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antagonists, and nitroglycerin
Analysis of Cardiac Function During Hyperacute Rejection: Effects of PAF Antagonist, TXA2 Inhibitor/Antagonists, and Nitroglycerin T. Miyatake, S. Kubota, K. Miyazaki, S. Watanabe, N. Mafune, T. Murashita, and K. Yasuda
D
ECREASE in left ventricular end-systolic pressure (LVESP) and increase in coronary perfusion pressure (CPP) of cardiac xenografts were the main characteristics of hyperacute rejection (HAR) when we evaluated cardiac function.1 These changes were abolished by depletion of complements using cobra venom factor (CVF). Platelet aggregation and fibrin deposition within the microvasculature are the main features of HAR.2 We hypothesized that if we used platelet activating factor (PAF) antagonists, thromboxane (TX) A2 inhibitor/antagonists or nitroglycerin (NTG) to suppress the platelet aggregation or vascular contraction, the changes of LVESP and CPP during HAR would be modified and the survival time (ST) would be prolonged. MATERIALS AND METHODS A blood-perfused, isolated, supported heart model was employed for the analysis of LVESP and CPP of hartley guinea pig hearts in
wister king aptekman (WKA) rats (Fig 1). The isolated hearts were paced at 300/min with the electric stimulator. The arterial blood of rats was perfused into the guinea pig hearts at 3 mL/min continuously by a roller pump. Changes in LVESP and CPP were measured for 120 minutes. Saline (control), PAF antagonist TCV309 (5 mg/kg IV; Takeda Chemical Industries Ltd, Osaka, Japan), TXA2 synthetase inhibitor CV4151 (10 mg/kg IV; Takeda Chemical Industries Ltd), TXA2/prostaglandin H2 receptor antagonist ONO3708 (0.5 mg/kg IV; Ono Pharmaceutical Co. Ltd, Osaka, Japan), and NTG (3 g/kg/min CIV; Nippon Kayaku Co. Ltd., Tokyo, Japan) were administered to rats. From the Departments of Cardiovascular Surgery, Laboratory Medicine, and Anatomy, Hokkaido University School of Medicine, Sapporo, Japan. Address reprint requests to Dr Tsukasa Miyatake, Department of Cardiovascular Surgery, Hokkaido University Hospital, Kita14, Nishi-5, Kita-ku, Sapporo, 060-8648, Japan.
Fig 1. A blood-perfused, isolated, supported heart model. A rat supplies an isolated guinea pig heart with oxygenated blood, which flows through coronary arteries and falls back to the support rat. A balloon is inserted in the left ventricular cavity of the isolated guinea pig heart and an electrode in the right ventricle through the pulmonary artery. An air chamber is useful for not only trapping the air but also keeping constant coronary pressure. © 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 999–1000 (2000)
0041-1345/00/$–see front matter PII S0041-1345(00)01083-6 999
1000
MIYATAKE, KUBOTA, MIYAZAKI ET AL Table 1. Summary of LVESP and CPP at 10 Minutes, and ST
Group
n
LVESP at 10 Minutes (Median, mm Hg)
CPP at 10 Minutes (Median, mm Hg)
ST (Mean, min)
Control TCV309 CV4151 ONO3708 NTG
9 4 7 7 7
50 38 49 100 100 (P ⬍ .05 vs control)
93 93 75 75 43 (P ⬍ .05 vs control)
46 43 69 69 71
The ST was analyzed by log rank test; others were by Mann-Whitney test.
RESULTS
In all groups, CPP gradually increased, LVESP dropped, and finally beating stopped. Only NTG suppressed the elevation of CPP and the decrease in LVESP at 10 minutes (P ⬍ .05), although it did not prolong ST statistically (Table 1). COMMENTS
The results suggest that only limited effects of anticoagulants or dilators alone on HAR can be expected, because even CPP, which is more direct index of those agents than
ST, was not modified by them largely. The efficiency of the vasodilator or antispastic agent, NTG, on CPP and LVESP indicates that the initial phase of decrease in LVESP during HAR is caused by the failure of coronary circulation, which is shown as the elevation of CPP.
