Epinephrine-induced pulmonary oedema in rats is inhibited by corticotropin-releasing factor.

In various animal models of injury to skin, mucous membranes, muscle and brain, corticotropin-releasing factor (CRF) attenuated vascular leakage in the injured tissues. Here, the effects of CRF on a rat model of pulmonary oedema were examined. Male albino rats (220-290 g) received saline or CRF s.c., 30 min before pentobarbital anaesthesia, 60 mg/kg i.p., and 1 h before 1-epinephrine bitartrate (Epi), 30 micrograms/kg i.v. Within 30 min after Epi all (n = 27) saline-pretreated rats were dead from pulmonary oedema, but animals receiving human/rat CRF at doses of 7 to 57 micrograms/kg s.c. (n = 25) were all alive. Body wt, wet and dry wt of lungs were used to calculate an oedema index. This index increased from 3.6 +/- 0.1 to 9.6 +/- 0.3 after Epi but was inhibited by 87% after CRF 28 micrograms/kg s.c. The ED50 of CRF for reducing pulmonary oedema was 3.2 (1.3-7.4) micrograms/kg s.c. Mean arterial pressure increased from 119 +/- 4 to 167 +/- 2 mmHg after Epi 10 micrograms/kg i.v., but was not different (118 +/- 3 to 169 +/- 4 mmHg) after CRF pretreatment, 6 micrograms/kg s.c., a dose which reduced lung oedema. Pharmacokinetic estimates suggest that plasma levels of CRF sufficient to attenuate lung oedema in rats approximate those seen in pregnant women at delivery, raising the possibility that endogenous CRF may protect the maternal organism during parturition.

Corticotropin-releasing factor inhibits the acute inflammatory response of rat pawskin to cold injury.

The anti-inflammatory effects of human/rat corticotropin-releasing factor (CRF), a 41-residue peptide hormone, on an experimental model of cold injury were examined. Male albino rats were anesthetized with sodium pentobarbital 60 mg/kg ip and the paws immersed for 1 or 2 min in a 22% NaCl solution maintained at -20 +/- 0.5 degrees C. Swelling in response to cold was measured by changes in paw volume using the fluid displacement method, and protein leakages from blood vessels were measured using Evans blue and Monastral blue dyes. Thirty minutes after cold exposure the paw volume increased from 1.5 +/- 0.1 to 2.4 +/- 0.1 ml/paw and the Evans blue content increased from 4 +/- 1 to 178 +/- 9 micrograms/pawskin. These responses to cold were inhibited by 40 to 60% after CRF was injected 56 micrograms/kg sc 30 min before or 28 micrograms/kg iv 10 min before or 5 min after cold exposures. Microscopic studies of the skin showed that CRF reduced leakage of Monastral blue pigment from the vascular compartment into the walls of capillaries and venules. The anti-inflammatory effects of CRF were blocked by alpha-helical CRF(9-41), a CRF receptor antagonist, injected 92 micrograms/kg iv 5 min before and 15 min before cold exposure.

Protective actions of corticotropin-releasing factor on thermal injury to rat pawskin.

Corticotropin-releasing factor (CRF), a 41-residue peptide, inhibits the edema and protein extravasation produced by heat applied to the rat pawskin. Here, the time course of CRFs actions against heat-induced swelling was investigated. The paws of pentobarbital-anesthetized rats were immersed in 58 degrees C water for 30 sec and the resultant swelling was measured by the fluid displacement method. Human/rat CRF, 28 micrograms/kg s.c., injected 0.5 to 2 hr before heat exposure reduced swelling by over 50%. Pretreatment at 4 hr before heat was also effective, but not at 12 or 24 hr. CRF, injected 28 micrograms/kg i.v. 0, 10 or 20 min after heat exposure, inhibited the progressive development of swelling immediately. Histological examination of skin showed that CRF, given before or after heat, reduced vesication, edema, epidermal necrosis and the disruption of tissue architecture produced by thermal injury. The alpha-helical CRF(9-41) antagonist administered alone, 92 micrograms/kg i.v., before or after heat did not affect heat injury. The antagonist, however, both prevented and reversed the inhibitory effects of CRF on the swelling produced by heat. The antagonist-induced reversal occurred as late as 2 hr after CRF, 28 micrograms/kg s.c. Overall, these results suggested that CRF is a potent and efficacious agent in protecting skin against experimental thermal injury.