title: Facilitation of cardiac vagal activity by CRF-R1 antagonists during swim stress in rats.
abstract: Exposure to stressors that elicit fear and feelings of hopelessness can cause severe vagal activation leading to bradycardia, syncope, and sudden death. These phenomena though documented, are difficult to diagnose, treat clinically, and prevent. Therefore, an animal model incorporating these cardiovascular conditions could be useful. The present study examined 'sinking' during a 2-h swim stress, a phenomenon that occurs in 50% of rats during 25 degrees C water exposure. Concurrent measurements of body temperature, immobility, heart rate (HR), and PR interval (a measure of vagal activity) were made. Neither decreases in immobility nor variations in hypothermia during swim were correlated with sinking. Bradycardia was more severe in sinking rats (average minimum HR+/-SEM; 143+/-13 vs 247+/-14; p<0.01), and PR interval was elevated (p<0.0001). To examine potential modulation of vagal activity during stress, corticotropin-relasing factor (CRF) receptor antagonists (antalarmin, R121919 and astressin B), a glucocorticoid receptor antagonist (RU486), and a peripherally acting cholinergic antagonist (methylatropine nitrate) were administered. The centrally acting CRF antagonist, antalarmin (32 mg/kg), produced elongation of the PR interval (p<0.0001), robust bradycardia (135+/-18; p<0.001), and increased sinking (92%; p<0.05), and methylatropine nitrate (3.2 mg/kg) blocked these effects. Corroborating these data, two different CRF antagonists, R121919 (30 mg/kg) and astressin B (intracerebroventricular (i.c.v.), 0.03 mug/rat) increased sinking to 100%. RU486 (20 mg/kg) blocked HPA axis negative feedback and decreased percent sinking to 25%. From these studies, we concluded that sinking during a 2-h water exposure was a result of extreme vagal hyperactivity. Furthermore, stress-induced CRF release may serve to protect against elevated cardiac vagal activity.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA. howells@umich.edu
authors.forename: Susan K
authors.initials: SK
authors.lastname: Wood
authors.forename: Robert E
authors.initials: RE
authors.lastname: Verhoeven
authors.forename: Aaron Z
authors.initials: AZ
authors.lastname: Savit
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Peter S
authors.initials: PS
authors.lastname: Fischbach
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D016757:Death, Sudden, Cardiac; D004195:Disease Models, Animal; D017079:Exercise Tolerance / Q000187:drug effects* / Q000502:physiology; D005221:Fatigue / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007036:Hypothermia, Induced; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011595:Psychomotor Agitation / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications* / Q000503:physiopathology; D013550:Swimming / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology; D020421:Vagus Nerve Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D000099052:CRF Receptor, Type 1
chemical_list: D018680:Cholinergic Antagonists; D010446:Peptide Fragments; D011743:Pyrimidines; D011758:Pyrroles; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; C120841:astressin B; D015735:Mifepristone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone