Abstract 935: A Novel Protective Mechanism Underlying Endotoxin-Induced Hypotension: Role of the TRPV1 Receptor
The transient receptor potential vanilloid type 1 (TRPV1) channels, expressed primarily in sensory nerves, function as a molecular integrator of multiple stimuli and trigger the release of sensory neurotransmitters such as substance P (SP) upon activation. This study was designed to test the novel hypothesis that TRPV1 and SP play a protective role against endotoxic hypotension and mortality induced by systemic administration of lipopolysaccharide (LPS). LPS (10 mg/kg, iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min with a fall in mean arterial pressure (MAP, mmHg) up to 66 ± 4 and gradually recovered 1 hr after the injection with a smaller fall of 25 ± 4 in MAP. Blockade of TRPV1 with its selective antagonist, capsazepine (CAPZ, 3 mg/kg, iv), impaired recovery given that the fall in MAP was greater 1 hr after CAPZ plus LPS injections (47 ± 5) compared to LPS injection alone (25 ± 4, p<0.05). Degeneration of TRPV1-positive sensory nerves caused by neonatal capsaicin treatment elicited similar MAP responses to LPS as that of CAPZ. Blockade of the neurokinin-1 (NK1) receptor with its selective antagonists, RP67580 (5 mg/kg, iv) or L-733,060 (4 mg/kg, iv), prevented recovery considering that falls in MAP were not different 1 hr after injections of NK1 antagonists plus LPS from their peak decreases (66 ± 9 vs 74 ± 5, and 61 ± 8 vs 69 ± 3, respectively, p>0.05). LPS increased plasma SP (pg/ml), norepinephrine (NE, ng/ml), and epinephrine (EP, ng/ml) levels compared to vehicles (SP: 29.4 ± 5.1 vs 17.3 ± 3.2; NE: 2.75 ± 0.24 vs. 1.63 ± 0.28; EP: 10.53 ± 0.88 vs 5.27 ± 0.89, p<0.05), and increases in plasma NE and EP were inhibited by RP67580. The survival rate during the first 24 hrs after LPS injection (20 mg/kg, ip) was lower in conscious rats pretreated with CAPZ (22.2%) or RP67580 (11.1%) compared to rats treated with LPS alone (55.5%, p<0.05). Thus, our results show for the first time 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. Our data indicate that intact TRPV1 and TRPV1-postive sensory nerve function are essential in protecting vital organ perfusion and survival during the endotoxic condition.