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 actas myocardial modulators in the mammalian heart. Using the Langendorffperfusedrat heart, the cardiac effects of the two recombinant human CGAN-terminal fragments STA-CGA1-78 and STA-CGA1-115, containing thevasostatin-1 (CGA 1-76) and vasostatin-2 (CGA 1-113) sequences, respectively,were evaluated at concentrations of 11 165 nM. Cardiac performancewas evaluated by analyzing left ventricular pressure (LVP) and the rate pressureproduct (RPP: HR LVP), used as indexes of contractile activity andcardiac work, respectively. Under basal conditions, STA-CGA1-78 at all concentrationstested elicited a dose-dependent negative inotropism (LVP variationsranging from –9.6% ± 2 to –23% ± 2.9) without affecting coronarypressure (CP). In contrast, STA-CGA1-115 increased CP at 110 and 165 nMwithout affecting inotropism. Both STA-CGA1-78 and STA-CGA1-115 counteractedthe cardio-stimulatory effects of isoproterenol (ISO). The ISO-dependentpositive chronotropism was unaffected by STA-CGA1-78, while being reduced by STA-CGA1-115. Both peptides abolished the ISO-inducedpositive inotropism without modifying either the beta-adrenergic-dependentcoronary dilation or the ouabain-induced positive inotropism. The analysisof 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. Takentogether, these