Endothelin: A Potent Stimulus of Atrial Natriuretic Peptide Secretion by Superfused Rat Atria and Its Dependency on Calcium*

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Abstract
Endothelin, a hormone secreted by endothelial cells, has potent vasoconstrictive properties. Due to its potential paracrine nature, we examined the effect of endotheline-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- 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 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 nM calcium. Influx of calcium through voltage-dependent calcium channels was examined by superfusion with 50 .mu.mM nitredipine. Nitredipine 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 .mu.M ryanodine, an inhibitor of SR calcium release. Ryanodine had no effect on endothelin-stimulated NAP secretion. We conclude: 1) Enodthelin 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 on 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, enodthelin 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.