title: Antihypertensive and neuroprotective effects of catestatin in spontaneously hypertensive rats: interaction with GABAergic transmission in amygdala and brainstem.
abstract: The chromogranin A-derived peptide catestatin (CST) exerts sympathoexcitatory and hypertensive effects when microinjected into the rostral ventrolateral medulla (RVLM: excitatory output); it exhibits sympathoinhibitory and antihypertensive effects when microinjected into the caudal ventrolateral medulla (CVLM: inhibitory output) of vagotomized normotensive rats. Here, continuous infusion of CST into the central amygdalar nucleus (CeA) of spontaneously hypertensive rats (SHRs) for 15 days resulted in a marked decrease of blood pressure (BP) in 6-month- (by 37 mm Hg) and 9-month- (by 65 mm Hg)old rats. Whole-cell patch-clamp recordings on pyramidal CeA neurons revealed that CST increased both spontaneous inhibitory postsynaptic current (sIPSC) amplitude plus frequency, along with reductions of sIPSC rise time and decay time. Inhibition of GABAA receptors (GABAARs) by bicuculline completely abolished CST-induced sIPSC, corroborating that CST signals occur through this major neuroreceptor complex. Hypertension is a major risk factor for cerebrovascular diseases, leading to vascular dementia and neurodegeneration. We found a marked neurodegeneration in the amygdala and brainstem of 9-month-old SHRs, while CST and the GABAAR agonist Muscimol provided significant neuroprotection. Enhanced phosphorylation of Akt and ERK accounted for these neuroprotective effects through anti-inflammatory and anti-apoptotic activities. Overall our results point to CST exerting potent antihypertensive and neuroprotective effects plausibly via a GABAergic output, which constitute a novel therapeutic measure to correct defects in blood flow control in disorders such as stroke and Alzheimer's disease.
authors.affiliation: Comparative Neuroanatomy Laboratory of Biology, Ecology and Earth Science Dept. (DiBEST), University of Calabria, Ponte P. Bucci 4B, 87030 Arcavacata di Rende, Cosenza, Italy; VA San Diego Healthcare System/Department of Medicine, University of California-San Diego, La Jolla, CA 92093-0838, USA; Department of Pathology, University of California-San Diego, La Jolla, CA 92093-0838, USA. Electronic address: eavolio@ucsd.edu.
authors.forename: E
authors.initials: E
authors.lastname: Avolio
authors.affiliation: VA San Diego Healthcare System/Department of Medicine, University of California-San Diego, La Jolla, CA 92093-0838, USA. Electronic address: smahata@ucsd.edu.
authors.forename: S K
authors.initials: SK
authors.lastname: Mahata
authors.affiliation: Department of Pathology, University of California-San Diego, La Jolla, CA 92093-0838, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mantuano
authors.affiliation: Comparative Neuroanatomy Laboratory of Biology, Ecology and Earth Science Dept. (DiBEST), University of Calabria, Ponte P. Bucci 4B, 87030 Arcavacata di Rende, Cosenza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mele
authors.affiliation: Comparative Neuroanatomy Laboratory of Biology, Ecology and Earth Science Dept. (DiBEST), University of Calabria, Ponte P. Bucci 4B, 87030 Arcavacata di Rende, Cosenza, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Alò
authors.affiliation: Comparative Neuroanatomy Laboratory of Biology, Ecology and Earth Science Dept. (DiBEST), University of Calabria, Ponte P. Bucci 4B, 87030 Arcavacata di Rende, Cosenza, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Facciolo
authors.affiliation: Institute of Neuroscience, National Research Council of Italy, 09042 Monserrato, Cagliari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Talani
authors.affiliation: Comparative Neuroanatomy Laboratory of Biology, Ecology and Earth Science Dept. (DiBEST), University of Calabria, Ponte P. Bucci 4B, 87030 Arcavacata di Rende, Cosenza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Canonaco
mesh_terms: D000367:Age Factors; D000679:Amygdala / Q000187:drug effects* / Q000503:physiopathology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001933:Brain Stem / Q000187:drug effects* / Q000503:physiopathology; D053379:Chromogranin A / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011918:Rats, Inbred SHR; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D053379:Chromogranin A; D058785:GABA-A Receptor Agonists; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C109084:chromogranin A (344-364); D009118:Muscimol; D051057:Proto-Oncogene Proteins c-akt
keywords: GABAergic agonist; SHRs; catestatin; hypertension; neurodegeneration
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