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PACAP causes PAC1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rats.

ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide that plays an important role in hypertension and stress responses. PACAP acts at three G protein-coupled receptors [PACAP type 1 receptor (PAC(1)) and vasoactive intestinal peptide receptor types 1 and 2 (VPAC(1) and VPAC(2))] and is localized to sites involved in cardiovascular control, most significantly the rostral ventrolateral medulla (RVLM). The RVLM is crucial for the tonic and reflex control of efferent sympathetic activity. Increases in sympathetic activity are observed in most types of hypertension and heart failure. PACAP delivered intrathecally also causes massive sympathoexcitation. We aimed to determine the presence and abundance of the three PACAP receptors in the RVLM, the role, in vivo, of PACAP in the RVLM on tonic and reflex cardiovascular control, and the contribution of PACAP to hypertension in the spontaneously hypertensive rat (SHR). Data were obtained using quantitative PCR and microinjection of PACAP and its antagonist, PACAP(6-38), into the RVLM of anesthetized artificially ventilated normotensive rats or SHRs. All three receptors were present in the RVLM. PACAP microinjection into the RVLM caused sustained sympathoexcitation and tachycardia with a transient hypertension but did not affect homeostatic reflexes. The responses were partially mediated through PAC(1)/VPAC(2) receptors since the effect of PACAP was attenuated (?50%) by PACAP(6-38). PACAP was not tonically active in the RVLM in this preparation because PACAP(6-38) on its own had no inhibitory effect. PACAP has long-lasting cardiovascular effects, but altered PACAP signaling within the RVLM is not a cause of hypertension in the SHR.

SUBMITTER: Farnham MM

PROVIDER: S-EPMC3774201 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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PACAP causes PAC1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rats.

Farnham M M J MM Lung M S Y MS Tallapragada V J VJ Pilowsky P M PM

American journal of physiology. Heart and circulatory physiology 20120810 7

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide that plays an important role in hypertension and stress responses. PACAP acts at three G protein-coupled receptors [PACAP type 1 receptor (PAC(1)) and vasoactive intestinal peptide receptor types 1 and 2 (VPAC(1) and VPAC(2))] and is localized to sites involved in cardiovascular control, most significantly the rostral ventrolateral medulla (RVLM). The RVLM is crucial for the tonic and reflex control of effer ...[more]

PMID: 22886412

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Project description:Introduction:Accumulated evidence indicates that obesity is associated with enhanced sympathetic activation. Hypothalamic leptin-mediated signaling may contribute to the exaggerated sympathoexcitation of obesity. The goal of this study was to investigate the "neuron-astrocyte" interaction affecting leptin-mediated sympathoexcitation within the arcuate nucleus (ARCN) of the hypothalamus in obese rats. Methods and Results:Obesity was induced by high-fat diet (HFD, 42% of calories from fat) in Sprague Dawley rats. Twelve weeks of HFD produced hyperleptinemia, hyperlipidemia, and insulin resistance. In anesthetized rats, microinjections of leptin into the ARCN induced increases in heart rate (HR), renal sympathetic nerve activity (RSNA), and mean arterial pressure (MAP) in both control and HFD rats. However, microinjections of leptin in HFD rats elicited higher responses of RSNA and arterial pressure than control-fed rats. It also caused the inhibition of astrocytes within the ARCN using an astrocytic metabolic inhibitor, fluorocitrate, and reduced leptin-induced sympathetic activity and blood pressure responses. Moreover, the expression of the leptin receptor in the ARCN of HFD-fed rats was significantly increased compared to rats fed a control diet. Immunohistochemistry analysis revealed leptin receptor localization from both neurons and astrocytes of the ARCN. HFD rats exhibited increased protein expression of glial fibrillary acidic protein (GFAP) in the ARCN. We also found that the expression of astrocyte-specific glutamate transporters and excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2) were decreased within the ARCN of the HFD rats. In cultured astrocytic C6 cells, 24 h of leptin treatment increased the protein expression of GFAP and reduced the expression of EAAT1 and EAAT2. Conclusion:The results suggest that central leptin signaling occurs via neuron-astrocyte interactions in the ARCN and contributing to the exaggerated sympathoexcitation observed in obese rats. The effects may be mediated by the action of leptin on regulating astrocytic glutamate transporters within the ARCN of the hypothalamus.

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PACAP causes PAC1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rats.

Publications

PACAP causes PAC1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rats.

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