Blockade of orexin receptors attenuates the cardiovascular response to air-jet stress in spontaneously hypertensive rats.

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.

Chronic heart failure alters orexin and melanin concentrating hormone but not corticotrophin releasing hormone-related gene expression in the brain of male Lewis rats.

OBJECTIVE: The aim of this study was to investigate the effect of chronic heart failure (HF; 16 weeks post left coronary artery ligation) on the brain's orexin (ORX) and related neuropeptide systems. METHODS: Indicators of cardiac function, including the percent fractional shortening (%FS) left ventricular posterior wall shortening velocity (LVPWSV) were assessed via echocardiography at 16 weeks post myocardial infarction or sham treatment in male Lewis rats (n=5/group). Changes in gene expression in HF versus control (CON) groups were quantified by real-time PCR in the hypothalamus, amygdala and dorsal pons. RESULTS: HF significantly reduced both the %FS and LVPWSV when compared to CON animals (P<0.02). In the hypothalamus ORX gene expression was significantly reduced in HF and correlated with changes in cardiac function when compared to CON (P<0.02). No significant changes in hypothalamic ORX receptor (type 1 or type 2) gene expression were identified. Alternatively hypothalamic melanin concentrating hormone (MCH) gene expression was significantly upregulated in HF animals and negatively correlated with LVPWSV (P<0.006). In both the amygdala and dorsal pons ORX type 2 receptor expression was significantly down-regulated in HF compared to CON. ORX receptor type 1, CRH and CRH type 1 and type 2 receptor expressions were unchanged by HF in all brain regions analyzed. CONCLUSION: These observations support previous work demonstrating that cardiovascular disease modulates the ORX system and identify that in the case of chronic HF the ORX system is altered in parallel with changes in MCH expression but independent of any significant changes in the central CRH system. This raises the new possibility that ORX and MCH systems may play an important role in the pathophysiology of HF.

Effect of DOCA/salt hypertension on CRF expression in the amygdala and the autonomic stress response in conscious rats.

The effects of DOCA/salt treatment on amygdala-area CRF gene expression and the autonomic response to air jet stress (AJS) were evaluated in conscious male Sprague Dawley (SD) rats. Fifteen days of DOCA/salt treatment significantly increased resting arterial pressure (AP), decreased resting heart rate (HR) and significantly reduced regional CRF mRNA compared to controls (23±7% vs. 100±26%) independent of changes in regional CRF receptor expression. Twenty min of AJS elicited a rise in AP (~15mmHg) that was similar in both DOCA/salt animals (n=11) and controls (n=6). Alternatively, increases in HR were significantly different in the DOCA/salt animals compared to controls; including one group of DOCA/salt animals (n=5) which responded with an attenuated HR response at the onset of AJS (low-responders) and a second group (n=6) which demonstrated an elevated HR response to AJS (high-responders), specifically during the last 10min of AJS. The divergent HR responses to AJS in the DOCA/salt animals were linked to differences in resting heart rate variability. During recovery HR returned to baseline within 10min in both control and the low responder DOCA group but indicators of spontaneous baroreflex gain only increased significantly in controls. HR in the high-responder DOCA animals did not return to baseline during the same period. These results show that DOCA/salt treatment triggers downregulation of CRF gene expression in the region of the amygdala and significantly alters the HR response to acute stress but does not alter the pressor response to stress compared to normotensive controls.