Role of substance P in neutral endopeptidase modulation of hypoxic response of the carotid body.
Carotid body expresses neutral endopeptidase (NEP)-like enzyme activity and phosphoramidon, an inhibitor of NEP augments sensory response of the carotid body to hypoxia (Kumar et al., 1990). NEP hydrolyzes substance P (SP) and methionine enkephalin (Met-ENK) in the nervous system. In the present study, we determined whether NEP hydrolyzes Met-ENK and SP in the carotid body and whether these peptides contribute to the phosphoramidon-induced potentiation of the sensory response to hypoxia. Experiments were performed on carotid bodies excised from anaesthetized adult cats. HPLC analysis showed that both SP and Met-ENK were hydrolyzed by the carotid body. Phosphoramidon (400 microM) markedly inhibited SP (approximately 90%) but had only marginal effect on Met-ENK hydrolysis (approximately 15%). Sensory responses of the carotid body in vitro to hypoxia (pO2, 68 +/- 6 mmHg) and SP (10 nmoles) were potentiated by phosphoramidon by approximately 80% and approximately 275% respectively (p < 0.01). SP-receptor antagonist abolished phosphoramidon-induced potentiation of the sensory response to hypoxia as well as to SP. These results demonstrate that SP is a preferred substrate for NEP in the carotid body and SP plays a major role in the potentiation of the hypoxic response of the carotid body by phosphoramidon.
Kumar
G K
GK
Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Yu
R K
RK
Overholt
J L
JL
Prabhakar
N R
NR
D000818:Animals; D002344:Carotid Body / Q000187:drug effects / Q000378:metabolism*; D002415:Cats; D004744:Enkephalin, Methionine / Q000378:metabolism; D005260:Female; D006020:Glycopeptides / Q000494:pharmacology; D006868:Hydrolysis; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D015260:Neprilysin / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology
D006020:Glycopeptides; D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P; D004744:Enkephalin, Methionine; C042867:spantide; D015260:Neprilysin; C008890:phosphoramidon