Recent studies of cGMP metabolism in renal cortex and medulla have demonstrated important influences of extracellular Ca2 ion and Na ion and of O2 on this parameter. Studies with various agonists imply the existence of at least two distinct pathways for control of cGMP in kidney: one dependent upon the presence of extracellular Ca2 ion, Na ion and O2 availability and one relatively unaffected by these factors. Alterations in extracellular Ca2 ion or Na ion or in O2 availability also result in marked changes in basal cGMP levels, but the effects of these factors and the interrelationships between them differ in cortex versus inner medulla. Initial observations indicate that the extracellular cations Ca2 ion and Na ion may serve as key signals for modulation of cellular cGMP in kidney through actions dependent on the presence of O2. It is possible that cellular cGMP in turn influences the transport of Ca2 ion and Na ion in kidney. The objectives of the present study are: (a) to define the renal cortical site(s) of action of various agonists of cGMP by examining their effects in preparation of isolated glomeruli and tubule cells from rat renal cortex; (b) to define further those factors, including Ca2 ion, Na ion, O2 and hormonal agents which influence cGMP metabolism in cortical slices, isolated glomeruli or cortical tubule cells and to delineate the interrelationships between these control factors; (c) to assess the influence of cGMP on Ca2 ion and Na ion flux in renal cortical slices and isolated cortical tubule cells; (d) to assess the apparent unique and integrated impact of osomolality and O2 availability in the regulation of cGMP and cAMP metabolism and of soluble cAMP-dependent protein kinase activity in renal inner medulla and the role of these factors in expression of hormonal control of cyclic nucleotide metabolism in slices of this tissue. The proposed investigation should further our understanding of the regulation of cGMP metabolism in renal tissues and its influence on renal Ca2 ion and Na ion transport. It should also provide further insight into control of cGMP and cAMP metabolism in inner medulla under the unique conditions (low O2 tension, high osmolality) which pertain in this tissue in vivo.