title: Interactions between histamine and bradykinin in stimulation of ischaemically sensitive cardiac afferents in felines.
abstract: Cardiac spinal afferents are activated during myocardial ischaemia. Our previous studies have shown that during ischaemia, histamine and bradykinin (BK) stimulate cardiac spinal afferents. Because the two mediators are released together during ischaemia, the present study examined the interactions between these two mediators with respect to their influence on ischaemically sensitive cardiac afferents. Single-unit cardiac afferent activity was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) in anaesthetized cats. Fifty-five ischaemically sensitive cardiac afferents (conduction velocity (CV) = 0.2-5.6 m s(-1), 8 Adelta- and 47 C-fibres) were identified. Administration of histamine (10 microg kg(-1)) and BK (1 microg) in combination into the left atrium (LA) caused an additive response in 16 afferents compared with administration of either BK or histamine alone (2.62 +/- 0.39 versus 1.67 +/- 0.20 versus 1.24 +/- 0.23 impulses s(-1) (imp s(-1)), BK + histamine versus BK versus histamine). To further evaluate interactions between these mediators, we observed that injection of histamine (10 microg kg(-1), LA) 4 min after the administration of BK (1 microg, LA) induced a significantly larger cardiac afferent response than the response to histamine before BK (1.24 +/- 0.23 versus 1.96 +/- 0.39 imp s(-1), before versus after, n = 10). In contrast, six other afferents responded reproducibly to repeated injections of histamine (10 microg kg(-1), LA) in the absence of BK. BK sensitization of the afferent response to histamine lasted for less than 10 min. Cyclooxygenase blockade with indomethacin (5 mg kg(-1), i.v.) abolished BK sensitization of the response to histamine (1.09 +/- 0.11 versus 1.11 +/- 0.10 imp s(-1), n = 10). Conversely, the response of most (7/9) cardiac afferents to repeat application of BK (1 microg, LA) 4 min after histamine (10 microg kg(-1), LA) was attenuated compared with the BK response before histamine (1.84 +/- 0.25 versus 1.31 +/- 0.18 imp s(-1), before versus after, P < 0.05). Repeat BK (1 microg, LA) induced a consistent response in five other afferents in the absence of histamine. Thus, BK interacts with histamine, and together they cause a larger response than either one alone. BK sensitizes cardiac afferents responding to histamine in a time-dependent fashion, and the BK sensitization effect is dependent on an intact cyclooxygenase pathway. Conversely, histamine reduces the response of most afferents to BK.
authors.affiliation: Department of Medicine, College of Medicine, University of California at Irvine, Irvine, CA 92697, USA. lwfu@uci.edu
authors.forename: Liang-Wu
authors.initials: LW
authors.lastname: Fu
authors.forename: John C
authors.initials: JC
authors.lastname: Longhurst
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002415:Cats; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006321:Heart / Q000294:innervation*; D006632:Histamine / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology
chemical_list: D016861:Cyclooxygenase Inhibitors; D006632:Histamine; D011451:Prostaglandin-Endoperoxide Synthases; D001920:Bradykinin; D007213:Indomethacin