Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

Abstract

Background: The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia.

Methods: First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion.

Results: Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours.

Conclusions: Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.

Figure 1

Effect of TRPV1 agonist on temperature in rat. (A) Temperature profiles for transient receptor potential vanilloid type 1 agonists dihydrocapsaicin, resiniferatoxin, olvanil, arvanil, MSK-195 and rinvanil, and vehicle control during 4 hour intravenous administration to conscious rats. (B) Area under the curve during the infusion (t = 0 to 4 hours). Statistics: Each of the transient receptor potential vanilloid type 1 agonists were compared to the vehicle control by an unpaired student's t-test ***p < 0.001, **p < 0.01. Values are expressed as average ± SE, with n = 2 - 6, see Methods for further details.

Figure 2

Hypothermic effects of DHC infusion in rats. (A) Dose-response temperature profiles in conscious rats during 6 hour intravenous infusion of the transient receptor potential vanilloid type 1 agonist dihydrocapsaicin at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h. (B) Area under the curve during the infusion (t = 0 to 6 hours). Statistics: Each of the transient receptor potential vanilloid type 1 agonists were compared to the vehicle control by an unpaired student's t-test ***p < 0.001, **p < 0.01. Values are expressed as average ± SE, with n = 5, see Methods for further details.

Figure 3

Hypothermic effects of DHC infusion in monkeys. (A) Dose-response temperature profiles in conscious cynomologus monkeys during 12 hour repeated intravenous infusions of the transient receptor potential vanilloid type 1 agonist dihydrocapsaicin at doses of 0.3, 0.6, 1.2, and 1.8 mg/kg/h. (B) Area under the curve during the infusion (t = 0 to 12 hours). Statistics: Each of the transient receptor potential vanilloid type 1 agonists were compared to the vehicle control by a one-way ANOVA followed by Dunnett's post-test ***p < 0.001, *p < 0.05. Values are expressed as average ± SE, with n = 2, see Methods for further details.

Figure 4

Hypothermic effects of DHC infusion in monkeys. Temperature profiles in conscious calves during intravenous infusion of various amounts of the transient receptor potential vanilloid type 1 agonist dihydrocapsaicin (n = 8) or control (n = 2). Target temperature of ΔT = -3 to -5°C are shown as shaded area. Statistics: Blood temperature was compared by a 2-way ANOVA followed by Bonferroni's post-test: ***p < 0.001 at t = 0.5 to 14 hours. Values are expressed as average ± SE, see Methods for further details.