(" thiazide ") derivatives unquestionably are effective hypotensive agents, but the mechanism by which they reduce blood pressure has not been elucidated. Theories advanced to explain their hypotensive action include reduction of the volume of plasma and extracellular fluids, depletion of body sodium, other more obscure effects of diuresis, and a depressor effect unrelated to their known diuretic action.This study was undertaken in an effort to acquire more information regarding possible mechanisms by which thiazide diuretics reduce the blood pressure of hypertensive patients.Methods and Materials A group of 28 hypertensive patients was included in this study; 19 were men, and the ages of the patients ranged from 36 to 75 years. All had sustained diastolic hypertension of mild to moderate severity. Only two had the retinal findings of group 3 hypertension;' the remainder had retinal arteriolar changes of group 2. None had congestive cardiac failure or detectable edema from any cause at the time the studies were made. Blood urea measured less than 50 mg. per 100 ml. before therapy with thiazide agents was started in all patients. No restriction of dietary sodium was imposed on any of the patients during these studies, and none received supplementary potassium.The patients were chosen for this investigation on the basis of (1) their availability for repeated laboratory determinations during treatment, (2) adequate records of blood pressure before and during therapy, and (3) their expressed willingness to cooperate in this study. Twenty-one patients were residents of Rochester, Minnesota, or the immediate vicinity; of the remainder, three took their own blood pressure at home. Two patients had undergone previous sympathectomy. One or more of the following laboratory determinations were done at least once before treatment and on one or more occasions during therapy with one of the thiazide diuretics: The total plasma volume was determined by injecting intravenously 18 ml. of a sterile 1.5 per cent solution of Congo red and determining the amount of dye in the plasma 5 minutes later.* Exchangeable sodium (Nae) in the body was calculated from the specific activity of radiosodium (Na24) in the serum as measured in a standard sodium iodide (thallium-activated) well-type scintillation counter 24 hours after the injection of a known quantity of this isotope. In four instances, the exchangeable potassium (Ke) in the body was calculated from the specific activity of radiopotassium (K42) in urine as measured in a beta-sensitive, plastic, well-type scintillation counter 24 hours after the injection of a known quantity of this isotope. In one patient (case 10), Ke was calculated from the specific activity of K42 in the serum as measured in a standard scintillation counter. It is our opinion that determinations of Ke are more accurate when calculated from the specific activity of urine, but this method was not being used when the studies were made in case 10.

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A B S T R A C T After intravenous administration of radiolabeled 1,25-dihydroxyvitamnin D3 to rats, -25% of the administered radioactivity appeared in the bile within 24 h. Instillation of the biliary radioactivity into the duodena of other rats was followed by recovery of 15% of the radioactivity in newly secreted bile within 24 h. The process by which products of 1,25-dihydroxyvitamin D3 were excreted in bile was not saturable in the dose range tested (0.275-650 ng). The metabolites of 1,25-dihydroxyvitamin D3 present in bile were found to be much more polar than 1,25-dihydroxyvitamin D3 and were resolved into three fractions on high performanice liquid chromatography. 60% of the radioactivity present in bile was retained selectively by DEAE-cellulose; the radioactive material could be eluted from the gel at a low pH or at high salt concentrations. When bile containing the radiolabeled metabolites was incubated at 37°C and pH 5 with f3-glucuronidase, there was an increase in the amount of radioactivity comigrating with 1,25-dihydroxyvitamin D3. Treatment of the products of radiolabeled 1,25-dihydroxyvitamin D3 in bile with diazomethane, an agent which converts acids into methyl esters, transformed one of the metabolites into a less polar compound. These results demonstrate that there is a quantitatively important enterohepatic circulation of the products of 1,25-dihydroxyvitamin D3 in the rat.