Murray J J, Reed P W, Dobson J G
Am J Physiol. 1985 Dec;249(6 Pt 2):H1204-10. doi: 10.1152/ajpheart.1985.249.6.H1204.
We have reported that the divalent cation ionophore A23187, like the beta-adrenergic agonist isoproterenol, increased the force of contraction and rate of relaxation and shortened the duration of contraction of papillary muscles isolated from guinea pigs. A23187 produced a fall in resting tension and decreased the contracture tension of K +/- depolarized muscles, as did isoproterenol. In the present studies, isoproterenol produced a concentration-dependent, rapid, and sustained increase in the cyclic AMP (cAMP) content of papillary muscle. In contrast, A23187 had no detectable effect on cAMP levels, even in the presence of the phosphodiesterase inhibitor, papaverine. Neither drug, at concentrations maximal for contractile effects, altered cyclic GMP (cGMP). Isoproterenol increased the cAMP-dependent protein kinase activity ratio, whereas A23187 did not change the activity of this enzyme. However, both A23187 and isoproterenol produced a concentration-dependent increase in phosphorylase activity. Concentrations of A23187 or isoproterenol that enhanced contractility maximally increased the alkali-labile phosphate (by ca. 35%) but were without effect on the acid-labile, alkali-stable phosphate in the total acid precipitable protein. Contractile effects of isoproterenol, which reflect activated Ca2+ uptake, and the increase in phosphorylase activity produced by this agent are believed to be due to an increase in cAMP with subsequent activation of cAMP-dependent protein kinases and phosphorylation of proteins. A23187 may produce similar contractile effects without an increase in cAMP or cAMP-dependent protein kinase activity by activating other protein kinases and/or inhibiting phosphoprotein phosphatases, most likely by its effects on intracellular calcium.
我们曾报道，二价阳离子载体A23187与β-肾上腺素能激动剂异丙肾上腺素一样，可增强豚鼠离体乳头肌的收缩力和舒张速率，并缩短收缩持续时间。A23187可使静息张力降低，也能降低K⁺/⁻去极化肌肉的挛缩张力，异丙肾上腺素也有此作用。在本研究中，异丙肾上腺素可使乳头肌中环状AMP（cAMP）含量呈浓度依赖性、快速且持续地增加。相比之下，即使存在磷酸二酯酶抑制剂罂粟碱，A23187对cAMP水平也无明显影响。两种药物在产生最大收缩效应的浓度下，均未改变环状GMP（cGMP）。异丙肾上腺素可提高cAMP依赖性蛋白激酶活性比值，而A23187并未改变该酶的活性。然而，A23187和异丙肾上腺素均可使磷酸化酶活性呈浓度依赖性增加。能最大程度增强收缩力的A23187或异丙肾上腺素浓度可使碱不稳定磷酸盐（约增加35%）增加，但对总酸沉淀蛋白中的酸不稳定、碱稳定磷酸盐无影响。异丙肾上腺素的收缩效应反映了Ca²⁺摄取的激活，该药物引起的磷酸化酶活性增加被认为是由于cAMP增加，随后激活了cAMP依赖性蛋白激酶并使蛋白质磷酸化。A23187可能通过激活其他蛋白激酶和/或抑制磷蛋白磷酸酶，最有可能是通过其对细胞内钙的作用，产生类似的收缩效应，而不增加cAMP或cAMP依赖性蛋白激酶活性。
