Recombinant N-terminal fragments of chromogranin-A modulate cardiac function of the Langendorff-perfused rat heart.
In this study we tested the hypothesis that vasostatins could act as myocardial modulators in the mammalian heart. Using the Langendorff-perfused rat heart, the cardiac effects of the two recombinant human CGA N-terminal fragments STA-CGA1-78 and STA-CGA1-115, containing the vasostatin-1 (CGA 1-76) and vasostatin-2 (CGA 1-113) sequences, respectively, were evaluated at concentrations of 11 / 165 nM. Cardiac performance was evaluated by analyzing left ventricular pressure (LVP) and the rate pressure product (RPP: HR x LVP), used as indexes of contractile activity and cardiac work, respectively. Under basal conditions, STA-CGA1-78 at all concentrations tested elicited a dose-dependent negative inotropism (LVP variations ranging from -9.6% +/- 2 to -23% +/- 2.9) without affecting coronary pressure (CP). In contrast, STA-CGA1-115 increased CP at 110 and 165 nM without affecting inotropism. Both STA-CGA1-78 and STA-CGA1-115 counteracted the cardio-stimulatory effects of isoproterenol (ISO). The ISO-dependent positive chronotropism was unaffected by STA-CGA1-78, while being reduced by STA-CGA1-115. Both peptides abolished the ISO-induced positive inotropism without modifying either the beta-adrenergic-dependent coronary dilation or the ouabain-induced positive inotropism. The analysis of the percentage of variations of RPP in terms of EC50 values of ISO alone (-8.5 +/- 0.3; r2 = 0.88) and in presence of STA-CGA1-78 (11, or 33, or 65 nM: -7.7 +/- 0.15, r2 = 0.97; -7.7 +/- 0.15, r2 = 0.97; -7.8 +/- 0.78, r2 = 0.55, respectively) revealed a non-competitive type of antagonism of STA-CGA1-78. Taken together, these data suggest vasostatins as novel cardioregulatory peptides in mammals.
Cerra
Maria Carmela
MC
Department of Pharmaco-Biology, University of Calabria, 87030, Arcavacata di Rende (CS), Italy. cerramc@unical.it
De Iuri
Lucia
L
Angelone
Tommaso
T
Corti
Angelo
A
Tota
Bruno
B
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology; D053379:Chromogranin A; D002864:Chromogranins / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D006706:Homeostasis; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D016415:Sequence Alignment
D000318:Adrenergic beta-Agonists; D002317:Cardiovascular Agents; D053379:Chromogranin A; D002864:Chromogranins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C064110:vasostatin I; C102106:vasostatin II; D007545:Isoproterenol