Chromogranin A N-terminal fragments vasostatin-1 and the synthetic CGA 7-57 peptide act as cardiostatins on the isolated working frog heart.
Chromogranin A (CGA) N-terminal fragments corresponding to residues 1-76 and 1-113, named vasostatins for their inhibitory effects on vascular tension, have been postulated as important homeostatic regulators of the cardiovascular system. We have used an in vitro isolated working frog (Rana esculenta) heart as a bioassay to study the effects of exogenous human recombinant CGA 1-76 (VS-1) and human CGA 7-57 synthetic peptide on cardiac performance. Under basal conditions, the concentration-response curves of the two peptides exhibited a significant negative inotropism. This vasostatin response was unaffected by pretreatment with either Triton X-100 or two nitric oxide synthase inhibitors, i.e., N(G)-monomethyl-L-arginine and L-N5 (5)(1-iminoethyl) ornithine or the soluble guanylate cyclase inhibitor 1H-(1,2,4) oxadiazolo-(4,3-a) quinoxalin-1-one, indicating an endocardial endothelium-nitric oxide-cGMP-independent mechanism. The negative inotropism was also unaffected by either adrenergic (i.e., phentolamine and propranolol) or muscarinic (atropine) receptor or G proteins (pertussis toxin) inhibition. On the contrary, it was dependent from both extracellular Ca(2+) and K(+) channels, since it was abolished by pretreatment to either the Ca(2+) channel inhibitors lanthanum and diltiazem or the K(+) channel inhibitors Ba(2+), 4-aminopyridine, tetraethylammonium chloride, and glibenclamide. In conclusion, the findings that vasostatins exert an inhibitory modulation on basal cardiac performance and counteract, as previously reported, the adrenergic-mediated positive inotropism, strongly support a cardio-regulatory role for these peptides.
Corti
Angelo
A
Department of Biological and Technological Research, San Raffaele H Scientific Institute, Milan 20132, Italy.
Mannarino
Cinzia
C
Mazza
Rosa
R
Angelone
Tommaso
T
Longhi
Renato
R
Tota
Bruno
B
D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000494:pharmacology*; D037282:Calreticulin; D053379:Chromogranin A; D002864:Chromogranins / Q000737:chemistry*; D003864:Depression, Chemical; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011893:Rana esculenta; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology; D012261:Ribonucleoproteins / Q000737:chemistry / Q000494:pharmacology*; D016415:Sequence Alignment
C506150:CHGA protein, human; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D053379:Chromogranin A; D002864:Chromogranins; D010446:Peptide Fragments; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D012261:Ribonucleoproteins; C121986:vasostatin; D011188:Potassium