2007 Fiscal Year Final Research Report Summary
Investigation of vascular resistance reducing therapy for primary pulmonary hypertension: replacement of RBC with nano-order liposomal hemoglobin
| Project/Area Number |
17390230
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Okayama University |
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Principal Investigator |
MOHRI Satoshi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Assistant Professor (00294413)
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| Co-Investigator(Kenkyū-buntansha) |
KAJIYA Fumihiko Kawasaki Medical and Welfare University, Professor (70029114)
OHE Tohru Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor (70263556)
NAKAMURA Kazufumi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Research Associate (10335630)
SHIMIZU Juichiro Nara Medical University, Department of medicine, Associate Professor (80294403)
KUSANO Kengo Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Associate Professor (60314689)
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| Project Period (FY) |
2005 – 2007
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| Keywords | pulmonary hypertension / oxygen carrier / right ventricular dysfunction / vascular resistance / oxygen affinity / liposome / pulmonary vascular smooth muscle / cardiac output |
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| Research Abstract |
While many vasodilatory agents have been used for primary pulmonary hypertension (PPH) treatment, their tolerances are major limitations and the development of the novel therapy is expected for a better outcome. We investigated whether the partial replacement of red blood cells with small-size (200 nm in diameter), polyethylene glycol-modified liposomal hemoglobin (LHb) decreased pulmonary resistance by its lower viscosity and prevented right ventricular hypertrophy using rat model. PH was induced by monocrotaline injection in SD rats (6 mg/100gBW sc) . LHb suspension included approximately 6 g/dL Hb (LHb suspended in physiological saline; Terumo, Japan) and 6g/dl albumin. LHb suspension was intravenously infused with intra-arterial withdrawal of blood at a rate of 1 ml/min for 10 min, resulting in 50% blood-LHb exchange transfusion. Pulmonary arterial pressure (PAP), aortic pressure (AoP), left ventricular pressure (LVP), and cardiac output (CO) were measured to evaluate hemodynamics
… More
before and after exchange transfusion. Systemic and pulmonary resistances were calculated as mAoP/C0 and (mPAP - LVEDP)/CO respectively. CO was increased from 16±2.0 to 22±2.1 ml/min. mAoP and mPAP were unchanged (from 58±2.6 to 60±2.9 and from 49±2.3 to 50±3.2 mmHg). Systemic and pulmonary resistances were significantly decreased (from 3.6±0.5 to 2.8±0.1 and from 2.9±0.4 to 2.0±0.2 mmHg〓 min/ml). Increased LV preload i.e. LVEDP (from 3.3± 2.1 to 6.6±3.2 mmHg) preserved mAoP by an increase of CO despite a decrease of systemic resistance. LHb effectively decreased pulmonary vascular resistance without a drop of AoP by an increase of CO. Because of different mechanisms from vasodilatory agents in a decrease of vascular resistance, LHb administration can be a novel treatment for PPH. In chronic experiments, we found that LHb administration prevented right ventricular hypertrophy by preserving the activity of Na/Ca exchanger via preventing expression of protein kinese C α on plasma membrane. Less
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