Ouabain caused rabbit cortical collecting tubule (CCT) principal cells to swell 67%. Swollen cells downregulated their volume at a rate of 4%/min to a new volume 16% below control. A qualitatively similar pattern of swelling and volume regulation was observed with peritubular addition of 2.0 microM prostaglandin E2 (PGE2), a putative endogenous Na+ pump inhibitor. Regulatory volume decrease (RVD) in ouabain-swollen cells was inhibited 50-70% by bilateral addition of 2.0 mM Ba2+ or 5.0 mM TEA+. Peritubular TEA+ had no effect on RVD. Luminal addition of 5.0 mM TEA+ or 0.2 mM quinidine inhibited RVD 50-60%, suggesting involvement of an apical K+ channel. This channel appeared to be distinct from the resting apical K+ conductance. Replacement of cellular K+ with Rb+, which is commonly used as a tracer of K+ secretion in the CCT, had little effect on the rate and magnitude of ouabain swelling but inhibited RVD 50-60%. A 10-fold elevation of luminal K+ before ouabain or after completion of RVD caused principal cells to swell 10% and 31%, respectively. In control cells, this K(+)-induced swelling was unaffected by the presence of 1.0 mM quinidine in the perfusate and could be mimicked by elevation of Rb+ instead of K+ concentration. The magnitude of swelling in volume-regulated principal cells, however, was reduced 50-60% by the presence of luminal quinidine or by luminal addition of Rb+ instead of K+. The putative apical RVD K+ channel may be similar to high-conductance K+ channels described in principal cell patch-clamp studies from other laboratories.