| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Research Abstract |
We have previously reported that protamine itself caused selective regional vasodilation and that heparin potentiated protamine-induced vascular changes via a nitric oxide dependent mechanism. However, nitric oxide system was not involved in protamine induced myocardial dysfunction. This study was designed to assess the relationship between intracellular calcium ([Ca2+]i) dynamics and myocardial dysfunction induced by protamine in the isolated rat hearts. We have also investigated whether negatively charged heparin changes the toxic myocardial effects of protamine. Rat hearts were perfused with a Langendorff system and loaded with Fura-2/AM, as a [Ca2+]i marker.
At 5 min after protamine (20 mg/L) exposure, initial and transient increase in myocardial oxygen consumption was observed, whereas LV dP/dt max, systolic [Ca2+]i and diastolic [Ca2+]i did not change yet. At 10 min after protamine, LV dP/dt max decreased and systolic [Ca2+]i decreased. After washout with buffer, systolic [Ca2+]i
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returned to baseline level within 2 min. However, decrease in LV dP/dt max was sustained for 10 min. The presence of heparin (2000 IU/L) prior to protamine exposure resulted in deleterious responses in LV dP/dt max. When heparin and protamine were administered simultaneously, negative inotropic effect of protamine itself was diminished. When the hearts were washed out with heparin, the amplitude of the [Ca2+]i transient recovered more rapidly, whereas no protective response in LV dP/dt max was observed.
These results suggested that protamine has a direct negative inotropic effect, which is mediated by a decrease in [Ca2+]i. Protamine also decreases myofilament Ca2+ sensitivity, which may cause sustained myocardial depression after reperfusion. The presence of heparin before protamine exposure enhances negative inotropic effect of protamine. However, heparin-protamine complex has minimum effects on myocardial function and [Ca2+]i dynamics. The presence of heparin after protamine exposure enhances the recovery of the amplitude of the [Ca2+]i transient. Less
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