Purinergic receptors in the carotid body as a new drug target for controlling hypertension

Pijacka, Wioletta; Moraes, Davi J. A.; Ratcliffe, Laura E K; Nightingale, Angus K; Hart, Emma C J; Silva, Melina P. da; Machado, Benedito H.; McBryde, Fiona D; Abdala, Ana Paula; Ford, Anthony; Paton, Julian F. R.

doi:10.1038/nm.4173

Cited by 158 publications

(193 citation statements)

References 59 publications

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“…Moreover, previous studies have evidenced that severe loss of A5 neurons in the A5 area contributes to the manifestation of autonomic disorder associated with the neurodegenerative disease of multiple system atrophy (Benarroch et al, 2008). These observations open the possibility that changes in the functioning of A5 neurons may underpin the development of augmented sympathetic levels, especially in pathological conditions associated with hyperactivity of peripheral chemoreceptors, such as obstructive sleep apnea (Narkiewicz et al, 1998), heart failure (Toledo et al, 2017) and neurogenic hypertension (Pijacka et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Role of A5 noradrenergic neurons in the chemoreflex control of respiratory and sympathetic activities in unanesthetized conditions

et al. 2017

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The A5 area at the ventrolateral pons contains noradrenergic neurons connected with other medullary areas involved in the cardiorespiratory control. Its contribution to the cardiorespiratory regulation was previously evidenced in anesthetized conditions. In the present study, we investigated the involvement of the A5 noradrenergic neurons to the basal and chemoreflex control of the sympathetic and respiratory activities in unanesthetized conditions. A5 noradrenergic neurons were lesioned using microinjections of anti-dopamine β-hydroxylase saporin (anti-DβH-SAP). After 7–8 days, we evaluated the arterial pressure levels, heart rate and minute ventilation in freely moving adult rats (280–350 g) as well as recorded from thoracic sympathetic (tSN) and phrenic nerves (PN) using the arterially perfused in situ preparation of juvenile rats (80–90 g). Baseline cardiovascular, sympathetic and respiratory parameters were similar between control (n = 7–8) and A5-lesioned rats (n = 5–6) in both experimental preparations. In adult rats, lesions of A5 noradrenergic neurons did not modify the reflex cardiorespiratory adjustments to hypoxia (7% O2) and hypercapnia (7% CO2). In the in situ preparations, the sympatho-excitation, but not the PN reflex response, elicited by either the stimulation of peripheral chemoreceptors (ΔtSN: 110 ± 12% vs 58 ± 8%, P < 0.01) or hypercapnia (ΔtSN: 9.5 ± 1.4% vs 3.9 ± 1.7%, P < 0.05) was attenuated in A5-lesioned rats compared to controls. Our data demonstrated that A5 noradrenergic neurons are part of the circuitry recruited for the processing of sympathetic response to hypoxia and hypercapnia in unanesthetized conditions.

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Section: Discussionmentioning

confidence: 99%

Role of A5 noradrenergic neurons in the chemoreflex control of respiratory and sympathetic activities in unanesthetized conditions

et al. 2017

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“…Within the carotid body, the transduction of hypoxia to afferent discharge depends, in part, on ATP release and activation of P2 receptors. 45,46 Purinergic receptor plasticity was revealed in chemoreceptive petrosal afferent neurons in hypertension. Selective blockade of these receptors reduced arterial pressure and may be a novel therapeutic target for hypertension.…”

Section: Reflex Control Of the Cardiovascular Systemmentioning

confidence: 99%

“…Recent studies have shown that there is an antihypertensive effect of P2X3 receptor antagonists, because of inhibition of sympathetic nerve activity via increased peripheral chemoreceptor reflex sensitivity involving the carotid body. 46 Microinjections of the selective P2X3 (as well as P2X1) receptor antagonist, α,β-meATP, into the dorsal facial area of the medulla increased common carotid artery blood flow. 162 Therefore, P2X3 receptor antagonists are being explored for the treatment of hypertension.…”

