Influence of vasostatins, the chromogranin A-derived peptides, on the working heart of the eel (Anguilla anguilla): negative inotropy and mechanism of action.
We have studied the effects of exogenous human recombinant Vasostatin-1 (VS-1), Vasostatin-2 (VS-2) and the human Chromogranin A (CGA) 7-57 synthetic peptides on the mechanical performance of the isolated and perfused working eel (Anguilla anguilla) heart. Under basal conditions, the three peptides decreased stroke volume (SV) and stroke work (SW), thus exerting negative inotropism. The VS-1-mediated negative inotropism was abolished by exposure to inhibitors of either Gi/o protein (pertussis toxin; PTx) or M1 muscarinic receptors (Pirenzepine) or calcium (Lantanum and Diltiazem) and potassium (Ba2+, 4-aminopyridine, tetraethylammonium, glibenclamide) channels, while it required an intact endocardial endothelium (EE). Using NG-monomethyl-L-arginine (L-NMMA) as an inhibitor of nitric oxide (NO) synthase (NOS), and hemoglobin as a NO scavenger, we demonstrated the obligatory role of NO signaling in mediating the vasostatin response. Pretreatment with either a specific inhibitor of soluble guanylate cyclase (GC) 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), or the inhibitor of the cGMP-activated protein kinase (PKG) KT5823, abolished the VS-1-mediated inotropism, indicating the cGMP-PKG component as a crucial target of NO signaling. Of note, VS-1 was effective in counteracting the adrenergic (Isoproterenol and Phenylephrine)-mediated positive inotropism. These findings provide the first evidence that vasostatins exert cardiotropic action in fish, thus suggesting their long evolutionary history as well as their species-specific mechanisms of action.
Department of Cellular Biology, University of Calabria, Via P. Bucci, Arcavacata di Rende 87030, CS, Italy.
Sandra
S
Imbrogno
Tommaso
T
Angelone
Angelo
A
Corti
Cristina
C
Adamo
Karen B
KB
Helle
Bruno
B
Tota
D018663:Adrenergic Agents / Q000494:pharmacology; D000811:Anguilla / Q000502:physiology*; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D053379:Chromogranin A; D002864:Chromogranins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004699:Endocardium / Q000502:physiology; D004727:Endothelium / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D015221:Potassium Channels / Q000502:physiology; D011941:Receptors, Adrenergic / Q000502:physiology; D011950:Receptors, Cholinergic / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013318:Stroke Volume / Q000187:drug effects
D018663:Adrenergic Agents; C506150:CHGA protein, human; D015220:Calcium Channels; D053379:Chromogranin A; D002864:Chromogranins; D010446:Peptide Fragments; D015221:Potassium Channels; D011941:Receptors, Adrenergic; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; C499788:chromogranin A (7-57); C064110:vasostatin I; C102106:vasostatin II; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D006152:Cyclic GMP