Development of the modulator drug specifically targeting biomechanical reaction in the circulatory system and the application for experimental therapeutics.

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Purpose The cardiovascular response to hemodynamic/biomechanical stimuli, including pressure and flow, is a type of physical reception and a subsequent intra/inter cellular signaling in the heart and blood vessels. Pathophysiological conditions, such as vasospasm, hypertension, and myocardial hypertrophy, are also caused by the abnormal biomechanical stimuli. In order to elucidate the mechanism for mechano-transduction and to develop a new modulator of biomechanical reaction in the cardiovascular system, the following experiments were undertaken : 1) intra/intercellular signaling mechanism of arterial tissues and cells isolated from brain artery and lung in response to pressure and stretch with the special regard to protein tyrosyl phosphorylation, intracellular Ca2+ concentration, and mechanical activity. 2) Search for a new modulator of the response to hemodynamic stimuli. 3) Experimental therapeutics in the monocrotaline-induced pulmonary hypertensive rats. Results and discussions A … More s to the mechanism for mechano-transduction, the following process could be suggested : The membrane depolarization and activation of L-type Ca2+ channels through protein tyrosyl phosphorylation of the mechano-gated channel triggers the mechanical activity. Morcover, platelet-derived growth factor receptor- b chain, a receptor type of tyrosine kinase, and an intracellular messenger, such as Rho, a low molecular GTP-binding protein, are specifically involved in the signaling of mechano-transduction. Future prospect The cardiovascular response to hemodynamic stimuli touch the core of up to-date problems, including regulation of blood pressure and flow, myogenic tone, mechano-gated ion channels, shear stress and endothelial function, and pathophysiological implications of high and low shear stress and hemodynamic overload. Our present studies will surely open the way to an era for the development of new cardiovascular drugs with a novel mechanism of action, and our general principle will improve the knowledge about the cardiovascular system in health and disease. Less