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

Abstract

Stimulation of cardiac sympathetic afferents during myocardial ischemia with metabolites such as bradykinin (BK) evokes sympathoexcitatory reflex responses and activates neurons in the external lateral parabrachial nucleus (elPBN). The present study tested the hypothesis that this region in the pons processes sympathoexcitatory cardiac reflexes through an ionotropic glutamate receptor mechanism. The ischemic metabolite BK (0.1-1 μg) was injected into the pericardial space of anesthetized and bilaterally vagotomized or intact cats. Hemodynamic and renal sympathetic nerve activity (RSNA) responses to repeated administration of BK before and after unilateral 50-nl microinjections of kynurenic acid (Kyn; 25 mM), 2-amino-5-phosphonopentanoic acid (AP5; 25 mM), and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzol(F)quinoxaline (NBQX; 10 mM) into the elPBN were recorded. Intrapericardial BK evoked significant increases in mean arterial pressure (MAP) and RSNA in seven vagotomized cats. After blockade of glutamate receptors with the nonselective glutamate receptor antagonist Kyn, the BK-evoked reflex increases in MAP (50 ± 6 vs. 29 ± 2 mmHg) and RSNA (59 ± 8.6 vs. 29 ± 4.7%, before vs. after) were significantly attenuated. The BK-evoked responses returned to pre-Kyn levels 85 min after the application of Kyn. Similarly, BK-evoked reflex responses were reversibly attenuated by blockade of glutamate N-methyl-d-aspartate (NMDA) receptors with AP5 (n = 5) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with NBQX (n = 5). In contrast, we observed that the repetitive administration of BK evoked consistent reflex responses including MAP and RSNA before and after microinjection of 50 nl of the artificial cerebrospinal fluid vehicle into the elPBN in five animals. Microinjection of glutamate receptor antagonists into regions outside the elPBN did not alter BK-induced reflex responses. Microinjection of Kyn into the elPBN reversibly attenuated BK-induced reflex responses in four vagus intact animals. These data are the first to show that NMDA and AMPA ionotropic glutamate receptors in the elPBN play an important role in processing cardiac excitatory reflex responses.

elPBN neurons regulate rVLM activity through elPBN-rVLM projections during activation of cardiac sympathetic afferent nerves

“…Some LPBN neurons have been reported to mediate respiratory changes accompanying changes in BP (23,35). We have observed that cardiac sympathetic afferent stimulation activates neurons in the elPBN (16,17) and evokes pressor reflexes that are reduced after inhibition of the elPBN (11), suggesting that the cardiovascular neurons responsive to cardiac afferent input likely also exist in the elPBN. Thus the present study was designed to determine if cardiovascular neurons are present in the elPBN and to examine their contribution to central processing of cardiac sympathetic afferent input.…”

“…ACTIVATION OF CARDIAC SYMPATHETIC afferent nerves, especially during myocardial ischemia, causes cardiac pain and excitatory reflex cardiovascular responses characterized by increases in sympathetic outflow, elevations in blood pressure (BP) and heart rate (HR), and tachyarrhythmia (11,12,24,34). These reflex responses increase the morbidity and mortality of patients with heart diseases, because they exacerbate the extent of ischemia and infarction, which leads to severe heart failure and lethal ventricular arrhythmias (11,24,34).…”

“…ACTIVATION OF CARDIAC SYMPATHETIC afferent nerves, especially during myocardial ischemia, causes cardiac pain and excitatory reflex cardiovascular responses characterized by increases in sympathetic outflow, elevations in blood pressure (BP) and heart rate (HR), and tachyarrhythmia (11,12,24,34). These reflex responses increase the morbidity and mortality of patients with heart diseases, because they exacerbate the extent of ischemia and infarction, which leads to severe heart failure and lethal ventricular arrhythmias (11,24,34). We have demonstrated that a number of metabolites produced during myocardial ischemia, including bradykinin (BK) and adenosine 5=triphosphate (ATP), among others, activate cardiac sympathetic afferent nerves (CSAN) and evoke sympathoexcitatory reflex responses (11,12,24).…”

“…These reflex responses increase the morbidity and mortality of patients with heart diseases, because they exacerbate the extent of ischemia and infarction, which leads to severe heart failure and lethal ventricular arrhythmias (11,24,34). We have demonstrated that a number of metabolites produced during myocardial ischemia, including bradykinin (BK) and adenosine 5=triphosphate (ATP), among others, activate cardiac sympathetic afferent nerves (CSAN) and evoke sympathoexcitatory reflex responses (11,12,24). However, how the central nervous system processes inputs from CSAN and, ultimately, regulates reflex cardiovascular responses is largely unknown.…”

Role of opioid receptors in modulation of P2X receptor-mediated cardiac sympathoexcitatory reflex response

“…To eliminate the influence of vagal cardiac afferents that could mask the CSR responses to stimulation of sympathetic afferents and minimize the BP “buffering” action of arterial baroreceptors, bilateral cervical vagotomy and sinoaortic denervation with sectioning of carotid sinus nerves were conducted in rats used in first four protocols (see in following protocols), as described previously 3,76 . Vagotomy was not performed in rats used in the last protocol (described in protocols section) for examining the CSR responses in vagus-intact animals.…”