Endogenous bradykinin activates ischaemically sensitive cardiac visceral afferents through kinin B2 receptors in cats.

Abstract

1. Activity of ischaemically sensitive cardiac visceral afferents during myocardial ischaemia induces both angina and cardiovascular reflexes. Increased production of bradykinin (BK) and cyclo-oxygenase products (i.e. prostaglandins (PGs)) occurs during myocardial ischaemia. However, the role of these agents in activation of ischaemically sensitive cardiac afferents has not been established. The present study tested the hypothesis that BK produced during ischaemia activates cardiac afferents through kinin B2 receptors. 2. Single-unit activity of cardiac afferents innervating the left ventricle was recorded from the left thoracic sympathetic chain (T1-T4) of anaesthetized cats. Ischaemically sensitive cardiac afferents were identified according to their response to 5 min of myocardial ischaemia. The mechanism of BK in activation of ischaemically sensitive cardiac afferents was determined by injection of BK (1 microgram kg-1 i.a.), des-Arg9-BK (1 microgram kg-1 i.a., a specific kinin B1 receptor agonist), kinin B2 receptor antagonists: HOE140 (30 micrograms kg-1 i.v.) and NPC-17731 (40 micrograms kg-1 i.v., cyclo-oxygenase inhibition with indomethacin (5 mg kg-1 i.v.) and NPC-17731 (40 micrograms kg-1 i.v.) after pretreatment with indomethacin (5 mg kg-1 i.v.). 3. We observed that BK increased the discharge rate of all eleven ischaemically sensitive cardiac afferents from 0.39 +/- 0.12 to 1.47 +/- 0.37 impulses s-1 (P < 0.05). Conversely, des-Arg9-BK did not significantly increase the activity of eleven ischaemically sensitive fibres (0.58 +/- 0.02 vs. 0.50 +/- 0.18 impulses s-1. HOE140 significantly attenuated the response of twelve afferents to ischaemia (0.61 +/- 0.22 to 1.85 +/- 0.5 vs. 0.53 +/- 0.16 to 1.09 +/- 0.4 impulses s-1). NPC-17731, another kinin B2 receptor antagonist, had similar inhibitory effects on six other ischaemically sensitive cardiac afferents (0.35 +/- 0.14 to 1.19 +/- 0.29 vs. 0.22 +/- 0.08 to 0.23 +/- 0.07 impulses s-1). Indomethacin significantly reduced the responses of seven afferents to ischaemia (0.35 +/- 0.13 to 1.89 +/- 0.48 vs. 0.40 +/- 0.10 to 0.76 +/- 0.24 impulses s-1). Indomethacin also significantly reduced the responses of six ischaemically sensitive cardiac afferents to BK (2.65 +/ 1.23 to 1.2 +/- 0.51 impulses s-1. In six cats pretreated with indomethacin, NPC-17731 attenuated the impulse activity of six ischaemically sensitive cardiac afferents (0.39 +/- 0.12 to 1.0 +/- 0.3 vs. 0.26 +/- 0.14 to 0.48 +/- 0.20 impulses s-1. 4. This study demonstrates that BK produced during ischaemia contributes to stimulation of ischaemically sensitive cardiac visceral afferents through activation of kinin B2 receptors. Furthermore, BK stimulates ischaemically sensitive cardiac visceral afferents through a mechanism that is, at least in part, independent of cyclo-oxygenase activation.