Izawa T, Nomura S, Kizaki T, Oh-ishi S, Ookawara T, Ohno H
Department of Kinesiology, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Japan.
Life Sci. 2000;66(25):PL359-64. doi: 10.1016/s0024-3205(00)80012-0.
Papaverine, despite being a potent phosphodiesterase inhibitor, actually blocks adipocyte lipolysis. The present study was designed to clarify the mechanism of the inhibitory effect of papaverine on lipolysis. Lipolysis, stimulated by either 10 microM isoproterenol or 5 mM dibutyryl cAMP, was significantly inhibited by papaverine (100 microM and above). Papaverine, however, did not affect the isoproterenol-induced increase in the protein kinase A (A-kinase) activity ratio. In cell-free extract from non-stimulated adipocytes, cAMP-stimulated A-kinase activities were almost completely blocked by H-89, a potent inhibitor of A-kinase, but not by papaverine. Thus, the inhibitory effect of papaverine on lipolysis could be responsible for a deficit in step(s) distal to A-kinase activity. Hormone-sensitive lipase activities in the infranatant fraction of centrifuged homogenates of cells, which were maximally stimulated with isoproterenol were significantly reduced. This result indicates that hormone-sensitive lipase redistributes from cytosol to its substrate in lipolytically stimulated cells. Papaverine completely blocked the isoproterenol-induced decrease in lipase activity in the infranatant fraction. These results suggest that papaverine blocks lipolysis through its inhibitory effect on the redistribution of hormone-sensitive lipase.
罂粟碱尽管是一种有效的磷酸二酯酶抑制剂，但实际上会抑制脂肪细胞的脂解作用。本研究旨在阐明罂粟碱对脂解作用的抑制机制。由10微摩尔异丙肾上腺素或5毫摩尔二丁酰环磷酸腺苷刺激引起的脂解作用，被罂粟碱（100微摩尔及以上）显著抑制。然而，罂粟碱并不影响异丙肾上腺素诱导的蛋白激酶A（A激酶）活性比值的增加。在未受刺激的脂肪细胞的无细胞提取物中，环磷酸腺苷刺激的A激酶活性几乎完全被A激酶的强效抑制剂H-89阻断，但未被罂粟碱阻断。因此，罂粟碱对脂解作用的抑制可能是由于A激酶活性下游步骤的缺陷所致。用异丙肾上腺素最大程度刺激的细胞离心匀浆的上清液部分中的激素敏感性脂肪酶活性显著降低。这一结果表明，在脂解刺激的细胞中，激素敏感性脂肪酶从胞质溶胶重新分布到其底物上。罂粟碱完全阻断了异丙肾上腺素诱导的上清液部分中脂肪酶活性的降低。这些结果表明，罂粟碱通过其对激素敏感性脂肪酶重新分布的抑制作用来阻断脂解作用。
