Bradykinin and thromboxane A₂reciprocally interact to synergistically stimulate cardiac spinal afferents during myocardial ischemia

Abstract

Myocardial ischemia is a complex process leading to the simultaneous release of a number of mediators, including thromboxane A(2) (TxA(2)) and bradykinin (BK), that activate cardiac spinal afferents. The present study tested the hypothesis that TxA(2) and BK reciprocally interact to excite ischemically sensitive cardiac afferents. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) of anesthetized cats. Fifty-two ischemically sensitive afferents (conduction velocity = 0.27-3.35 m/s, 7 Adelta-fibers and 45 C-fibers) were identified. Repeated injections (1 microg) of BK into the left atrium (LA) 4 min after the administration of U-46619 (5 microg into the LA), a TxA(2) mimetic, induced a significantly larger cardiac afferent response than the first response to BK (0.61 +/- 0.14 to 1.95 +/- 0.29 vs. 0.66 +/- 0.09 to 2.75 +/- 0.34 impulses/s, first injection vs. second injection, n = 8). Conversely, blockade of TxA(2) receptors with BM-13,177 (30 mg/kg iv) attenuated the responses of eight other afferents to BK (1 microg into the LA) by 45%. In contrast, repeated BK (1 microg into the LA) induced consistent discharge activity in six separate afferents. We then observed that the coadministration of U-46619 (5 microg) and BK (1 microg into the LA) together caused a total response that was significantly higher than the predicted response by the simple addition of the individual responses. BK (1 microg) facilitated eight cardiac afferent responses to U-46619 (5 microg into the LA) by 64%. In contrast, repeated U-46619 (5 microg into the LA) without intervening BK stimulation evoked consistent responses in seven other ischemically sensitive afferents. Finally, inhibition of cyclooxygenase with indomethacin (5 mg/kg iv) eliminated the potentiating effects of BK on the cardiac afferent response to U-46619 (5 microg into the LA) but did not alter the afferent response to U-46619. These data suggest that BK and TxA(2) reciprocally interact to stimulate ischemically sensitive cardiac afferent endings leading to synergistic afferent responses and that the BK sensitization effect is mediated by cyclooxygenase products.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…In anesthetized rats, PGE 2 increased the discharge activity of single pulmonary C-fibers evoked by capsaicin, lactate, or adenosine (287). Another COX product, an analog of TXA 2 , enhanced the bradykinin-induced activation of ischemia-sensitive cardiac afferent C-fibers in anesthetized cats, whereas a TP receptor antagonist diminished the bradykinin response, suggesting a facilitatory role for endogenous TXA 2 (213). PGE 2 augmented CGRP release induced by bradykinin in the bovine dental pulp and isolated rat skin (29, 240).…”

Ionotropic glutamate receptors in the external lateral parabrachial nucleus participate in processing cardiac sympathoexcitatory reflexes

“…BK (1-10 g/ml, 0.1 ml) was injected into the pericardial sack to evoke repetitive reflex increases in blood pressure and RSNA in response to BK. BK is produced during myocardial ischemia and participates in the activation of cardiac sympathetic afferents (15,57). Intrapericardial saline (1 ml) was applied three times to wash out BK after its application.…”

Characterization of thromboxane A2 receptor and TRPV1 mRNA expression in cultured sensory neurons

“…Our laboratory, as well as others, have reported that TxA2 stimulates vagal sensory nerves from the lung [11, 16, 18] as well as the heart [19, 22]. In addition we have shown that TxA2 stimulates spinal sensory nerves (group III and IV) from the hindlimb [13] while Fu et al has shown that TxA2 stimulates spinal afferent nerves innervating the heart [5, 7]. Since TxA2 is released from platelets and other cell types during tissue trauma or events that activate platelets, the stimulation of sensory nerves by TxA2 could play an important role in activation of reflexes during hemorrhage, inflammation, ischemia, tissue injury, or trauma.…”

“…Inhibition of TxA2R with various pharmacological antagonists have inhibited TxA2-induced neural stimulation using in vivo experiments of peripheral nerve recordings as well as using in vitro experiments with cultured neurons [1, 5, 21]. While the exact intracellular signaling mechanism for TxA2 excitation is not yet known, the mechanism likely involves calcium.…”