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Am J Physiol Regul Integr Comp Physiol 285: R581-R593, 2003. First published May 15, 2003; doi:10.1152/ajpregu.00671.2002
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NEUROHUMORAL CONTROL OF CIRCULATION AND HYPERTENSION

Attenuated defense response and low basal blood pressure in orexin knockout mice

Yuji Kayaba,1,2 Akira Nakamura,1 Yoshitoshi Kasuya,3 Takashi Ohuchi,4,5 Masashi Yanagisawa,4,5 Issei Komuro,2 Yasuichiro Fukuda,1 and Tomoyuki Kuwaki1,6

Departments of 1Autonomic Physiology, 2Cardiovascular Science and Medicine, 3Biochemistry and Molecular Pharmacology, and 6Molecular and Integrative Physiology, Chiba University Graduate School of Medicine, Chiba-city, Chiba 260-8670; 4ERATO, Japan Science and Technology, Tokyo 135-0064, Japan; and5Howard Hughes Medical Institute, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9050

Submitted 31 October 2002 ; accepted in final form 14 May 2003

The perifornical area of the hypothalamus has been known as the center for the defense response, or "fight or flight" response, which is characterized by a concomitant rise in arterial blood pressure (AP), heart rate (HR), and respiratory frequency (Rf). We examined whether orexin, a recently identified hypothalamic neuropeptide, contributes to the defense response and basal cardiovascular regulation using orexin knockout mice. Microinjection of a GABA-A receptor antagonist, bicuculline methiodide (0.1-1 mM in 20 nl), to the perifornical area in urethane-anesthetized wild-type mice elicited dose-dependent increases in AP, HR, and Rf. Although similar changes were observed in orexin knockout mice, intensities were smaller and duration was shorter than those in wild-type mice. Moreover, in an awake and freely moving condition, telemeter-indwelling orexin knockout mice showed diminished cardiovascular and behavioral responses to emotional stress in the resident-intruder test. We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 ± 8 mmHg in wild type and 92 ± 3 in knockout) and conscious (125 ± 6 mmHg in wild type and 109 ± 2 in knockout) conditions. {alpha}-Adrenergic blockade with prazosin or ganglion blockade with hexamethonium canceled the difference in basal AP. HR and cardiac contractile parameters by echocardiography did not differ between the two strains of mice. These results indicate lower sympathetic vasoconstrictor tone in knockout mice. The present study suggests that orexin-containing neurons in the perifornical area play a role as one of the efferent pathways of defense response and also operate as a regulator of AP at basal condition by activating sympathetic outflow.

hypothalamus; stress; respiration; sympathetic nervous system; circadian rhythm


Address for reprint requests and other correspondence: T. Kuwaki, Dept. of Molecular and Integrative Physiology, Chiba Univ. Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan (E-mail: kuwaki{at}faculty.chiba-u.jp).




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