Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs.
Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P < .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n = 5) or α- and β-adrenoceptors (n = 5 each) did not abolish the observed responses, NO synthase inhibition (n = 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells.
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Elena
E
Grossini
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Giulia
G
Raina
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Serena
S
Farruggio
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Lara
L
Camillo
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Claudio
C
Molinari
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
David
D
Mary
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Gillian Elisabeth
GE
Walker
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Gianni
G
Bona
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Giovanni
G
Vacca
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Stefania
S
Moia
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Flavia
F
Prodam
Laboratory Physiology/Experimental Surgery (E.G., G.R., S.F., L.C., C.M., D.M., G.V., D.S.), Department of Translational Medicine, and Pediatric Unit (G.E.W., G.B., S.M., F.P.), Department of Health Sciences, University E Piedmont "A. Avogadro," Azienda Ospedaliera Universitaria Maggiore della Carità, I-12800 Novara, Italy.
Daniela
D
Surico
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D005260:Female; D054439:Ghrelin / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D054439:Ghrelin; C422650:ghrelin, des-n-octanoyl; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases