Modulation of cardiac vagal tone by bradykinin acting on nucleus ambiguus

Abstract

Bradykinin (BK), a component of the kallikrein-kininogen-kinin system exerts multiple effects via B1 and B2 receptor activation. In the cardiovascular system, bradykinin has cardioprotective and vasodilator properties. We investigated the effect of BK on cardiac-projecting neurons of nucleus ambiguus, a key site for the parasympathetic cardiac regulation. BK produced a dose-dependent increase in cytosolic Ca2+ concentration. Pretreatment with HOE140, a B2 receptor antagonist, but not with R715, a B1 receptor antagonist, abolished the response to BK. A selective B2 receptor agonist, but not a B1 receptor agonist, elicited an increase in cytosolic Ca2+ similarly to BK. Inhibition of N-type voltage-gated Ca2+ channels with ω-conotoxin GVIA had no effect on the Ca2+ signal produced by BK, while pretreatment with ω-conotoxin MVIIC, a blocker of P/Q-type of Ca2+ channels, significantly diminished the effect of BK. Pretreatment with xestospongin C and 2-aminoethoxydiphenyl borate, antagonists of inositol 1,4,5-trisphosphate receptors, abolished the response to BK. Inhibition of ryanodine receptors reduced the BK-induced Ca2+ increase, while disruption of lysosomal Ca2+ stores with bafilomycin A1 did not affect the response. BK produced a dose-dependent depolarization of nucleus ambiguus neurons, which was prevented by the B2 receptor antagonist. In vivo studies indicate that microinjection of BK into nucleus ambiguus elicited bradycardia in conscious rats via B2 receptors. In summary, in cardiac vagal neurons of nucleus ambiguus, BK activates B2 receptors promoting Ca2+ influx and Ca2+ release from endoplasmic reticulum, and membrane depolarization; these effects are translated in vivo by bradycardia.

Establishing low‐density lipoprotein apheresis tolerability in patients with prior anaphylactoid reactions to lipoprotein apheresis using magnesium sulfate

“…Brailoiu et al demonstrated that bradykinin acts on B2 receptors in the nuclease ambiguous to increase parasympathetic cardiac tone, ultimately leading to bradycardia 15 . Indeed, increased parasympathetic tone, as manifested by bradycardia, could be felt clinically and could mimic anaphylactoid reactions.…”

Analysis of Heart-Rate Variability during Angioedema Attacks in Patients with Hereditary C1-Inhibitor Deficiency

“…Its effects on cardiovascular regulation are little-known. Bradykinin modulates the parasympathetic tone acting on B 2 receptors in nucleus ambiguous [ 13 , 23 ]. However, the physiologic and pathophysiologic significance of such interaction is yet to be defined, although a role for bradykinin is suggested in some conditions such as hypertension and diabetes [ 24 , 25 ].…”

“…Similarly, the vagus nerve has a protective role in models of inflammation such as ischemia–reperfusion injury [ 12 ]. The parasympathetic tone, acting on B 2 receptors in nucleus ambiguous, can also be modulated by bradykinin [ 13 ]. Moreover, in idiopathic systemic capillary leak syndrome, a disease characterized by unexplained episodes of plasma extravasation dealing severe hypovolemic shock, heart-rate variability (HRV) analysis showed that, during the hyperacute phase of shock, both sympathetic and vagal modulations were totally absent, mimicking the pattern of a denervated transplanted heart [ 14 ].…”

Effects of effortful swallowing on cardiac autonomic control in individuals with neurogenic dysphagia: a prospective observational analytical study

“…These authors advise that motor neurons of nucleus ambiguus and trigeminal afferent terminals are linked for the coordination of muscles related to swallowing phase. Similarly, trigeminal nerve and the nucleus ambiguus are involved in the heart's rhythm 28,29 . So, it is expected that swallowing influences the HRV.…”