| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
The myocardium has a local kallikrein-kinin system including bradykinin(BK)-B_2 receptors, and the level of BK is further increased by angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE-inhibitor may provide cardioprotection by inhibiting the degradation of BK and/or by potentiating the pharmacological actions of BK. However, direct effect of BK on myocardial cells is as yet equivocal. As a pilot study, we have investigated the direct actions of BK (10^<-7>〜10^<-5> M) on action potentials, whole-eell membrane currents, and contraction in cardiac muscles and enzymatically-isolated single cells of guinea-pig atria and ventricle, using conventional microelectrode technique, patch clamp method and strain gauge.
BK was, under physiologically-normal condition, shown to produce minimal or no changes in action potentials and membrane currents of guinea-pig ventricular myocytes. However, BK markedly shortened action potential duration prolonged by pretreatment with forskol in in
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both atrial and ventricular myocytes. These effects of BK were more pronounced in atrial myocytes as compared with ventricular ones, suggesting that atrial cell has higher density of BK-B_2 receptor than ventricular cell.
It is assumed that BK exerts its more potent inhibitory action when the protein kinase A )PKA) is fully activated by an application of forskolin or β-receptor stimulation, but BK may have little or no effect under condition without PKA activation )"accentuated antagonism"). The mode of action of BK appears to be quite similar to that of acetylcholine. It is quite plausible that BK may reduce L-type Ca current )ICa) in cells where it has already been raised by forskoline or β-stimulants, though it does not affect the basal level of ICa in unstimulated cells. On the other hand, in regard to the effect of BK on the contraction in ventricular papillary muscle, we could not obtain the specified effects of BK in our experiments. Individual inotropic responses to BK application were quite variable, and BK showed dual action from time to time. At present, we have no explanation of the findings.
Further studies into these problems are needed because the possible mechanisms underlying various BK's actions remain to be determined. Less
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