Studies performed in several animal species have demonstrated that glomerulotubular balance is maintained throughout development despite the many changes that occur in the factors known to control it. In an attempt to understand the nature of this phenomenon we quantified the magnitude and described the profile of these changes in guinea pigs. The changes in physical forces were assessed from measurements of hydrostatic and oncotic pressures, whereas those in the permeability characteristics of the proximal tubule epithelium were estimated from permeance to macromolecules of graded radii, histologic measurements of the intercellular channels, and measurements of end-proximal ratio of tubular fluid-to-plasma osmolality (TF/Posm). Between 1 and 50 days of age the net pressure for reabsorption increased from 15.0 to 30.9 mmHg (P less than 0.01, n = 15) with the major change occurring during the first 2-3 wk of postnatal life. The urinary recovery of inulin, sucrose, and creatinine, injected in the early segment of proximal tubules did not vary with age. The urinary recovery of mannitol (MW 180 daltons, Stokes-Einstein radius 4.0 X 10(-10) m) increased from 92% at birth to 100% at 49 days of age (P less than 0.001, n = 24), consistent with a decrease of approximately 0.5 X 10(-10) m in the luminal openings of the paracellular channels. The length of the zonulae occludens and the width of the intercellular channels did not change during this period; however, the length of the channels increased from 5.0 +/- 0.17 to 8.9 +/- 0.48 micron (P less than 0.01, n = 16). These changes should result in an increase in resistance across the intercellular channels. Consistent with this assertion is the observation that the mean TF/Posm of the fluid collected toward the end of the proximal convoluted tubule decreased as a function of age from 1.05 at day 2 to 0.98 at day 80 (P less than 0.001, n = 24). The findings support the hypothesis that during early postnatal life glomerulotubular balance is made possible by a high permeability of the proximal tubule, which compensates for the low net reabsorptive pressure. As the animal matures and the proximal tubule epithelium becomes tighter, for glomerulotubular balance to be maintained, an increase in the number of intercellular channels and in the active transport of sodium need to be postulated.