(" 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.

Sudden injections of boluses containing both 131I-albumin and 24NaCl were made into the coronary artery inflow of isolated blood-perfused dog hearts. Indicator dilution curves were recorded using gamma emissions from both the intact heart and the coronary sinus outflow, with plasma flows, Fs, ranging from 0.3 to 1.8 ml/g min-1. Three measures of sodium extraction, E, during transcapillary passage were obtained from each site by comparison of the sodium and albumin curves. The most useful estimates of E were "instantaneous extractions" obtained from the later part of the upslope and the peak of the venous dilution curves (coronary sinus) or from the corresponding early phase of washout of the externally monitored curves (intact organ). Extractions were lower at higher flows. Permeability-surface area products, PS, were computed (1) by the formula PS equals -Fsloge(1 - E), (2) by fitting the observed dilution curves with a Krogh capillary-tissue cylinder model, and (3) by the approximating formula PS equals -Fsloge (1 - 1.14E). The two latter approaches provided a correction for back diffusion of tracer from tissue to blood. For sodium, the values of PS averaged 0.88 +/- 0.36 (SD) ml/g min-1, (n equals 52). At high flows, with Fs greater than 1.0 ml/g min-1, the values of PS averaged 1.01 +/- 0.38 ml/g min-1 (N equals 11). Assuming S equals 500 cm2/g and plasma to be 93% water, our findings suggest capillary permeabilities for sodium of about 3.1 times 10(-5) cm/sec.

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We investigated the effect of diagnostic and low-level therapeutic radiation (less than 300 rads to the bone marrow) on the development of leukemia. During this study, 138 patients with leukemia (representing all known incidence cases of leukemia in residents of Olmsted County, Minnesota, between 1955 and 1974) were each matched with two controls, and the lifelong experiences of both groups with regard to diagnostic and therapeutic radiation were ascertained. No statistically significant increase was found in the risk of developing leukemia after radiation doses of 0 to 300 rads (3 Gy) to the bone marrow when these amounts were administered in small doses over long periods of time, as in routine medical care.