Mechanism of impaired natriuretic response to furosemide during prolonged therapy. The mechanism of the diuretic braking phenomenon was studied in nine male hypertensive patients by assessing the diurnal pattern of renal sodium (Na) excretion during furosemide therapy, and the response to a test dose of furosemide (10 to 15 mg hr-1 i.v.) infused alone and with chlorothiazide (500 mg bolus i.v.). Patients were studied after one month of twice-daily administration of: placebo(P); chlorothiazide 500 mg (C); furosemide 40 mg (F); furosemide with spironolactone (100 mg b.i.d.) for the last 36 hours (F + S; N = 6). During F therapy, furosemide-induced natriuresis was followed by six hour periods of decreased UNaV. Diuretic therapy with F or C for one month reduced BP, but did not alter body weight, plasma volume (PV), glomerular filtration rate or PAH clearance. After P, the test infusion of furosemide increased fractional Na excretion (FENa) by +10.5 % 0.7%; this increment was reduced after therapy with F (+8.9 % 0.7%; P < 0.05), C (+8.5 % 1.0%; P< 0.01), or F + S (+8.9 % 0.9%; P < 0.05). Renal furosemide excretion was greater (P < 0.05) after F and C treatments (133 % 10 µg· min-1 and 130 % 13 µg · min-1, respectively) compared with P (94 % 9 µg · min-1). After P, a test dose of chlorothiazide given during furosemide infusion increased FENa further (+7.5 % 1.2%); this increment was greater after therapy with F (+10.1 % 1.4%; P < 0.01) and F + S (+11.3 % 0.8%; P < 0.05) but not after C (+6.3 % 1.5%; P > 0.1). In conclusion, continuing Na losses during established furosemide therapy are prevented by reductions in UNaV following diuretic action, and by a reduced natriuretic response to furosemide despite its increased delivery to the tubule lumen. This reduced response was without detectable changes in PV, or renal hemodynamics, and was independent of the class of diuretic given. It was not prevented by an aldosterone antagonist, but was related to increased Na reabsorption in a thiazide-sensitive nephron segment, probably including the distal convoluted tubule.
