Scholz J, Schaefer B, Schmitz W, Scholz H, Steinfath M, Lohse M, Schwabe U, Puurunen J
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, FRG.
J Pharmacol Exp Ther. 1988 Apr;245(1):327-35.
The positive inotropic effect of the alpha-1 adrenoceptor agonist phenylephrine was accompanied by a concentration-dependent increase in inositol trisphosphate (IP3) in electrically driven left auricles isolated from rat hearts. Further analysis of the myocardial phosphoinositide pathway revealed an additional increase in inositol phosphate and inositol bisphosphate with a concomitant decrease in phosphatidylinositol phosphate and phosphatidylinositol bisphosphate. The decrease in phosphatidylinositol bisphosphate and increase in IP3 preceded the increase in force of contraction. All effects were antagonized by the alpha-1 adrenoceptor antagonist prazosin. For comparison the effects of the beta adrenoceptor agonist isoprenaline were studied. Isoprenaline produced a positive inotropic effect similar to that of phenylephrine but all phosphoinositide products remained unaffected. The influence of lithium and calcium ions were studied systematically. The stimulatory effect of phenylephrine on inositol phosphates was lithium-dependent. Without lithium phenylephrine did not detectably affect the phosphoinositide turnover. Phenylephrine caused a maximal increase in inositol phosphate, inositol bisphospate and IP3 at 10 mmol/l of lithium. Lithium itself had a concentration-dependent positive inotropic effect. However, lithium did not enhance the positive inotropic effect of phenylephrine. Variation of the extracellular concentration of calcium did not influence the stimulatory effect of phenylephrine on inositol phosphates indicating that inositol phosphate turnover does not require the presence of extracellular calcium. It is concluded that the stimulation of myocardial phosphoinositide breakdown generating an increased IP3 turnover may be involved in the mechanism(s) whereby alpha-1 adrenoceptor stimulation exerts an increase in myocardial force of contraction.
α1肾上腺素能受体激动剂去氧肾上腺素的正性肌力作用伴随着从大鼠心脏分离的电驱动左心房中肌醇三磷酸（IP3）浓度依赖性增加。对心肌磷酸肌醇途径的进一步分析显示，肌醇磷酸和肌醇二磷酸进一步增加，同时磷脂酰肌醇磷酸和磷脂酰肌醇二磷酸减少。磷脂酰肌醇二磷酸的减少和IP3的增加先于收缩力的增加。所有这些效应均被α1肾上腺素能受体拮抗剂哌唑嗪拮抗。作为对照，研究了β肾上腺素能受体激动剂异丙肾上腺素的作用。异丙肾上腺素产生了与去氧肾上腺素相似的正性肌力作用，但所有磷酸肌醇产物均未受影响。系统研究了锂离子和钙离子的影响。去氧肾上腺素对肌醇磷酸的刺激作用依赖于锂。没有锂时，去氧肾上腺素对磷酸肌醇代谢没有明显影响。在10 mmol/L的锂浓度下，去氧肾上腺素使肌醇磷酸、肌醇二磷酸和IP3产生最大增加。锂本身具有浓度依赖性的正性肌力作用。然而，锂并没有增强去氧肾上腺素的正性肌力作用。细胞外钙浓度的变化不影响去氧肾上腺素对肌醇磷酸的刺激作用，表明肌醇磷酸代谢不需要细胞外钙的存在。结论是，心肌磷酸肌醇分解的刺激导致IP3代谢增加可能参与了α1肾上腺素能受体刺激使心肌收缩力增加的机制。
