P2X3 receptors and sensitization of autonomic reflexes

Ford, Anthony; Undem, Bradley J.; Birder, Lori A.; Grundy, David; Pijacka, Wioletta; Paton, Julian F. R.

doi:10.1016/j.autneu.2015.04.005

Cited by 29 publications

(21 citation statements)

References 91 publications

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“…As P2X3 receptors are found in the carotid body of normotensive rats 36 and associated with pathological afferent sensitisation in numerous other organs 28,29,33 we assessed whether they were involved in carotid body dysfunction in SH rats in situ . In SH rats, focal delivery via a glass micropipette inserted into the ipsilateral carotid body of a highly selective non-competitive P2X3 receptor antagonist (AF-353; 15 nl , 20 μM 40 ) caused hyperpolarisation (−9.9 ± 2.1 mV; n = 12, P < 0.001, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have considered in our current investigations the ATP gated ion channels (called purinergic P2X receptors), specifically the C-fiber localised P2X3 receptor subtypes, which are commonly associated with afferent sensitisation, and that apparently may contribute to hyperreflexic disease states in a variety of organs 28,29 . ATP is one of a number of transmitters involved in the transduction process of hypoxia in the carotid body 30–35 .…”

Section: Introductionmentioning

confidence: 99%

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

Pijacka

Moraes

Ratcliffe

et al. 2016

Nat Med

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162

173

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Given the proportion of individuals with resistance to, and poor compliance or tolerance of, antihypertensive medication new drugs to treat this syndrome are required urgently. We show that peripheral chemoreceptors generate aberrant signalling contributing to high blood pressure in hypertension and thus reveal a novel target. We discovered that P2x3 receptor mRNA expression was up regulated substantially in chemoreceptive petrosal sensory neurones in hypertensive rats. These neurones generated both tonic drive and hyperreflexia in hypertensive (but not normotensive rats), and both phenomena were normalised by blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduced arterial pressure and basal sympathetic activity and normalised carotid body hyperreflexia in conscious hypertensive rats; no effect was observed in normotensive rats. These preclinical data support the P2X3 receptor as a putative novel target for controlling human

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Pijacka

Moraes

Ratcliffe

et al. 2016

Nat Med

Self Cite

162

173

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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%

Purinergic Signaling in the Cardiovascular System

Burnstock

2017

Circulation Research

339

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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“…These observations raise the possibility that sensory pathways in the urinary bladder are sensitive to cholinergic modulatory mechanisms. The modulation may occur as a result of a direct action on afferent nerves which express nicotinic and muscarinic receptors (Kontani et al, 2009; Masuda et al, 2006; Nandigama et al, 2010; 2013; Yu and de Groat, 2010) or indirectly via an action on urothelial cells which also express these receptors (Beckel and Birder, 2012; Kullmann et al, 2008a) and release neurotransmitters such as ATP, ACh and NO (Birder et al, 1998; Ferguson et al, 1997; Hanna-Mitchell et al, 2007; Lips et al, 2007; Silva et al, 2015; Yoshida et al, 2010) that can influence the excitability of adjacent afferent nerves (Birder and Andersson, 2013; Cockayne et al, 2000; de Groat and Yoshimura, 2009; Ford et al, 2015; Kullmann et al, 2008b). …”

Section: Introductionmentioning

confidence: 99%

Effects of nicotinic receptor agonists on bladder afferent nerve activity in an in vitro bladder–pelvic nerve preparation

Daugherty

Groat

2016

Brain Research

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Effects of nicotinic receptor agonists (epibatidine and nicotine) on mechano-sensitive bladder afferent nerve (MS-BAN) activity were studied in an in vitro bladder-pelvic afferent nerve preparation. MS-BAN activity was induced by isotonic distention of the bladder at pressures of 10–40 cmH2O. The effect of epibatidine varied according to the concentration, route of administration and the intravesical pressure stimulus. Epibatidine (300–500 nM) administered in the perfusate to the serosal surface of the bladder decreased distension evoked afferent firing by 30%–50% depending on the bladder pressure. However these concentrations also produced an immediate increase in tonic afferent firing in the empty bladder. Lower concentrations (50–100 nM) elicited weaker and more variable effects. The inhibitory effects were blocked by bath application of mecamylamine (150 μM) a nicotinic receptor antagonist. Bath application of nicotine (20 μM) elicited similar effects. Intravesical administration of epibatidine (500 nM) significantly increased MS-BAN firing by 15–30%; while lower concentrations (200–300 nM) were ineffective. This facilitatory effect of epibatidine was blocked by intravesical administration of mecamylamine (250 μM). Electrical stimulation on the surface of the bladder elicited action potentials (AP) in BAN. Bath application of epibatidine (300 nM) or nicotine (20 μM) did not change either the voltage threshold or the area of evoked AP. These results indicate that nicotinic agonists: (1) enhance MS-BAN activity originating at afferent receptors near the urothelium, (2) inhibit MS-BAN activity originating at afferent receptors located at other sites in the bladder, (3) directly excite unidentified afferents, (4) do not alter afferent axonal excitability.

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P2X3 receptors and sensitization of autonomic reflexes

Cited by 29 publications

References 91 publications

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

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

Purinergic Signaling in the Cardiovascular System

Effects of nicotinic receptor agonists on bladder afferent nerve activity in an in vitro bladder–pelvic nerve preparation

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