| Co-Investigator(Kenkyū-buntansha) |
KINUGAWA Kouichirou FACULTY OF MEDICINE,UNIVERSITY OF TOKYO,FELLOW, 医学部(病), 医員
MATSUI Hiroshi FACULTY OF MEDICINE,UNIVERSITY OF TOKYO,FELLOW, 医学部(病), 医員
IKENOUCHI Hiroshi FACULTY OF MEDICINE,UNIVERSITY OF TOKYO,FELLOW, 医学部(病), 医員
KOHOMOTO Osami FACULTY OF MEDICINE,UNIVERSITY OF TOKYO,FELLOW, 医学部(病), 医員
MOMOMURA Shin-ichi FACULTY OF MEDICINE,UNIVERSITY OF TOKYO,ASSISTANT PROFESSOR OF MEDICINE, 医学部(病), 助手 (10190985)
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| Research Abstract |
An initial purpose of this project was to investigate the cellular mechanisms of diastolic dysfunction in various pathological state including demand ischemia, using video motion detector, Ca2+ sensitive fluorescence dye (indo-1) and intracellular pH indicator (BCECF). We succeeded in establishing demand ischemia model in cultured ventricular myocytes and isolated single myocytes with partial metabolic inhibition and rapid pacing (Ikenouchi et al, 1991, JCI). In this demand ischemia model, diastolic dysfunction was explained by increased end-diastolic intraccllular calcium concentration ([Ca2+]i). During this project, it has been clinically proven that ACE inhibitors improve the long-term prognosis of CHF,not only by vasodilation but also via direct cardiac effects. We, therefore, applied cellular cardiodynamics and microfluometry techniques to study the direct effects of angiotensin II (ANG II) and related peptide (vasopressin (AVP) and endothelin (ET)) on myocardium. In adult ventricular myocytes, these peptide produced a positive inotropic effect through intracellular alkalosis without increasing [Ca2+]i. Conversely, in embryonic or neonatal myocytes, these produced a negative inotropic effect via decreased [Ca2+]i transients and mild intracellular acidosis (Kohmoto et al, AJP,1993). It has been reported that ANG II does increase contractility of normal hearts but not failing human hearts. Recently, orally effective, non-peptide AT1 and V1 blockers were developed. Thus, we studied the direct effects of these drugs on cultured ventricular myocytes. Cellular effects of AVP on myocytes were completely inhibited by V1 blocker (Matsui et al, 1992, Hypertension) and also those of ANG II were by AT1 blocker (Kinugawa et al, unpublished observation).
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