Recombinant N–terminal fragments of chromogranin–A modulate cardiac function of the Langendorff–perfused rat heart
Tóm tắt
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 × 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 β–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.
Từ khóa
Tài liệu tham khảo
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