title: 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.
authors.affiliation: Macquarie University, Sydney, New South Wales, Australia.
authors.forename: M M J
authors.initials: MM
authors.lastname: Farnham
authors.forename: M S Y
authors.initials: MS
authors.lastname: Lung
authors.forename: V J
authors.initials: VJ
authors.lastname: Tallapragada
authors.forename: P M
authors.initials: PM
authors.lastname: Pilowsky
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006339:Heart Rate; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D010446:Peptide Fragments / Q000008:administration & dosage; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000235:genetics / Q000378:metabolism*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000235:genetics / Q000378:metabolism*; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism; D012018:Reflex; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C075647:pituitary adenylate-cyclase-activating-peptide (6-38)