Short-circuit current (SCC) techniques were used to monitor the effects of various diuretic agents on Na+ transport in isolated frog skin, a model for the late distal tubule and the collecting duct of the mammalian kidney. Acetazolamide, hydrochlorothiazide, torasemide, and ethacrynic acid did not affect sodium transport (as indicated by the SCC) or transepithelial electrical resistance when added either to the apical (outer) or to the inner (basolateral, corial) bathing solution of the tissue. However, Na+ transport was sensitive to amiloride, the triamterene derivate dimethylamino-hydroxypropoxytriamterene (RPH 2823), and to furosemide. Whereas apical amiloride, and RPH 2823 induced a dose-dependent decrease in SCC and increase in transepithelial electrical resistance, apical furosemide resulted in a dose-dependent increase in SCC and a decrease in electrical resistance. None of the three diuretic agents caused a significant change in SCC when applied to the inner bathing Ringer's solution. The small furosemide-induced decrease in resistance compared with the huge increase in SCC suggests that furosemide affects Cl- permeability as well as Na+ permeability. Evidence for this notion was achieved by the following findings: The decrease in resistance after furosemide was more pronounced in tissues bathed in Cl(-)-free solutions compared with Cl(-)-containing solutions. n contrast, SCC stimulation by apical furosemide is Cl(-)-ion independent, but strongly Na+-ion dependent. SCC stimulation by furosemide is amiloride-sensitive. With respect to the onset, locus, and reversibility of action, it seems reasonable to assume that amiloride, RPH 2823, and furosemide all influence transepithelial Na+ transport by interacting with the Na+ channel or a regulator site of it within the apical membrane. The stoichiometry of the amiloride (RPH 2823)-receptor site interaction revealed Hill-coefficient(s) of less than 1, indicating a negative cooperativity among the receptor sites. The interaction between Na+ ions and amiloride or RPH 2823 displayed mixed competitive-noncompetitive inhibition. Taken together, these results support the hypothesis that amiloride and Na+ as well as RPH 2823 and Na+ may act at different loci on the apical entry mechanism in Rana esculenta skin.

01 Jan 1985·Arzneimittel-Forschung

Pharmacodynamics and pharmacokinetics of the basic triamterene analogue dimethylaminohydroxypropoxytriamterene.

Article

Author: Mutschler, E ; Kraft, H ; Priewer, H

The diuretic, natriuretic and potassium retaining effects of dimethylaminohydroxypropoxytriamterene (RPH 2823), a basic triamterene derivative, were studied in male Wistar rats. Compared to triamterene (TA) RPH 2823 has a pronounced effect on urine volume and on the excretion of sodium; in addition it possesses a higher antikaliuretic potency than TA. In combination with furosemide, 2.5 mumol/kg RPH 2823 can avoid the kaliuresis of 25 mumol/kg furosemide. The pharmacokinetics of RPH 2823 after i.v. application of 1 mg/kg and 5 mg/kg were studied in female rats. The substance is not metabolized. RPH 2823 has a terminal elimination half-life of 3 h. About 47% of the given dose are excreted unchanged with urine. Furthermore, the volume of distribution VD beta and the total body clearance were calculated.

01 Jan 1985·Pharmaceutical ResearchQ3 · MEDICINE

Evidence for an acute antimagnesiuretic effect of triamterene derivatives.

Q3 · MEDICINE

Article

Author: Priewer, Helmut ; Mutschler, Ernst ; Kraft, Helga

The acute natriuretic, antikaliuretic and antimagnesiuretic effects of two triamterene derivatives, carboxybutoxytriamterene ethyl amide and dimethylaminohydroxypropoxytriamterene (RPH 2823), are shown in male Wistar rats during urine collection periods of 1 to 2.5 h. In combination with furosemide both compounds reduce the potassium excretion that is caused by the loop diuretic. Furthermore, RPH 2823 strongly decreases the magnesiuresis after application of furosemide, and the ethyl amide derivative (25 µmol/kg) reduces the magnesium losses produced by 25 µmol/kg furosemide close to control values. The evaluation of dose-response curves gave further evidence for the hypothesis that the renal handling of K(-) and Mg(2-) is coupled to some extent.

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Indication	Highest Phase	Country/Location	Organization	Date
Kidney Diseases	Discovery	US	Rohm & Haas Co.	-

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