1. ¹Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
2. ²Department of Biology, Earlham College, Richmond, IN, USA
3. ³Laboratory of Medicinal Chemistry, NIDDK, National Institute of Heath, Bethesda, MD, USA

Correspondence: Dr SK Wood, Department of Pharmacology, University of Michigan Medical School, 1301 MSRB 3, Ann Arbor, MI 48109-0632, USA. Tel: +1 734 763 6858; Fax: +1 734 764 7118; E-mail: howells@umich.edu

Received 17 August 2005; Revised 17 January 2006; Accepted 7 March 2006; Published online 3 May 2006.

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°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 HRSEM; 14313 vs 24714; 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 (13518; 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 g/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.