Activation of P2X receptors for adenosine triphosphate evokes cardiorespiratory reflexes in anaesthetized rats.
1. We tested the hypothesis that activation of P2X receptors associated with vagal afferent nerves can evoke a Bezold-Jarisch (B-J) depressor reflex in anaesthetized rats. 2. Injection of alphabeta-methylene ATP (alphabeta-MeATP; 0.6-600 nmol i.v.) evoked a dose-dependent B-J reflex comprising bradycardia, hypotension and apnoea in rats anaesthetized with pentobarbitone. Apnoea was commonly preceded by hyperventilation. Bilateral vagotomy significantly reduced the bradycardia and most of the apnoeic response without affecting hyperventilation, and unmasked a vasopressor response. Hypotension and apnoea were subject to desensitization, and ATP was about 100 times less potent than alphabeta-MeATP in evoking the B-J reflex. 3. ED50 values for responses to alphabeta-MeATP were: bradycardia 14.6 +/- 3.8 nmol; apnoea 47.1 +/- 8.5 nmol; hyperventilation 23.3 +/- 6.0 nmol, n = 14. The ED50 for apnoea was significantly greater than that for bradycardia or hyperventilation (P < 0.05). Atropine (2.8 micromol (kg body wt)-1 i.v.) antagonized the reflex bradycardia and hypotension. 4. The P2 antagonists suramin (14 micromol (kg body wt)-1 i.v.) and PPADS (17 micromol (kg body wt)-1 i.v.) antagonized the bradycardic and apnoeic components of the reflex response to alphabeta-MeATP, without reducing the vasopressor or hyperventilatory responses to the agonist. 5. Recordings from vagal afferents showed that pulmonary inflation receptors were activated by alphabeta-MeATP in 62 % of units recorded (ED50 22 +/- 5 nmol) and this was blocked by PPADS (17 micromol (kg body wt)-1 i.v.); unidentified vagal afferents were also activated. 6. alphabeta-MeATP activated carotid chemoreceptor afferents (ED50 23 +/- 9 nmol), an action that was unaffected by PPADS or suramin. 7. The results support the hypothesis that P2X receptor subtypes for ATP are associated with specific sensory nerves that form part of the homeostatic mechanism for cardiovascular and respiratory regulation and these receptors therefore have physiological, pathological and therapeutic significance.
McQueen
D S
DS
Department of Pharmacology, University of Edinburgh Medical School, Edinburgh EH8 9JZ, UK. D.S.McQueen@ed.ac.uk
Bond
S M
SM
Moores
C
C
Chessell
I
I
Humphrey
P P
PP
Dowd
E
E
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001049:Apnea; D001794:Blood Pressure / Q000187:drug effects*; D002344:Carotid Body / Q000187:drug effects / Q000502:physiology; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects*; D006985:Hyperventilation; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000502:physiology*; D012018:Reflex / Q000187:drug effects / Q000502:physiology*; D012119:Respiration / Q000187:drug effects*; D012121:Respiration, Artificial; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate