MATURATION OF A71915-DEPENDENT INHIBITION OF ATRIAL NATRIURETIC PEPTIDE-STIMULATED CYCLIC-GMP PRODUCTION IN ISOLATED RAT GLOMERULI

Atrial natriuretic peptide (ANP) regulates glomerular hemodynamics by interaction with biologic receptors (GC-A/ANP) that possess particulat e guanylyl cyclase activity. In a previous study we have shown a devel opmental difference in glomerular response to ANP where preweaned glom eruli produced significantly less extracellular cGMP in response to AN P. Because of the possibility that functional differences in the ANP b iologic receptor might exist during development, further characterizat ion of GC-A/ANP receptor response in glomeruli of developing rats was done using a structural analogue of ANP. A71915 (Abbott Laboratories) is a structural analogue of ANP which has been shown to inhibit activa tion of ANP receptor-associated guanylyl cyclase in vascular smooth mu scle cells. The purpose of this study was to investigate the ability o f A71915 to inhibit ANP-stimulated cGMP response in isolated glomeruli of adult and pre weaned rats. Isolated glomeruli from preweaned or ad ult rat kidneys were preincubated for 15 min with A71915 (10(-5) M) pr ior to addition of ANP (up to 10(-6) M). Glomerular response of produc tion of intracellular and extracellular cGMP was measured by radioimmu noassay. Adult glomeruli produced significantly greater amounts of ext racellular cGMP compared to preweaned glomeruli for concentrations of ANP greater than or equal to 10(-9) M. Infant glomeruli had a signific ant decrease in the production of ANP-stimulated intracellular cGMP in the presence of A71915 (10(-5) M), whereas extracellular cGMP product ion was unchanged. In contrast both ANP-stimulated intracellular and e xtracellular cGMP were significantly decreased by A71915 in adult glom eruli. These results demonstrate the maturation of the glomerular resp onse to ANP. The lack of effect of A71915 on extracellular release of cGMP by glomeruli from preweaned rats is likely due to immaturity of t he cGMP extrusion mechanism rather than a reduced GC-A/ANP receptor re sponse or signal transduction.