Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle.
Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle.
复制标题
DOI：
--
复制
发表时间：
1986-03
期刊：
影响因子：
37.8
通讯作者：
M. Endoh;T. Yanagisawa;N. Taira;Blinks
中科院分区：
文献类型：
--
作者：
M. Endoh;T. Yanagisawa;N. Taira;Blinks
在37℃、0.5赫兹的电驱动下，米力农、氨力农、MDL 17,043、MDL 19,205、OPC-8212和Forsklin的正性变力作用均与组织环磷酸腺苷水平同时升高有关。给予舒马唑(AR-L 115BS)后，肌力的增加先于cAMP水平的增加。Bay k 8644增加了等长收缩的力量，但没有引起环磷酸腺苷水平的任何变化。这些药物均不影响循环GMP水平。在多个表层细胞显微注射钙敏感生物发光蛋白Aequorin的类似制剂中，也测定了细胞内钙瞬变。在米力农、氨力农、MDL 17,043、OPC-8212、Forsklin和低浓度的舒马唑(小于或等于3×10(-4)M)累积给药后，Aequorin信号的增强与作用力的增加平行。与其他药物相比，福司可林和舒马唑使钙瞬变幅度的增加更大，变力作用的幅度变化较小。高浓度(大于3×10~(-4)M)的舒马唑降低了钙瞬变的幅度，同时进一步增加了作用力。卡巴胆碱可有效拮抗除Bay k 8644和高浓度舒马唑外的所有变力药物引起的环磷酸腺苷水平、钙瞬变和肌力的增加。这些结果表明，在新型正性肌力药米力农、氨力农、MDL 17,043、MDL 19,205、OPC-8212和舒马唑(小于或等于3×10~(-4)M)的作用中，抑制cAMP磷酸二酯酶导致的cAMP积聚起重要作用。
In isolated canine ventricular trabeculae and papillary muscles driven electrically at 0.5 Hz at 37 degrees C, the positive inotropic effects of milrinone, amrinone, MDL 17,043, MDL 19,205, OPC-8212, and forskolin were all associated with simultaneous elevations in tissue cyclic AMP levels. After the administration of sulmazole (AR-L 115 BS), the increase in force preceded that of cyclic AMP levels. Bay k 8644 increased the force of isometric contractions without producing any change in cyclic AMP levels. None of these agents affected the cyclic GMP level. Intracellular calcium transients were determined in similar preparations in which multiple superficial cells had been microinjected with the Ca++-sensitive bioluminescent protein aequorin. The aequorin signals increased in parallel with increases in force in response to cumulative administration of milrinone, amrinone, MDL 17,043, OPC-8212, forskolin, and low concentrations of sulmazole (less than or equal to 3 X 10(-4) M). Forskolin and sulmazole produced larger increases in the amplitude of the calcium transients than the other agents, and their inotropic effects were less variable in magnitude. High concentrations (greater than 3 X 10(-4)M) of sulmazole decreased the amplitude of the calcium transients while increasing further the force. The increases in cyclic AMP levels, calcium transients, and force produced by all of the inotropic agents except Bay k 8644 and high concentrations of sulmazole were effectively antagonized by carbachol. These results indicate that the accumulation of cyclic AMP resulting from the inhibition of cyclic AMP phosphodiesterase plays an important role in the action of new positive inotropic agents, milrinone, amrinone, MDL 17,043, MDL 19,205, OPC-8212, and sulmazole (less than or equal to 3 X 10(-4)M), on dog ventricular muscle.