Kinnunen P, Vuolteenaho O, Ruskoaho H
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Endocrinology. 1993 May;132(5):1961-70. doi: 10.1210/endo.132.5.8477647.
Ventricular hypertrophy is characterized by augmentation of the synthesis and storage of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). To evaluate in vitro the cellular mechanisms of immunoreactive ANP (IR-ANP) and BNP (IR-BNP) release from ventricular cardiocytes, we measured the secretory response to graded passive myocardial stretch in isolated atrialectomized perfused hypertrophied hearts of 14- to 18-month-old spontaneously hypertensive rats. At this age, the ventricular levels of both IR-ANP and IR-BNP were markedly higher in spontaneously hypertensive (182 +/- 27 and 32 +/- 3 pmol/ventricle, respectively) than in age-matched normotensive Wistar-Kyoto rats (35 +/- 4 and 12 +/- 1 pmol/ventricle, respectively; P < 0.001), whereas the differences between the strains in atrial levels of these peptides were small. The release of natriuretic peptides from ventricles in response to stretch was examined by increasing the volume of the intraventricular balloon for 10 min. Stretching of the hypertrophied ventricles produced a rapid transient (from 1-5 min) increase in both IR-ANP and IR-BNP secretion. As left ventricular pressure rose from 0 to 26 +/- 1 mm Hg, IR-ANP and IR-BNP release into the perfusion fluid increased 1.8 +/- 0.4- and 2.5 +/- 0.2-fold, respectively. Infusion of staurosporine, known to inhibit protein kinase-C activity in heart cells, blocked the stretch-induced increase in IR-ANP release (F = 3.10; P < 0.001, by analysis of variance), but had no effect on basal ventricular IR-ANP secretion (F = 0.87; P = NS). An L-type calcium channel antagonist, diltiazem, had no significant effect on basal (F = 1.20; P = NS) or stretch-stimulated (F = 1.47; P = NS) IR-ANP release from hypertrophied rat myocardium. Chromatographical analysis revealed that the ventricles primarily release the active processed 28- and 45- amino acid ANP- and BNP-like peptides, respectively, both before and during stretch. This study indicates that stretch stimulates both ANP and BNP secretion from hypertropic ventricular myocytes. The results further suggest that protein kinase-C may be involved in stretch-induced ventricular ANP release, whereas the influx of extracellular calcium may not be necessary.
心室肥厚的特征是心房利钠肽（ANP）和脑利钠肽（BNP）的合成与储存增加。为了在体外评估免疫反应性ANP（IR-ANP）和BNP（IR-BNP）从心室心肌细胞释放的细胞机制，我们在14至18月龄自发性高血压大鼠的离体心房切除灌注肥厚心脏中，测量了对分级被动心肌拉伸的分泌反应。在这个年龄段，自发性高血压大鼠的心室IR-ANP和IR-BNP水平（分别为182±27和32±3 pmol/心室）显著高于年龄匹配的正常血压Wistar-Kyoto大鼠（分别为35±4和12±1 pmol/心室；P<0.001），而这些肽在心房水平上的品系差异较小。通过增加心室内球囊体积10分钟来检查心室利钠肽对拉伸的释放。肥厚心室的拉伸导致IR-ANP和IR-BNP分泌迅速短暂增加（1至5分钟）。随着左心室压力从0升至26±1 mmHg，IR-ANP和IR-BNP向灌注液中的释放分别增加了1.8±0.4倍和2.5±0.2倍。已知抑制心脏细胞中蛋白激酶-C活性的星形孢菌素的输注，阻断了拉伸诱导的IR-ANP释放增加（方差分析，F=3.10；P<0.001），但对基础心室IR-ANP分泌没有影响（F=0.87；P=无显著性差异）。L型钙通道拮抗剂地尔硫䓬对肥厚大鼠心肌的基础（F=1.20；P=无显著性差异）或拉伸刺激的（F=1.47；P=无显著性差异）IR-ANP释放没有显著影响。色谱分析表明，在拉伸前和拉伸过程中，心室主要分别释放活性加工的28和45个氨基酸的ANP样和BNP样肽。本研究表明，拉伸刺激肥厚心室肌细胞释放ANP和BNP。结果进一步表明，蛋白激酶-C可能参与拉伸诱导的心室ANP释放，而细胞外钙的流入可能不是必需的。
