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.

Imbrogno S, et al. Gen Comp Endocrinol. 2004 Oct;139(1):20-8

• acts as a potent endogenous nicotinic cholinergic antagonist to inhibit catecholamine release.
• induces release of histamine from mast cells
• displays potent antimicrobial activity

Relationship of CHGA-mediated dense-core secretory granule (DCG) biogenesis, catecholamine (CA) secretion, and its subsequent inhibition by the CHGA-derived peptide catestatin in the maintenance of blood pressure by the adrenal gland. CHGA, as a full-length molecule, initiates dense-core secretory granule biogenesis at the trans-Golgi network of adrenal chromaffin cells. Current data suggests that CHGA enhances granule biogenesis by preventing posttranslational degradation of other granule proteins in the Golgi complex. In the cytoplasm, catecholamine is synthesized and transported into the dense-core secretory granules via vesicular monoamine transporters. Upon stimulation by acetylcholine (Ach), catecholamine is coreleased with CHGA and catestatin from the granules. Secreted catecholamine triggers cardiovascular target cells to augment blood flow. This sympathoadrenal activity is then antagonized by the action of catestatin on cholinergic receptors to inhibit catecholamine secretion. [Ca2+]i, intracellular calcium concentration. Taeyoon Kim and Y. Peng Loh. J. Clin. Invest. 115:1711-1713 (2005)