REFERENCES 1. Miyatake T, Hokkaido J: Med Sci 69:35, 1994 2. Bach FH, Robson SC, Ferran C, et al: Immunol Rev 141:5, 1994
D
ECREASE in left ventricular end-systolic pressure (LVESP) and increase in coronary perfusion pressure (CPP) of cardiac xenografts were the main characteristics of hyperacute rejection (HAR) when we evaluated cardiac function.1 These changes were abolished by depletion of complements using cobra venom factor (CVF). Platelet aggregation and fibrin deposition within the microvasculature are the main features of HAR.2 We hypothesized that if we used platelet activating factor (PAF) antagonists, thromboxane (TX) A2 inhibitor/antagonists or nitroglycerin (NTG) to suppress the platelet aggregation or vascular contraction, the changes of LVESP and CPP during HAR would be modified and the survival time (ST) would be prolonged. MATERIALS AND METHODS A blood-perfused, isolated, supported heart model was employed for the analysis of LVESP and CPP of hartley guinea pig hearts in
wister king aptekman (WKA) rats (Fig 1). The isolated hearts were paced at 300/min with the electric stimulator. The arterial blood of rats was perfused into the guinea pig hearts at 3 mL/min continuously by a roller pump. Changes in LVESP and CPP were measured for 120 minutes. Saline (control), PAF antagonist TCV309 (5 mg/kg IV; Takeda Chemical Industries Ltd, Osaka, Japan), TXA2 synthetase inhibitor CV4151 (10 mg/kg IV; Takeda Chemical Industries Ltd), TXA2/prostaglandin H2 receptor antagonist ONO3708 (0.5 mg/kg IV; Ono Pharmaceutical Co. Ltd, Osaka, Japan), and NTG (3 g/kg/min CIV; Nippon Kayaku Co. Ltd., Tokyo, Japan) were administered to rats. From the Departments of Cardiovascular Surgery, Laboratory Medicine, and Anatomy, Hokkaido University School of Medicine, Sapporo, Japan. Address reprint requests to Dr Tsukasa Miyatake, Department of Cardiovascular Surgery, Hokkaido University Hospital, Kita14, Nishi-5, Kita-ku, Sapporo, 060-8648, Japan.
Fig 1. A blood-perfused, isolated, supported heart model. A rat supplies an isolated guinea pig heart with oxygenated blood, which flows through coronary arteries and falls back to the support rat. A balloon is inserted in the left ventricular cavity of the isolated guinea pig heart and an electrode in the right ventricle through the pulmonary artery. An air chamber is useful for not only trapping the air but also keeping constant coronary pressure. © 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 999–1000 (2000)
0041-1345/00/$–see front matter PII S0041-1345(00)01083-6 999
1000
MIYATAKE, KUBOTA, MIYAZAKI ET AL Table 1. Summary of LVESP and CPP at 10 Minutes, and ST
Group
n
LVESP at 10 Minutes (Median, mm Hg)
CPP at 10 Minutes (Median, mm Hg)
ST (Mean, min)
Control TCV309 CV4151 ONO3708 NTG
9 4 7 7 7
50 38 49 100 100 (P ⬍ .05 vs control)
93 93 75 75 43 (P ⬍ .05 vs control)
46 43 69 69 71
The ST was analyzed by log rank test; others were by Mann-Whitney test.
RESULTS
In all groups, CPP gradually increased, LVESP dropped, and finally beating stopped. Only NTG suppressed the elevation of CPP and the decrease in LVESP at 10 minutes (P ⬍ .05), although it did not prolong ST statistically (Table 1). COMMENTS
The results suggest that only limited effects of anticoagulants or dilators alone on HAR can be expected, because even CPP, which is more direct index of those agents than
ST, was not modified by them largely. The efficiency of the vasodilator or antispastic agent, NTG, on CPP and LVESP indicates that the initial phase of decrease in LVESP during HAR is caused by the failure of coronary circulation, which is shown as the elevation of CPP.
REFERENCES 1. Miyatake T, Hokkaido J: Med Sci 69:35, 1994 2. Bach FH, Robson SC, Ferran C, et al: Immunol Rev 141:5, 1994