Tachykinin antagonists in carotid body responses to hypoxia and substance P in the rat.
In the present study, we tested the hypothesis that substance P (SP) is an excitatory peptide to the rat carotid body and plays an important role in chemosensory excitation by hypoxia. Chemosensory discharge was recorded from the cut carotid sinus nerve in 19 anaesthetized, paralyzed and mechanically ventilated rats. Intracarotid administration of SP augmented the chemoreceptor activity in a dose-dependent manner. Maximal excitation was seen with 10 nmol SP. Carotid body stimulation by SP was independent of its effects on arterial blood pressure. The effect of SP antagonists, D-Pro2-D-Trp7,9-SP (DPDT-SP) or Spantide, on chemoreceptor responses to SP and hypoxia was examined in 12 rats. Close carotid body administration of either antagonist at doses of 40 micrograms.kg-1.min-1 elicited an augmentation followed by a progressive depression of baseline carotid body activity. SP antagonists significantly reduced peptide-induced carotid body stimulation and also markedly attenuated the chemoreceptor response to hypoxia. Systemic administration of sodium bicarbonate stimulated the carotid bodies, presumably by releasing CO2, and the bicarbonate-induced chemoreceptor stimulation was not affected by SP antagonists. From these results we conclude that in rats (a) SP stimulates the carotid bodies independently of its effects on arterial blood pressure, and (b) SP is associated with the chemosensory stimulation by hypoxia but not with other excitatory stimuli.
Cragg
P A
PA
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106.
Runold
M
M
Kou
Y R
YR
Prabhakar
N R
NR
D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000502:physiology; D002344:Carotid Body / Q000187:drug effects*; D005260:Female; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors; D017693:Sodium Bicarbonate / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015320:Tachykinins / Q000037:antagonists & inhibitors*
D018039:Receptors, Tachykinin; D015320:Tachykinins; D013373:Substance P; C041817:substance P, Pro(2)-Phe(7)-Trp(9)-; D017693:Sodium Bicarbonate; C042867:spantide