Purinergic receptors in the carotid body as a new drug target for controlling hypertension.
In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.
School of Physiology, Pharmacology &Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.
Wioletta
W
Pijacka
Department of Physiology, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Davi J A
DJ
Moraes
CardioNomics Research Group, Clinical Research and Imaging Centre, University of Bristol, Bristol, UK.
Laura E K
LE
Ratcliffe
CardioNomics Group, Department of Cardiology, Bristol Heart Institute, University Hospitals Bristol National Health Service Foundation Trust, Bristol, UK.
Angus K
0000-0001-9435-726X
AK
Nightingale
School of Physiology, Pharmacology &Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.
Emma C
EC
Hart
Department of Physiology, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Melina P
MP
da Silva
Department of Physiology, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Benedito H
BH
Machado
School of Physiology, Pharmacology &Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.|Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Fiona D
FD
McBryde
School of Physiology, Pharmacology &Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.
Ana P
0000-0001-6051-2591
AP
Abdala
Afferent Pharmaceuticals, San Mateo, California, USA.
Anthony P
AP
Ford
School of Physiology, Pharmacology &Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.
Julian F R
JF
Paton
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D002344:Carotid Body / Q000166:cytology / Q000378:metabolism*; D002628:Chemoreceptor Cells / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics; D008297:Male; D018408:Patch-Clamp Techniques; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D058477:Receptors, Purinergic P2X3 / Q000235:genetics*; D012021:Reflex, Abnormal / Q000235:genetics; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism
C546410:P2rx3 protein, rat; D058920:Purinergic P2X Receptor Antagonists; D012333:RNA, Messenger; D058477:Receptors, Purinergic P2X3