We characterized altered adenosine 3',5'-cyclic monophosphate (cAMP) regulation in deoxycorticosterone acetate (DOCA)-Na hypertensive rats using endogenous cAMP accumulation in the intact cell system of microdissected renal tubule fragments. Increased cAMP accumulation in response to vasopressin (VP) in cortical collecting tubules (CCT) began on day 5 (67%) after exposure to DOCA-Na and increased by 320% on day 42. Increased blood pressure began after day 7 and polyuria after day 17. The increased response to VP was DOCA dependent and appears to be exaggerated by dietary NaCl. Anatomic and hormone specificity studies were done on days 21-30. These included cAMP responses to prostaglandin E2, parathyroid hormone, thyrocalcitonin, VP, and isoproterenol in the CCT. The cAMP response to VP was measured in the glomerulus, proximal convoluted tubule, thin descending limb of Henle, medullary thick ascending limb of Henle, cortical thick ascending limb of Henle, medullary collecting tubule, and CCT. The supersensitivity occurred only to VP and only in the CCT. Thus this alteration in the VP response is anatomic and hormone specific and does not appear to be an acute effect of DOCA, since it was not present on day 1 and on day 3 of DOCA exposure. DOCA-Na hypertension is VP dependent. A specific exaggerated cAMP response to this hormone in the CCT would be expected to cause increased sodium retention. Whether increased sodium retention at this site contributes to hypertension in the DOCA-Na rat is unknown.