1997 Fiscal Year Final Research Report Summary
Pathogenesis and molecular mechanisms of coronary circulatory dysfunction in congestive heart failure
| Project/Area Number |
08670805
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | KYUSHU UNIVERSITY FACULTY OF MEDICINE |
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Principal Investigator |
MOHRI Masahiro KYUSHU UNIVERSITY,FACULTY OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 助手 (60264032)
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| Co-Investigator(Kenkyū-buntansha) |
ICHIKI Toshihiro KYUSHU UNIVERSITY,FACULTY OF MEDICINE,RESEARCH FELLOW, 医学部, 非常勤研究員
OHARA Yuichi KYUSHU UNIVERSITY,FACULTY OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 助手 (90185364)
EGASHIRA Kensuke KYUSHU UNIVERSITY,FACULTY OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 講師 (60260379)
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| Project Period (FY) |
1996 – 1997
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| Keywords | congestive heart failure / coronary circulation / endothelium / nitric oxide / substance-P / bradykinin / oxygen radical |
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| Research Abstract |
The aims of the present investigations were to elucidate the pathogenesis and the mechanisms of coronary circulatory dysfunction in congestive heart failure. We have focused on endogenous vasoactive substances derived from the vascular endothelium and related substrates and drugs, and performed the following studies in an animal model of as well as in patients with congestive heart failure.
First, we have developed a conscious canine model of congestive heart failure in which ventricular tachypacing was performed for 4 to 6 weeks using a surgically implanted pacing catheter. This model is characterized by depressed systolic and diastolic ventricular function and systemic neurohumoral alterations that resembled human congestive heart failure. In this model, we found that ATP-sensitive potassium channels of the coronary circulation exerted greater contribution to myocardial perfusion in dogs with heart failure as compared with those with normal LV function. Furthermore, coronary vascular
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free radical generation was increased through an activation of coronary endothelial xanthine oxidase. The control of coronary blood flow in response to metabolic stimuli was also examined. The contribution of endothelium-derived nitric oxide (EDNO) to the metabolic coronary microvascular dilation was augmented in heart failure.
Second, the role of EDNO in regulating coronary blood flow in response to endogenous vasoactive peptides, bradykinin (BK) and substance-P (SP) was examined in awake patients. Both agonists dilated coronary arteries and arterioles via EDNO-dependent mechanism. Angiotensin-converting enzyme inhibitor (ACEI) acutely augmented dilator response of BK in patients, suggesting that ACEI may exert its beneficial effects on the clinical outcome by ameliorating myocardial perfusion. Finally, we studied the functional role of EDNO in regulating coronary blood flow in patients with heart failure by testing the effects of L-arginine analog, LNMMA given in the coronary circulation. We found that constrictor effect of LNMMA was blunted in heart failure, therefore suggesting that basal release of EDNO is decreased in the coronary circulation in patients with heart failure. Less
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