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The present study originates in two experimental data: circadian variations evidence of water, electrolytes and solutes urinary excretion and theophylline diuretic and salidiuretic effects knowledge; we purpose to evidence theophylline-induced water and sodium renal excretion in rats as modified by the time of drug administration. Theophylline single dose is injected in 100 animals (20 lots of 5 rats) at 8 h, 14 h, 20 h or 2 h and urines are collected during a consecutive to injection hours long period: 8 h-14 h (I), 14 h-20 h (II), 20 h-2 h (III) or 2 h-8 h (IV). Diuresis increases in + 40,4 p. cent (I), in + 123,7 p. cent (II), in + 123,3 p. cent (III) in + 65,4 p. cent (IV). So, natriuresis increases in 39,6 p. cent (I), in 223,2 p. cent (II), in 114,3 p cent (III) and in 109,6 p. cent (IV). These results evidence that theophylline diuretic and natriuretic effects change strongly with injection time, being largest if it is injected at 14 h and slightest if injected at 8 h. Such observations prompt to study if the other pharmacological properties of theophylline, especially at pulmonary level, response also with a time-dependant intensity.

The present microscopic study evaluates the quantitative variations of ferritin particules density within the glomerular ultrastructures after theophyllin perfusion in the Rat. The ferritin particules density increases 3,65 times in the glomerular basement membrane and decreases 3,28 times in the glomerular capillary lumen. So, theophyllin increases considerably the glomerular pathway of the protein macromolecules. This results confirm the increased volumic flow (Jv) and macro-solutes flow (Js') noted with clearance methods and urinary excretion studies.

In 3 lots of 15 rats, urinary proteins excretion (U.P.E.) during 6 hours periods is compared : 1) daily and nightly in physiological conditions, where U.P.E. increases nightly (+ 97,47%) : 2) daily, before and after theophylline injection, where U.P.E. increases after theophylline injection (+ 78,62%) ; 3) nightly, before and after theophylline injection, where U.P.E. increase is only tiny (+ 3,53%) after theophylline injection. So, in nightly physiological and in daily experimental conditions the important U.P.E. increases can be in part explained by those of renal functions. This result can explain after nightly theophylline injection (where renal functions are already very higher than in daily period) the so small nightly proteinuria increase with the xanthic diuretic ; it cannot be compared to the daily value, because the renal functions cannot increase beyond some limits. Lastly, the present paper exhibits how a pharmacomolecule (as theophylline here) can act differently daily and nightly and open a new investigation field in chronopharmacology of diuretics.

A fine quantitative evaluation of ferritin aggregates in rat GBM permits to counts 5.08 +/- 1.51 and 18.30 +/- 3.21 g/cm2, respectively 30 and 60 min after ferritin injection; likewise, 30 min after ferritin administration, 5.08 +/- 1.51 and 17.11 +/- 3.9 g/cm2, respectively in normal and theophylline-treated animals.

Theophylline, infused i.v. into rats increased the diameter of the glomerular afferent arterioles by 35.78%; when added to a suspension of isolated glomeruli, it increased the diameter of the capillary tuft within the glomerulus by 25-30%. These variations in diameter can be explained by the myorelaxant effect of theophylline on the smooth contractile fibers present in the arteriolar cells and in certain glomerular cells, such as the mesangial cells. These observations explain, in part, the marked changes in glomerular hemodynamics caused by the injection of theophylline.

Agar-agar and indian ink mixture intrarenal injections enable the precise glomerular afferent arteriole diameter and the evaluation of its variations after theophyllin perfusion. The increased diameter (+ 35, 78 %) confirms the peripheral vasodilating theophyllin effect, never to our knowledge proven in situ in the kidney.

After confirmation of the intense and very fast myorelaxant effect of theophylline on isolated glomeruli, xanthic reagent myotoxic effects are shown during more or less long contacts with these glomerular suspensions. We studied isolated glomeruli diameter evolution according to reagent dose (0,25 to 10 mg/ml) and its contact length (1, 5, 10 minutes). If the diameter remains practically constant during all the period for the lowest doses, it begins to decrease after the 5th minute for higher (1 and 2,5 mg/ml) and cracks up in the first minutes for the biggest ones (5 and 10 mg/ml). Pharmacologic and toxic actions are discussed ; hypothesis of a toxic effect at smooth muscular cells level is proposed.

The present study considers the quantitative variations of the physiologic proteinuria with theophyllin in the rat. The urins are collected, during 8 hours, every Rat being its own reference. The single theophyllin injection (20 mg/kg) induces an increased diuresis (+ 42,1 %) and proteinuria (+ 73,7 %). The repetitive theophyllin injections (during 5 days) confirms this constation. The hypothesis of a modification of the permeability of the glomerular barrier to proteic macromolecules is proposed to agree this result.