TRPV1-mediated protection against endotoxin-induced hypotension and mortality in rats.
This study was designed to test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channel, expressed primarily in sensory nerves, and substance P (SP), released by sensory nerves, play a protective role against lipopolysaccharide (LPS)-induced hypotension. LPS (10 mg/kg iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min and gradually recovered 1 h after the injection. Blockade of TRPV1 with its selective antagonist capsazepine (CAPZ, 3 mg/kg iv) impaired recovery given that the fall in mean arterial pressure (MAP) was greater 1 h after CAPZ plus LPS injections compared with LPS injection alone (45 +/- 5 vs. 25 +/- 4 mmHg, P < 0.05). Blockade of the neurokinin 1 (NK1) receptor with its selective antagonists RP-67580 (5 mg/kg iv) or L-733,060 (4 mg/kg iv) prevented recovery, considering that falls in MAP were not different 1 h after injections of NK1 antagonists plus LPS from their peak decreases (66 +/- 9 vs. 74 +/- 5 mmHg or 60 +/- 7 vs. 69 +/- 3 mmHg, respectively, P > 0.05). LPS increased plasma SP, norepinephrine (NE), and epinephrine (Epi) levels compared with vehicles, and the increases in plasma SP, NE, and Epi were significantly inhibited by CAPZ or RP-67580. The survival rate at 24 or 48 h after LPS injection (20 mg/kg ip) was lower in conscious rats pretreated with CAPZ or RP-67580 compared with rats treated with LPS alone (P < 0.05). Thus our results show that the TRPV1, possibly via triggering release of SP which activates the NK1 and stimulates the sympathetic axis, plays a protective role against endotoxin-induced hypotension and mortality, suggesting that TRPV1 receptors are essential in protecting vital organ perfusion and survival during the endotoxic condition.
Wang
Youping
Y
Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
Novotny
Martin
M
Quaiserová-Mocko
Veronika
V
Swain
Greg M
GM
Wang
Donna H
DH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002395:Catecholamines / Q000097:blood; D004731:Endotoxins / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control*; D054833:Isoindoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000502:physiology*
D002395:Catecholamines; D004731:Endotoxins; D054833:Isoindoles; D008070:Lipopolysaccharides; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D013373:Substance P; C071423:capsazepine; D002211:Capsaicin