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 divided by 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; r(2) = 0.88) and in presence of STA-CGA1-78 (11, or 33, or 65 nM: -7.7 +/- 0.15, r(2) = 0.97; -7.7 +/- 0.15, r(2) = 0.97; -7.8 +/- 0.78, r(2) = 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.