title: Endogenous endothelin stimulates cardiac sympathetic afferents during ischaemia.
abstract: Myocardial ischaemia activates cardiac sympathetic afferents leading to chest pain and reflex cardiovascular responses. Previous studies have shown that a brief period of myocardial ischaemia increases endothelin in cardiac venous plasma draining ischaemic myocardium and that exogenous endothelin excites cutaneous group III and IV sensory nerve fibres. The present study tested the hypothesis that endogenous endothelin stimulates cardiac afferents during ischaemia through direct activation of endothelin A receptors (ET(A)Rs). Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicates (T(2)-T(5)) in anaesthetized cats. Single fields of 38 afferents (CV = 0.25-3.86 m s(-1)) were identified in the left or right ventricle with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 38 cardiac afferents (8 Adelta, 30 C-fibres) and the responses of these 38 afferents to chemical stimuli were further studied in the following protocols. In the first protocol, injection of endothelin 1 (ET-1, 1, 2 and 4 microg) into the left atrium (LA) stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BQ-123, a selective ET(A)R antagonist, abolished the responses of nine afferents to 2 microg of ET-1 injected into the left atrium and attenuated the ischaemia-related increase in activity of eight other afferents by 51%. In contrast, blockade of ET(B) receptors caused inconsistent responses to exogenous ET-1 as well as to ischaemia. Furthermore, in the absence of ET(A)R blockade, cardiac afferents responded consistently to repeated administration of ET-1 (n = 7) and to recurrent myocardial ischaemia (n = 7). Finally, using an immunocytochemical staining approach, we observed that ET(A) receptors were expressed in cardiac sensory neurons in thoracic dorsal root ganglia. Taken together, these data indicate that endogenous endothelin contributes to activation of cardiac afferents during myocardial ischaemia through direct stimulation of ET(A) receptors likely to be located in the cardiac sensory nervous system.
authors.affiliation: Department of Medicine, School of Medicine, University of California, 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: D000818:Animals; D002415:Cats; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000502:physiology; D006321:Heart / Q000294:innervation; D007150:Immunohistochemistry; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000503:physiopathology*
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1