cardiovascular-agents and almorexant

This study tested the hypothesis that orexin plays a role in the elevated pressor response to acute stress in the spontaneously hypertensive rat (SHR). The pressor response to air jet stress (AJS) (n=11/group) was 2.5 times greater in vehicle treated SHR versus Wistar (WIS) rats. Systemic delivery of 30mg/kg of the dual orexin receptor antagonist almorexant did not significantly change resting mean arterial pressure (MAP) but did attenuate the pressor response elicited by AJS to a greater extent in the SHR compared to the Wistar rats (~65% versus ~33% reduction respectively; n=6/group). Alternatively 100mg/kg almorexant reduced resting MAP in the SHR (~25mm Hg drop) and attenuated both the heart rate (HR; ~50% reduction) and MAP (~62% reduction) response to AJS in both strains (n=6/group). Systemic application of SB-334867 (3mg/kg), an orexin receptor type 1 antagonist (n=5/group), selectively reduced resting MAP and attenuated the HR response to AJS in the SHR but had no effect on the pressor response in either strain. The potential role of endogenous orexin release in cardiovascular control in the SHR was linked to a significant increase in brain-derived neurotrophic factor mRNA expression in the hypothalamus and elevated orexin receptor expression (type 2 only) in the dorsal pons when compared to WIS (n=4/group). These results demonstrate that the exaggerated pressor response in the SHR to stress is linked to increased orexin receptor activation and possibly altered orexin receptor expression in the dorsal pons and BDNF expression in the hypothalamus.

Topics: Acetamides; Air; Animals; Benzoxazoles; Blood Pressure; Brain; Brain-Derived Neurotrophic Factor; Cardiovascular Agents; Dose-Response Relationship, Drug; Heart Rate; Isoquinolines; Male; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Physical Stimulation; Random Allocation; Rats, Inbred SHR; Rats, Wistar; RNA, Messenger; Species Specificity; Stress, Psychological; Urea