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The role of tubular accumulation in renal disposition and diuretic efficacy of hydrochlorothiazide was studied in the isolated perfused rat kidney. Hydrochlorothiazide resulted in a dose-dependent increase in the fractional excretion of sodium, chloride and potassium, and in urinary flow and pH. Renal clearance of the drug was low as a result of a low extraction ratio and extensive nonionic back-diffusion. Hydrochlorothiazide was subject to saturable tubular secretion, following Michaelis-Menten kinetics. Parameters obtained after nonlinear regression analysis were a maximum tubular transport velocity of 42 +/- 6 micrograms/min, a Michaelis-Menten constant of secretion of 38 +/- 11 micrograms/ml and a fraction of excreted drug reabsorbed passively of 0.49 +/- 0.03. The thiazide diuretic accumulated extensively in kidney tissue due to active cellular uptake (maximum capacity of renal accumulation of 500 +/- 270 micrograms/g; affinity constant of renal accumulation of 28 +/- 16 micrograms/ml) and passive diffusion. Plots were constructed of the sodium excretion rate versus hydrochlorothiazide perfusate concentration or the renal excretion rate. The perfusate plot could be described by the sigmoid Emax model, while a simplification of the model had to be used for the response curve in urine because a maximum effect was not observed. The apparent maximum effect resulting from the perfusate concentration-response curve and the discrepancy with the renal excretion rate-response curve indicates that the diuretic effect of hydrochlorothiazide is restricted by saturable accumulation and secretion.

1. The renal handling and effects of S(+)- and R(-)-ibuprofen have been studied in the isolated perfused kidney (IPK) of the rat. 2. Both ibuprofen enantiomers were extensively reabsorbed and accumulated in the kidney in a concentration-dependent manner. No pharmacokinetic differences were observed between the two enantiomers. 3. S(+)-ibuprofen concentrations ranging from 0.25 to 25 micrograms ml-1 (1.2 to 120 microM) caused a decrease in urinary flow, glomerular filtration rate (GFR) and electrolyte excretion. Urinary pH and excretion of glucose were not influenced. R(-)-ibuprofen concentrations ranging from 2.5 to 25 micrograms ml-1 (12 to 120 microM) also decreased urinary flow and electrolyte excretion. This decrease, however, was less than observed with S(+)-ibuprofen. GFR, urinary pH and glucose excretion were not affected by R(-)-ibuprofen. Prostaglandin E2 (PGE2) concentrations of 133 ng ml-1 reversed the effects on renal function of both enantiomers. 4. Very high S(+)- and R(-)-ibuprofen concentrations (greater than 400 micrograms ml-1) resulted in an increase in urinary flow and fractional excretion of sodium, chloride, potassium, glucose and calcium. 5. It is concluded that the pharmacokinetic behaviour of ibuprofen in the kidney is not stereoselective. Relatively high concentrations of both enantiomers increased the urinary flow and electrolyte excretion in a nonstereoselective manner. Lower concentrations of S(+)-ibuprofen decreased urinary flow and electrolyte excretion. The pharmacologically inactive R(-)-ibuprofen was also able to affect renal function in a similar way, but at different concentrations. These effects on renal function are probably caused by inhibition of PGE2 synthesis.

Acute effects of potassium and calcium on renal lithium and magnesium handling were studied in the isolated rat kidney. Fractional and absolute lithium as well as magnesium transport varied with extracellular potassium in the range of 3.0-6.0 mM. The changes in lithium reabsorption, induced by extracellular potassium are linearly related to the variations simultaneously observed in magnesium reabsorption. Independently of extracellular potassium, lithium reabsorption was stimulated by low calcium comparable to magnesium reabsorption. Bumetanide (3.10(-6) M) lowered lithium and magnesium reabsorption. The results favor the concept that lithium can also be reabsorbed in the thick ascending limb of Henle by as much as 17% of the filtered load, under the conditions of the present experiments.

Isolated kidneys of normotensive Wistar rats (NWR) and of genetically hypertensive Kyoto rats (SHR) were perfused. Contraction of intrarenal vascular smooth muscle cells were induced by barium ions (0.1 to 1.0 mmol) as well as by high potassium concentrations (40 mmol). It was shown that barium stimulates intracellular calcium stores to release activator calcium. Repeated stimulation with barium under calcium-free perfusion conditions resulted in depletion of these stores. In kidneys of SHR rats the tension development in response to barium was stronger as compared with NWR rats and the time needed to deplete the stores was prolonged. This suggests that smooth muscle cells of SHR rats contain more sequestered calcium. Diazoxide inhibited the barium contracture rapidly, reversibly and dose dependently. The inhibition was non-competitive. Percentual inhibition was equal in NWR and in SHR rat kidneys. Moreover, diazoxide did not block the calcium influx across the sarcolemma membrane. The magnitude of the potassium contractures depended entirely upon the extracellular calcium concentration. In the range of 0.1 to 1.0 mmol calcium, tension development varied linearly with log calcium concentration. Diazoxide also inhibited the potassium contractures, provided normally filled calcium stores were available. The combined results strongly suggest that diazoxide prevents intracellular calcium stores to release calcium and, furthermore, that this action is the basic mechanism of the vasodilating activity of diazoxide in smooth muscle cells of rat intrarenal vessels.

Pepsinogen A (PGA) and pepsinogen C (PGC) are low-molecular-weight proteins synthesized by the gastric mucosa. Data in man suggest that both pepsinogens are almost freely filtered through the glomerular basement membrane despite a molecular weight of about 43,000 dalton and a strongly negative charge. This promoted us to investigate the glomerular sieving of PGA and PGC in the isolated rat kidney model by measuring their fractional excretions before and after inhibition of tubular function with sodium iodoacetate. During the control episode fractional excretion of PGA was 40 +/- 0.04% and of PGC 42 +/- 0.04% (mean +/- SEM from 9 experiments). After complete inhibition of tubular function a large increase in fractional excretion was found for both pepsinogens: 87 +/- 0.04% for PGA and 95 +/- 0.09% for PGC. It is concluded that tubular secretion does not contribute to the high fractional excretion of pepsinogens and that both PGA and PGC are almost freely filtered through the glomerular basement membrane.