MECHANISMS OF ATRIAL AND BRAIN NATRIURETIC PEPTIDE RELEASE FROM RAT VENTRICULAR MYOCARDIUM - EFFECT OF STRETCHING

Ventricular hypertrophy is characterized by augmentation of the synthe sis and storage of atrial natriuretic peptide (ANP) and brain natriure tic peptide (BNP). To evaluate in vitro the cellular mechanisms of imm unoreactive ANP (IR-ANP) and BNP (IR-BNP) release from ventricular car diocytes, we measured the secretory response to graded passive myocard ial stretch in isolated atrialectomized perfused hypertrophied hearts of 14- to 18-month-old spontaneously hypertensive rats. At this age, t he ventricular levels of both IR-ANP and IR-BNP were markedly higher i n 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 th e differences between the strains in atrial levels of these peptides w ere small. The release of natriuretic peptides from ventricles in resp onse to stretch was examined by increasing the volume of the intravent ricular 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 staurospo rine, known to inhibit protein kinase-C activity in heart cells, block ed 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 hypertrophie d rat myocardium. Chromatographical analysis revealed that the ventric les 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 secretio n from hypertropic ventricular myocytes. The results further suggest t hat protein kinase-C may be involved in stretch-induced ventricular AN P release, whereas the influx of extracellular calcium may not be nece ssary.