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Cardiac effects of hypocretin-1 in nucleus ambiguus
John Ciriello1, Cleusa V R de Oliveira
1Department of Physiology and Pharmacology, Faculty of Medicine and Dentistry, Health Sciences Centre, University of Western Ontario, London, Ontario, Canada N6A 5C1. john.ciriello@fmd.uwo.ca
Insights
Hypocretin-1 (hcrt-1) in the nucleus ambiguus (Amb) region of the brainstem influences cardiovascular function. This study shows hcrt-1 activates vagal cardioinhibitory neurons, reducing heart rate and enhancing baroreflex bradycardia.
Area of Science:
- Neuroscience
- Cardiovascular Physiology
Background:
- Recent studies identified hypocretin-1 (hcrt-1)-like-immunoreactivity (ir) in the nucleus ambiguus (Amb).
- The specific function of hcrt-1 within the Amb concerning cardiovascular regulation remained unknown.
Purpose of the Study:
- To investigate the effects of microinjections of hcrt-1 into the Amb on heart rate (HR), mean arterial pressure (MAP), and the arterial baroreceptor reflex in rats.
- To map the distribution of hcrt-1 and its receptor (hcrtR-1) within the Amb region.
Main Methods:
- Detailed mapping of hcrt-1 and hcrtR-1-like-ir distribution in the Amb and adjacent ventrolateral medullary reticular formation.
- Microinjections of hcrt-1 into specific Amb subregions (Ambe) in anesthetized rats to assess cardiovascular responses.
- Administration of muscarinic receptor antagonist or vagotomy to elucidate the mechanism of HR changes.
- Assessment of baroreflex sensitivity following hcrt-1 administration.
Main Results:
- hcrt-1 and hcrtR-1-like-ir were found throughout the Amb, with highest hcrtR-1 concentration in the external formation of the nucleus (Ambe).
- Microinjections of hcrt-1 into the Ambe dose-dependently decreased HR, with minimal direct MAP changes. This bradycardia was abolished by atropine or vagotomy, indicating vagal activation.
- hcrt-1 in the Ambe potentiated reflex bradycardia induced by baroreceptor activation.
Conclusions:
- hcrt-1 within the Ambe activates vagal preganglionic cardioinhibitory neurons.
- This activation alters central cardiovascular control circuits, influencing heart rate and baroreflex function.
Abstract:
Although recent studies have reported hypocretin 1 (hcrt-1)-like-immunoreactivity (ir) within the region of the nucleus ambiguus (Amb) in the caudal brain stem, the function of hcrt-1 in the Amb on cardiovascular function is not known. Three series of experiments were done in male Wistar rats to investigate the effects of microinjections of hcrt-1 into Amb on heart rate (HR), mean arterial pressure (MAP), and the arterial baroreceptor reflex. In the first series, a detailed mapping of the distribution of hcrt-1- and hcrt-1 receptor (hcrtR-1)-like-ir was obtained of the Amb region. Although hcrt-1-like- and hcrtR-1-like-ir were found throughout the rostrocaudal extent of the Amb and adjacent ventrolateral medullary reticular formation, most of the hcrtR-1-like-ir was observed in the area just ventral to the compact formation of Amb, in the region of the external formation of the nucleus (Ambe). In the second series, the Amb region that contained hcrt-1 and hcrtR-1-ir was explored for sites that elicited changes in HR and MAP in urethane and alpha-chloralose-anesthetized rats. Microinjections of hcrt-1 (0.5-2.5 pmol) into the Ambe elicited a dose-related decrease in HR, with little or no direct change in MAP. The small decreases in MAP were found to be secondary to the HR changes. The largest bradycardia responses were elicited from sites in the Ambe. Administration (iv) of the muscarinic receptor antagonist atropine methyl bromide or ipsilateral vagotomy abolished the HR response, indicating that the HR response was due to activation of vagal cardiomotor neurons. In the final series, microinjections of hcrt-1 into the Ambe significantly potentiated the reflex bradycardia elicited by activation of the baroreflex as a result of the increased MAP after the intravenous injection of phenylephrine. These data suggest that hcrt-1 in the Ambe activates neuronal systems that alter the excitability of central circuits that reflexly control the circulation through the activation of vagal preganglionic cardioinhibitory neurons.