| Co-Investigator(Kenkyū-buntansha) |
TSUNODA Yukio Tokyo Medical and Dental University, Intensive Care Unit, Assistant Professor, 医学部, 助教授 (30092422)
NAGURA Takashi Tokyo Medical and Dental University, Intensive Care Unit, Assistant, 医学部, 助手 (80192243)
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| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1995: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥700,000 (Direct Cost: ¥700,000)
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| Research Abstract |
1.Effects of TNF-alpha on hemodynamic changes and circulating endothelium-derived vasoactive factors in dogs
After administration of TNF-alpha, mean arterial pressure and cardiac index significantly decreased, whereas systemic (SVRI) and pulmonary (PVRI) vascular resistance index increased. Plasma levels of ET-1, ET-3, NOx, and 6-keto-PGF_<1alpha> significantly (P<0.0) increased at 1 h. L-NNA or indomethacin blocked TNF-alpha induced hypotension and remarkably increased SVRI but did not affect decreased cardiac index. Our data suggest that endogenous ET-1 may partly contribute to TNF-alpha -induced increases in SVRI and PVRI,against which ET-3, NO,and prostacyclin may function as compensatory vasodilators.
2.Effects of nitric oxide synthase inhibitor on hemodynamic change and O_2 delivery in septic dogs
Infusion of LPS (250ng/kg/min) for 2 h decreased mean arterial pressure over 1-4 h. Although L-NNA (10mg/kg) blocked LPS-induced hypotension, it decreased cardiac index oxygen delivery index, arterial pH,and arterial PO_2 and increased systemic vascular resistance index in the presence or absence of LPS.Administration of D-NNA (10mg/kg) alone caused fewer hemodynamic effects (increased systemic vascular resistance index and decreased cardiac index) than L-NNA alone. Our study provides evidence that L-NNA prevents endotoxin-induced hypotension but decreases cardiac output and oxygen delivery, effects that may, in part, be due a nonspecific NO synthase-independent event. Thus clinical use of NO synthase inhibitors for the treatment of septic shock should be cautiously considered. Infusion of aminoguanidine (AG,5mg/kg/h, for 2 h), a putative inhibitor for iNOS,prevented LPS-induced hypotension and did not decrease cardiac index. Thus, AG may have some possibility for the treatment of septic shock.
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