Yew S F, Reeves K A, Woodward B
Department of Pharmacy and Pharmacology, University of Bath, UK.
Cardiovasc Res. 1998 Dec;40(3):538-45. doi: 10.1016/s0008-6363(98)00195-3.
We have studied the mechanisms underlying the positive inotropic action of prostaglandin F2 alpha (PGF2 alpha) by monitoring intracellular calcium transients, intracellular pH, L-type calcium currents and cell shortening in isolated ventricular myocytes.
Rat myocytes were loaded with fura-2AM for intracellular calcium measurements, or BCECF-AM for pH measurements. Cell shortening was recorded using an edge detection system, and L-type calcium currents measured using whole cell patch clamping.
PGF2 alpha (3 nmol l-1-3 mumol l-1 increased single myocyte shortening and reduced resting cell length in a concentration-dependent manner. While myocyte shortening was increased by PGF2 alpha, this was not associated with any change in the amplitude of intracellular calcium transients, diastolic calcium, or L-type calcium currents. However, the same myocytes were capable of responding to catecholamines with increases in calcium transient amplitude and L-type calcium currents. PGF2 alpha (3 mumol l-1 caused a reversible rise in intracellular pH of 0.08 +/- 0.01 pH units (n = 5, p < 0.05). The Na(+)-H+ exchanger inhibitor, HOE 694 (10 mumol l-1, abolished the PGF2 alpha-induced rise in pH and the increase in cell shortening. PGF2 alpha-induced increases in cell shortening and intracellular pH were also attenuated by the protein kinase C (PKC) inhibitor, chelerythrine (2 mumol l-1.
The positive inotropic action of PGF2 alpha appears to be mediated via activation of the Na(+)-H+ exchanger with the possible involvement of PKC. This suggests that PGF2 alpha-produces intracellular alkalosis, which then sensitizes cardiac myofilaments to calcium.
我们通过监测分离的心室肌细胞内的钙瞬变、细胞内pH值、L型钙电流和细胞缩短情况，研究了前列腺素F2α（PGF2α）正性肌力作用的潜在机制。
用fura-2AM加载大鼠心肌细胞用于测量细胞内钙，或用BCECF-AM加载用于测量pH值。使用边缘检测系统记录细胞缩短情况，并用全细胞膜片钳测量L型钙电流。
PGF2α（3 nmol l-1 - 3 μmol l-1）以浓度依赖的方式增加单个心肌细胞的缩短并减少静息细胞长度。虽然PGF2α增加了心肌细胞的缩短，但这与细胞内钙瞬变幅度、舒张期钙或L型钙电流的任何变化无关。然而，相同的心肌细胞能够对儿茶酚胺产生反应，使钙瞬变幅度和L型钙电流增加。PGF2α（3 μmol l-1）使细胞内pH值可逆性升高0.08±0.01个pH单位（n = 5，p < 0.05）。Na(+)-H+交换体抑制剂HOE 694（10 μmol l-1）消除了PGF2α诱导的pH值升高和细胞缩短增加。PGF2α诱导的细胞缩短和细胞内pH值增加也被蛋白激酶C（PKC）抑制剂白屈菜红碱（2 μmol l-1）减弱。
PGF2α的正性肌力作用似乎是通过激活Na(+)-H+交换体介导的，可能涉及PKC。这表明PGF2α产生细胞内碱中毒，进而使心肌肌丝对钙敏感。
