Schiebinger R J, Gomez-Sanchez C E
Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201.
Endocrinology. 1990 Jul;127(1):119-25. doi: 10.1210/endo-127-1-119.
Endothelin, a hormone secreted by endothelial cells, has potent vasoconstrictive properties. Due to its potential paracrine nature, we examined the effect of endothelin-I on atrial natriuretic peptide (ANP) secretion in vitro. Isolated superfused rat left atria, paced at 2 Hz, were used for study. Endothelin (1-100 nM) increased ANP secretion in a dose-dependent manner from 1.6- to 6.7-fold above baseline. Spontaneously beating right atria increased ANP secretion by 2.3-fold in response to 10 nM endothelin without a change in beat frequency. However, the right atrial ANP secretory response was less than the 3.8-fold increase seen by left atria, and the time to peak response was slower. The calcium dependency of endothelin-stimulated ANP secretion was examined using paced left atria. The dependency of endothelin-stimulated secretion on calcium influx was examined by lowering the superfusate calcium from 1.8 to 0.2 mM. The ANP secretory response to 10 nM endothelin was reduced by 65% with 0.2 mM calcium. Influx of calcium through voltage-dependent calcium channels was examined by superfusion with 50 microM nitrendipine. Nitrendipine decreased endothelin-stimulated ANP secretion by 51% without affecting endothelin binding. The role of intracellular calcium release from the sarcoplasmic reticulum (SR) was examined by superfusion with 1 microM ryanodine, an inhibitor of SR calcium release. Ryanodine had no effect on endothelin-stimulated ANP secretion. We conclude: 1) Endothelin is a potent stimulus of ANP secretion in vitro. 2) The relative secretory response of right atria to endothelin expressed as a function of basal secretion is less and the time to peak secretion delayed relative to left atria. 3) Enhanced calcium influx, primarily through voltage-dependent calcium channels, plays a significant role in endothelin-stimulated secretion. 4) Release of intracellular calcium from the SR does not participate in the secretory response. 5) Part of the stimulatory signal appears to be independent of calcium influx or intracellular calcium release. Thus, endothelin may be an important secretagogue or modulator of ANP secretion in vivo; however, its physiological role in regulating ANP secretion in vivo remains to be determined.
内皮素是一种由内皮细胞分泌的激素，具有强大的血管收缩特性。鉴于其潜在的旁分泌性质，我们在体外研究了内皮素-1对心房利钠肽（ANP）分泌的影响。研究使用了以2赫兹频率起搏的离体灌注大鼠左心房。内皮素（1 - 100纳摩尔）使ANP分泌呈剂量依赖性增加，比基线水平高出1.6至6.7倍。自发搏动的右心房在10纳摩尔内皮素作用下，ANP分泌增加了2.3倍，而搏动频率未改变。然而，右心房的ANP分泌反应低于左心房所观察到的3.8倍增加，且达到分泌峰值的时间较慢。使用起搏的左心房研究了内皮素刺激的ANP分泌对钙的依赖性。通过将灌注液中的钙浓度从1.8毫摩尔降至0.2毫摩尔，研究了内皮素刺激的分泌对钙内流的依赖性。在0.2毫摩尔钙浓度下，对10纳摩尔内皮素的ANP分泌反应降低了65%。通过用50微摩尔尼群地平灌注来研究通过电压依赖性钙通道的钙内流。尼群地平使内皮素刺激的ANP分泌减少了51%，而不影响内皮素的结合。通过用1微摩尔ryanodine（一种肌浆网钙释放抑制剂）灌注来研究肌浆网（SR）释放细胞内钙的作用。ryanodine对内皮素刺激的ANP分泌没有影响。我们得出以下结论：1）内皮素在体外是ANP分泌的有效刺激物。2）相对于左心房，右心房对内皮素的相对分泌反应（以基础分泌为函数表示）较小，且分泌达到峰值的时间延迟。3）主要通过电压依赖性钙通道增强的钙内流在内皮素刺激的分泌中起重要作用。4）肌浆网释放细胞内钙不参与分泌反应。5）部分刺激信号似乎独立于钙内流或细胞内钙释放。因此，内皮素在体内可能是ANP分泌的重要促分泌剂或调节剂；然而，其在体内调节ANP分泌的生理作用仍有待确定。
