Inhibition of PDE4 Induces Hypothermia in Mice

Abstract

Type 4 cyclic nucleotide phosphodiesterases (PDE4s), a group of isoenzymes that hydrolyze and inactivate the second messenger cAMP, are established targets for development of enzyme inhibitors with anti‐inflammatory properties. While testing the anti‐inflammatory effects of a nonselective PDE4 inhibitor in a murine model of bacterial lung infection, we noticed that PDE4 inhibition per se induced significant hypothermia in the animals in the absence of bacterial infection. Because drug‐induced hypothermia may critically impact our animal model, and the role cAMP‐phosphodiesterases play in the regulation of body temperature is poorly understood, we further explored this observation. We found that treatment with a number of structurally distinct PAN‐PDE4 inhibitors, including Rolipram, Roflumilast and RS25344 (all 1 mg/kg, i.p.), but not the PDE3‐selective inhibitor Cilostamide, induced a rapid decrease in core body temperature of C57Bl6 mice as measured with a rectal thermometer at 30 min after drug application, suggesting that hypothermia in mice is a class‐effect of PDE4 inhibitors. PDE4 inhibitor‐induced hypothermia was considerable (~4°C drop), rapid in onset (max effect is reached within 20–30 min), and long lasting (core body temperature remains below controls for up to 5 h). As little as 40 μg/kg of the archetypal PDE4 inhibitor Rolipram induced a hypothermic effect. Similar or higher doses of Rolipram were used in most published animal studies. Thus, the reported findings are likely associated with, or at least paralleled by, drug‐induced hypothermia. The initial decrease in body temperature after PDE4 inhibitor injection is so rapid that it is no different from heat dissipation after euthanasia, suggesting that PDE4 inhibition affects central body temperature regulation so that both heat‐generating (e.g. shivering/non‐shivering thermogenesis) as well as heat‐preserving (e.g. skin vasoconstriction) mechanisms are simultaneously suspended, either by lowering the cold defense set point or by impairing its enforcement. Indeed, PDE4 inhibitor treatment induced a temporary heat‐loss via tail vasodilation as assessed by thermography. Consistent with the idea of an effect on central body temperature regulation, hypothermia was induced by moderate doses (≤1 mg/kg) of various brain‐penetrant PDE4 inhibitors. Conversely, YM976, a PDE4 inhibitor that does not cross the blood‐brain barrier, had no effect. Finally, to begin delineating the mechanism of drug‐induced hypothermia, we show that a blockade of serotonergic‐ and dopaminergic‐, but not β‐adrenergic‐, histaminergic‐ or opiate receptors, can alleviate PDE4 inhibitor‐induced hypothermia.Support or Funding InformationSupported by grants from the Cystic Fibrosis Foundation (SALEH18H0,RICHTE16GO) and the NIH (HL76125, HL141473, HL066299).