Section: Vascular Diseasesmentioning

confidence: 99%

Purinergic Signaling in the Cardiovascular System

Burnstock

2017

Circulation Research

325

295

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Abstract:There is nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory-motor nerves, as well as in intracardiac neurons. Centers in the brain control heart activities and vagal cardiovascular reflexes involve purines. Adenine nucleotides and nucleosides act on purinoceptors on cardiomyocytes, AV and SA nodes, cardiac fibroblasts, and coronary blood vessels. Vascular tone is controlled by a dual mechanism. ATP, released from perivascular sympathetic nerves, causes vasoconstriction largely via P2X1 receptors. Endothelial cells release ATP in response to changes in blood flow (via shear stress) or hypoxia, to act on P2 receptors on endothelial cells to produce nitric oxide, endothelium-derived hyperpolarizing factor, or prostaglandins to cause vasodilation. ATP is also released from sensory-motor nerves during antidromic reflex activity, to produce relaxation of some blood vessels. Purinergic signaling is involved in the physiology of erythrocytes, platelets, and leukocytes. ATP is released from erythrocytes and platelets, and purinoceptors and ectonucleotidases are expressed by these cells. P1, P2Y 1 , P2Y 12 , and P2X1 receptors are expressed on platelets, which mediate platelet aggregation and shape change. Long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides promote migration and proliferation of vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis, vessel remodeling during restenosis after angioplasty and atherosclerosis. The involvement of purinergic signaling in cardiovascular pathophysiology and its therapeutic potential are discussed, including heart failure, infarction, arrhythmias, syncope, cardiomyopathy, angina, heart transplantation and coronary bypass grafts, coronary artery disease, diabetic cardiomyopathy, hypertension, ischemia, thrombosis, diabetes mellitus, and migraine. (Circ Res. 2017;120:207-228.

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“…Indeed, Pijacka et al . () found that antagonism of P2X3 receptors reduced BP, basal sympathetic activity and normalized enhanced CB hyperreflexia in conscious rats with hypertension, while no effect was observed in rats without hypertension. On the other hand, Del Rio et al .…”

Section: Introductionmentioning

confidence: 97%

Translating carotid body function into clinical medicine

Iturriaga

2017

The Journal of Physiology

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The carotid body (CB) is considered the main O chemoreceptor, which contributes to cardiorespiratory homeostasis and ventilatory acclimatization. In clinical medicine, the most common pathologies associated with the CB are tumours. However, a growing body of evidence supports the novel idea that an enhanced CB chemosensory discharge contributes to the autonomic dysfunction and pathological consequences in obstructive sleep apnoea (OSA), hypertension, systolic heart failure (HF) and cardiometabolic diseases. Heightened CB chemosensory reactivity elicited by oxidative stress has been involved in sympathetic hyperactivity, cardiorespiratory instability, hypertension and insulin resistance. CB ablation, which reduces sympathetic hyperactivity, decreases hypertension in animal models of OSA and hypertension, eliminates breathing instability and improves animal survival in HF, and restores insulin tolerance in cardiometabolic models. Thus, data obtained from preclinical studies highlight the importance of the CB in the progression of sympathetic-related diseases, supporting the idea that appeasing the enhanced CB chemosensory drive may be useful in improving cardiovascular, respiratory and endocrine alterations. Accordingly, CB ablation has been proposed and used as a treatment for moderating resistant hypertension and HF-induced sympathetic hyperactivity in humans. First-in-human studies have shown that CB ablation reduces sympathetic overactivity, transiently reduces severe hypertension and improves quality of life in HF patients. Thus, CB ablation would be a useful therapy to reverse sympathetic overactivation in HF and severe hypertension, but caution is required before it is widely used due to the crucial physiological function played by the CB. Further studies in preclinical models are required to assess side-effects of CB ablation.

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Purinergic receptors in the carotid body as a new drug target for controlling hypertension

Cited by 158 publications

References 59 publications

Role of A5 noradrenergic neurons in the chemoreflex control of respiratory and sympathetic activities in unanesthetized conditions

Role of A5 noradrenergic neurons in the chemoreflex control of respiratory and sympathetic activities in unanesthetized conditions

Purinergic Signaling in the Cardiovascular System

Translating carotid body function into clinical medicine

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