ENDOGENOUS BRADYKININ ACTIVATES ISCHEMICALLY SENSITIVE CARDIAC VISCERAL AFFERENTS THROUGH KININ B-2 RECEPTORS IN CATS

1. Activity of ischaemically sensitive cardiac visceral afferents duri ng myocardial ischaemia induces both angina and cardiovascular reflexe s. Increased production of bradykinin (BK) and cyclo-oxygenase product s (i.e. prostaglandins (PGs)) occurs during myocardial ischaemia. Howe ver, 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 aff erents through kinin B-2 receptors. 2. Single-unit activity of cardiac afferents innervating the left ventricle was recorded from the left t horacic sympathetic chain (T1-T4) of anaesthetized cats. Ischaemically sensitive cardiac afferents were identified according to their respon se to 5 min of myocardial ischaemia. The mechanism of BK in activation of ischaemically sensitive cardiac afferents was determined by inject ion of BK (1 mu g kg(-1) I.A.), des-Arg(9)-BK (1 mu g kg(-1) I.A., a s pecific kinin B-1 receptor agonist), kinin B-2 receptor antagonists: H OE140 (30 mu g kg(-1) I.V.) and NPC-17731 (40 mu g kg(-1) I.V.), cyclo -oxygenase inhibition with indomethacin (5 mg kg(-1) I.V.) and NPC-177 31 (40 mu g 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 t o 1.47 +/- 0.37 impulses s(-1) (P < 0.05). Conversely, des-Arg(9)-BK d id not significantly increase the activity of eleven ischaemically sen sitive fibres (0.58 +/- 0.02 vs. 0.50 +/- 0.18 impulses s(-1)). HOE140 significantly attenuated the response of twelve afferents to ischaemi a (0.61 +/- 0.22 to 1.85 +/- 0.5 vs. 0.53 +/- 0.16 to 1.09 +/- 0.4 imp ulses s(-1)). NPC-17731, another kinin B-2 receptor antagonist, had si milar 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 respons es 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 sig nificantly reduced the responses of six ischaemically sensitive cardia c afferents to BK (2.65 +/- 1.23 to 1.2 +/- 0.51 impulses s(-1)). In s ix 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 contribut es to stimulation of ischaemically sensitive cardiac visceral afferent s through activation of kinin B-2 receptors. Furthermore, BK stimulate s ischaemically sensitive cardiac visceral afferents through a mechani sm that is, at least in part, independent of cyclo-oxygenase activatio n.