Inhibitory effect of methylxanthines on feedback control of glomerular filtration rate in the rat kidney.

Microperfusion experiments were performed in rats to assess the effect of luminal application of theophylline and the more lipophilic 3-isobutyl-1-methylxanthine (IBMX) on feedback regulation of glomerular filtration rate. Elevation of loop of Henle flow from 0 to 40 nl/min caused a 20.3 +/- 4.5% reduction of stop flow pressure (SFP) and a 32.2 +/- 3.7% reduction of early proximal flow rate (EPFR) when the perfusate was a 140 mM NaCl solution. When theophylline was added in a concentration of 5mM SFP fell by only 5.3 +/- 1.8% and EPFR by 7.9 +/- 33%, changes which were significantly smaller than in the control perfusions (P less than 0.01). An identical change of loop of Henle flow in the presence of IBMX in concentration of 1 and 5 mM was associated with a 4.5 +/- 3.9% decrease and a 12.1 +/- 2.7% increase of EPFR. In orthograde perfusion experiments full inhibition of the feedback response was noted at an IBMX concentration of about 1 mM while during retrograde perfusion a concentration of 0.4 mM was sufficient to produce the same effect. This indicates that methylxanthines diffuse out of the loop of Henle to a considerable extent. Methylxanthines reduced absolute and fractional water absorption along the loop of Henle to some extent while Cl absorption rates and early distal Cl concentrations were not significantly altered. Cyclic AMP applied from the luminal side in a concentration of 10 mM did not affect the feedback response of EPFR to flow elevation from 0 to 40 nl/min. Luminal application of dibutyryl cyclic AMP at 10 mM induced a small, but significant reduction of the feedback response when tested by paired t-test (P less than 0.05). Our results show that luminal application of methylxanthines strongly interfere with feedback regulation of glomerular filtration rate. It is unclear at present whether this effect is related to inhibition of cyclic nucleotide phosphodiesterase and a rise in tissue cyclic AMP levels or to interference with a mechanism involving the local action of adenosine or 5'-AMP.