Pituitary Adenylate Cyclase Activating Polypeptide: A Neuropeptide with Potent Inotropic and Coronary Vasodilatory Effects in Neonatal Pig Hearts

Abstract

ABSTRACT. Cardiac effects of the neuropeptide pituitaryAbbreviations adenylate cyclase activating p o l y p e p t i d e -(~~~i~) have not previously been reported. W e investigated the influence of PACAP, vasoactive intestinal polypeptide (68% homology with PACAP) and the B-adrenergic receptor agonist isoproterenol on contractile function and coronary vascular tone in isolated piglet hearts (1 to 5 d of age). Paced (180 beatslmin) isovolumically beating hearts underwent retrograde aortic perfusion a t constant coronary flow (approximately 3 mL. min-' . g-') with an erythrocyte-enriched PACAP, pituitary adenylate cyclase activating polypeptide VIP, vasoactive intestinal polypeptide ISP, isoproterenol IBMX, isobutylmethylxanthine dP/dt,,, maximum rate of change of systolic pressure with respect to time (+), positive (-), negative (hematocrit 15 to 20%)~solution ( 3 7 "~) . ~g o n i s t s were injected into the aortic root of hearts, and the positive (+) and negative (-) changes in maximum rate of change of systolic pressure with respect to time (dP/dtma,) and in PACAP is a newly discovered neuropcptide isolated from the coronary perfusion pressure (that reflected alterations in ovine hypothalamus (1). PACAP is present in two forms: one vascular tone) were measured. PACAP (n = 8,O.l and 0.5 with 27 and the other with 38 N-terminal amino acid residues nmol) increased (+) dP/dt,, from 944 + 59 to 1519 f 206 (2). PACAP has a 68% sequence homology with VIP and appears mm ~g / s and from 867 2 40 to 2010 +: 226 mm ~g / s ( p to be more potent than VIP in stimulating adenylate cyclase in < 0.05); increased (-1 dpldt,, from 11 14 41 to 14-39 + pituitary cells (2). PACAP also has been shown to increase cAMP 9 5 mm ~g and from 999 f 37 to 1668 + 145 mm H~/ S levels in the human neuroblastoma cell line NB-OK (3), the rat ( p < 0.05); and decreased perfusion pressure from 61.4 2 pancreatic acinar cell line AR 4-25 (4), and rat liver cell mem-3.1 to 48.9 2 2.3 mm 1 1~ and from 60.5 + 2.4 to 43.9 branes ( 5 ) . Moreover, high affinity binding sites for PACAP have 2.3 mm H~ (p < 0.05), respectively. comparison, vase-been identified in several organ systems, including the rat lung active intestinal polypeptide (n = 6, 0.1 and 0.5 nmol) (6) and h m a n brain (7). increased (+) dP/dtmn, from 767 +. 53 to 806 + 37 mm Hg/ The ~h~s i o l o g i c role of PACAP has not been elucidated, and from 829 2 94 to 942 8 5 mm ~g /~ (NS); increased although it has been suggested that this peptide may be involved (-) dp/dtma, from 883 2 73 to 926 45 ,,,,,, ~g /~ and in the regulation of vascular smooth muscle tone, in addition to from 923 + 8 2 to 1054 f 78 mm Hg/s (NS); and decreased its presumed role as a hypothalamic, hypophysiotropic hormone perfusion pressure from 57.9 + 4.9 to 50.0 +. 3.6 mm H~ (8 VIP, have been demonstrated in the myocardium and coronary duced positive inotropic, luisitropic, and coronary vasodil-arteries of several adult species (12). The present study, therefore, effects in piglet which may make a was undertaken to inv...

Backup Mechanisms Maintain PACAP/VIP-Induced Arterial Relaxations in Pituitary Adenylate Cyclase-Activating Polypeptide-Deficient Mice

“…These diverse functions also include potent vasomotor effects [17,18]. There are studies showing relaxations to both PACAP isoforms and VIP in vessels of different origin, such as carotid [23], pulmonary [24], mesenteric and coronary [38], meningeal [20], cerebral and intracerebral [21,22], and middle cerebral arteries [10] of various species.…”

“…Although some data show that PACAP is able to exert a hypertensive action through the systemic release of catecholamines [15,16], PACAP, similarly to VIP, is considered a potent vasorelaxant peptide [17,18], causing a decrease in the mean arterial blood pressure [17,19]. The vasodilator activity of PACAP has been recorded in vessels of various organs in mice [20], rats [21,22,23], cats [15,24], rabbits [25], dogs [21], pigs [18], and humans [26].…”

“…The vasodilator activity of PACAP has been recorded in vessels of various organs in mice [20], rats [21,22,23], cats [15,24], rabbits [25], dogs [21], pigs [18], and humans [26]. These actions are mediated through all 3 PACAP receptors, which are highly expressed (alone/combined or all together) in the aorta [27], mesenteric [25], coronary [28], cranial arteries [10], pulmonary vascular bed [15], and many other blood vessels [1,29].…”

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…Although PACAP is able to exert an indirect hypertensive action mediated through the release of catecholamines (Ishizuka et al, 1992;Minkes et al, 1992a), this peptide, in very much the same way as VIP, is mainly considered as a highly potent vasorelaxant factor (Hirata et al, 1985;Ross-Ascuitto et al, 1993;Tong et al, 1993;Ascuitto et al, 1996). This vasodilatory activity, which can be ascribed at least in part to its activity on arterial smooth muscle cells Naruse et al, 1993;Steenstrup et al, 1996;Bruch et al, 1997), is well documented in various organs, including the brain (Tong et al, 1993;Anzai et al, 1995), the eye (Nilsson, 1994;Elsås and White, 1997;Dorner et al, 1998), the pulmonary vascular bed (Minkes et al, 1992b;Cheng et al, 1993;Foda et al, 1995), the mesentery (Wilson and Warren, 1993), the pancreas (Bertrand et al, 1996;Ito et al, 1998), the testis (Lissbrant et al, 1999), the ovary (Steenstrup et al, 1994;Yao et al, 1996), the vagina (Steenstrup et al, 1994;Giraldi et al, 2002;Aughton et al, 2008), the kidney (Gardiner et al, 1994), the gastrointestinal tract (Portbury et al, 1995;Badawy and Reinecke, 2003), and the skin (Wallengren, 1997).…”

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Induces Relaxations of Peripheral and Cerebral Arteries, which are Differentially Impaired by Aging

“…The vascular actions of PACAP1-38 are more effective compared to those of PACAP1-27 (Huang et al 1992 ;Okazaki et al 1992 ). The vasodilator activity of PACAP has been documented in vessels of various organs (Nandha et al 1991 ;Ross-Ascuitto et al 1993 ) via three specific receptors (PAC1R and VPAC1R/VPAC2R), both of which are highly expressed in the cerebral and peripheral blood vessels (Fahrenkrug et al 2000 ;Nandha et al 1991 ). They are localized in the smooth muscle cells of cerebral arteries and arterioles (Fahrenkrug et al 2000 ;Amenta et al 1991 ).…”