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

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 residentintruder test. We also found that basal AP in orexin knockout mice was significantly lower in both anesthetized (117 [+ or -] 8 mmHg in wild type and 92 [+ or -] 3 in knockout) and conscious (125 [+ or -] 6 mmHg in wild type and 109 [+ or -] 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