; D007150:Immunohistochemistry; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011493:Protein Kinase C / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000502:physiology; D013928:Thromboxane A2 / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D017482:Receptors, Thromboxane; C072093:protein kinase C (19-36); D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011493:Protein Kinase C