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Endomorphins potentiate acid-sensing ion channel currents and enhance the lactic acid-mediated increase in arterial blood pressure: effects amplified in hindlimb ischaemia.
- Source :
-
The Journal of physiology [J Physiol] 2017 Dec 01; Vol. 595 (23), pp. 7167-7183. Date of Electronic Publication: 2017 Nov 09. - Publication Year :
- 2017
-
Abstract
- Key Points: Chronic limb ischaemia, characterized by inflammatory mediator release and a low extracellular pH, leads to acid-sensing ion channel (ASIC) activation and reflexively increases mean arterial pressure; endomorphin release is also increased under inflammatory conditions. We examined the modulation of ASIC currents by endomorphins in sensory neurons from rats with freely perfused and ligated femoral arteries: peripheral artery disease (PAD) model. Endomorphins potentiated sustained ASIC currents in both groups of dorsal root ganglion neurons, independent of mu opioid receptor stimulation or G protein activation. Intra-arterial administration of lactic acid (to simulate exercising muscle and evoke a pressor reflex), endomorphin-2 and naloxone resulted in a significantly greater pressor response than lactic acid alone, while administration of APETx2 inhibited endomorphin's enhancing effect in both groups. These results suggest a novel role for endomorphins in modulating ASIC function to effect lactic acid-mediated reflex increase in arterial pressure in patients with PAD.<br />Abstract: Chronic muscle ischaemia leads to accumulation of lactic acid and other inflammatory mediators with a subsequent drop in interstitial pH. Acid-sensing ion channels (ASICs), expressed in thin muscle afferents, sense the decrease in pH and evoke a pressor reflex known to increase mean arterial pressure. The naturally occurring endomorphins are also released by primary afferents under ischaemic conditions. We examined whether high affinity mu opioid receptor (MOR) agonists, endomorphin-1 (E-1) and -2 (E-2), modulate ASIC currents and the lactic acid-mediated pressor reflex. In rat dorsal root ganglion (DRG) neurons, exposure to E-2 in acidic solutions significantly potentiated ASIC currents when compared to acidic solutions alone. The potentiation was significantly greater in DRG neurons isolated from rats whose femoral arteries were ligated for 72 h. Sustained ASIC current potentiation was also observed in neurons pretreated with pertussis toxin, an uncoupler of G proteins and MOR. The endomorphin-mediated potentiation was a result of a leftward shift of the activation curve to higher pH values and a slight shift of the inactivation curve to lower pH values. Intra-arterial co-administration of lactic acid and E-2 led to a significantly greater pressor reflex than lactic acid alone in the presence of naloxone. Finally, E-2 effects were inhibited by pretreatment with the ASIC3 blocker APETx2 and enhanced by pretreatment with the ASIC1a blocker psalmotoxin-1. These findings have uncovered a novel role of endomorphins by which the opioids can enhance the lactic acid-mediated reflex increase in arterial pressure that is MOR stimulation-independent and APETx2-sensitive.<br /> (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)
- Subjects :
- Acid Sensing Ion Channel Blockers pharmacology
Action Potentials
Analgesics, Opioid administration & dosage
Animals
Cell Line
Cells, Cultured
Drug Synergism
Ganglia, Spinal drug effects
Ganglia, Spinal metabolism
Hindlimb blood supply
Ischemia metabolism
Ischemia physiopathology
Lactic Acid administration & dosage
Male
Mice
Naloxone administration & dosage
Naloxone pharmacology
Oligopeptides administration & dosage
Peripheral Arterial Disease physiopathology
Rats
Rats, Sprague-Dawley
Reflex
Sensory Receptor Cells drug effects
Sensory Receptor Cells metabolism
Acid Sensing Ion Channels metabolism
Analgesics, Opioid pharmacology
Blood Pressure
Lactic Acid pharmacology
Oligopeptides pharmacology
Peripheral Arterial Disease metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1469-7793
- Volume :
- 595
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- The Journal of physiology
- Publication Type :
- Academic Journal
- Accession number :
- 29044528
- Full Text :
- https://doi.org/10.1113/JP275058