Leskinen H, Vuolteenaho O, Ruskoaho H
Department of Physiology, Biocenter Oulu, University of Oulu, Finland.
Circ Res. 1997 Jan;80(1):114-23. doi: 10.1161/01.res.80.1.114.
Volume expansion has been shown to increase plasma atrial natriuretic peptide (ANP) levels, but the precise role of paracrine and autocrine factors in stretch-induced cardiac hormone release is not clear. In the present study, we report the effects of endothelin (ET) and angiotensin receptor (AT receptor) antagonists on baseline and atrial stretch-induced immunoreactive ANP (IR-ANP) and immunoreactive N-terminal ANP (IR-NT-ANP) release in vivo by using BQ-123 (ETA receptor antagonist), bosentan (ETA and ETB receptor antagonist), and losartan (AT1 receptor antagonist). Intravenous administration of BQ-123 had no significant effect on baseline hemodynamics in conscious rats, whereas bosentan (10 mg/kg) and losartan (10 mg/kg) decreased slightly (4 to 7 mm Hg, P < .05 to .001) the mean arterial pressure. Both the ETA receptor antagonist BQ-123 and ETA/ETB receptor antagonist bosentan decreased plasma ANP and NT-ANP responses to volume load (P < .05 to .001), whereas the AT1 receptor antagonist losartan had no significant effect on this response. The relative increase in plasma IR-ANP corresponding to a 3 mm Hg increase in right atrial pressure was 2.7-fold in the vehicle-treated group. BQ-123 (0.3 and 1.0 mg/kg) decreased this response 2.5- and 2.1-fold (P < .05); bosentan (3 and 10 mg/kg), 1.7-fold (P < .001) and 1.9-fold (P < .05); and bosentan (10 mg/kg)+losartan (10 mg/kg), 1.6-fold (P < .001). The responses in plasma IR-NT-ANP decreased simultaneously. These results indicate that combined inhibition of ETA/B and AT1 receptors almost completely blocks ANP response to acute volume load. Therefore, our study shows that endogenous paracrine and/or autocrine factors liberated in response to atrial wall stretch rather than myocyte stretch itself are responsible for the activation of ANP peptide secretion in response to acute volume load. Our results also show that ETA receptors are more important in the regulation of mechanical stretch-induced changes in cardiac hormone secretion than AT1 receptors.
容量扩张已被证明可增加血浆心房利钠肽（ANP）水平，但旁分泌和自分泌因子在牵张诱导的心脏激素释放中的精确作用尚不清楚。在本研究中，我们报告了内皮素（ET）和血管紧张素受体（AT受体）拮抗剂对体内基线和心房牵张诱导的免疫反应性ANP（IR-ANP）和免疫反应性N端ANP（IR-NT-ANP）释放的影响，使用了BQ-123（ETA受体拮抗剂）、波生坦（ETA和ETB受体拮抗剂）和氯沙坦（AT1受体拮抗剂）。静脉注射BQ-123对清醒大鼠的基线血流动力学没有显著影响，而波生坦（10mg/kg）和氯沙坦（10mg/kg）使平均动脉压略有下降（4至7mmHg，P<.05至.001）。ETA受体拮抗剂BQ-123和ETA/ETB受体拮抗剂波生坦均降低了血浆ANP和NT-ANP对容量负荷的反应（P<.05至.001），而AT1受体拮抗剂氯沙坦对该反应没有显著影响。在载体处理组中，右心房压力升高3mmHg时，血浆IR-ANP的相对增加为2.7倍。BQ-123（0.3和1.0mg/kg）使该反应分别降低了2.5倍和2.1倍（P<.05）；波生坦（3和10mg/kg）分别降低了1.7倍（P<.001）和1.9倍（P<.05）；波生坦（10mg/kg）+氯沙坦（10mg/kg）降低了1.6倍（P<.001）。血浆IR-NT-ANP的反应同时降低。这些结果表明，联合抑制ETA/B和AT1受体几乎完全阻断了ANP对急性容量负荷的反应。因此，我们的研究表明，响应心房壁牵张而非心肌细胞牵张本身释放的内源性旁分泌和/或自分泌因子负责ANP肽分泌对急性容量负荷的激活。我们的结果还表明，ETA受体在调节机械牵张诱导的心脏激素分泌变化中比AT1受体更重要。
