Antikaliuretic action of trimethoprim is minimized by raising urine pH
| Autor: | Asit Patnaik, Thomas R. Kleyman, Mitchell L. Halperin, Ching-Bun Chen, Mahboob Lessan-Pezeshki, Lynn E. Schlanger, Brian N. Ling, Martin Schreiber |
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| Rok vydání: | 1996 |
| Předmět: |
Male
medicine.medical_specialty Patch-Clamp Techniques Potassium Channels Sodium Anti-Infective Agents Urinary chemistry.chemical_element 030204 cardiovascular system & hematology Sodium Channels Trimethoprim Membrane Potentials Rats Sprague-Dawley Excretion 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Animals 030212 general & internal medicine Patch clamp Ion transporter Chromatography Hydrogen-Ion Concentration Hyperpolarization (biology) Apical membrane Rats Amiloride Kidney Tubules Endocrinology chemistry Nephrology Potassium Injections Intraperitoneal Sodium Channel Blockers medicine.drug |
| Zdroj: | Kidney International. 49(1):82-87 |
| ISSN: | 0085-2538 |
| DOI: | 10.1038/ki.1996.11 |
| Popis: | Antikaliuretic action of trimethoprim is minimized by raising urine pH. This study was designed to test the hypothesis that the antikaliuresis caused by trimethoprim could be diminished by alkalinizing the luminal fluid in the CCD, thereby converting trimethoprim from its cationic, active form to an electroneutral, inactive form. Timethoprim-induced inhibition of transepithelial Na + transport was examined in A6 distal nephron cells by analysis of short circuit current. The voltage-dependence of the trimethoprim-induced block of Na + channels was examined with patch clamp recordings of A6 cells. The antikaliuretic effect of trimethoprim was examined in vivo in rats pretreated with desoxycorticosterone and with NH 4 Cl to lower urine pH, and in rats also receiving acetazolamide to raise urine pH. We found that the concentration of trimethoprim required to inhibit the amiloride sensitive component of short circuit current by 50% (IC 50 ) was 340 µ m (at pH 8.2) and 50 µ m (at pH 6.3). The IC 50 s of protonated trimethoprim were similar (34 µ m at pH 8.2 and 45 µ m at pH 6.3). The mean time open for the high selectivity, Na + channel was reduced from 1679 ± 387msec to 502 ± 98msec with addition of 10 -5 m trimethoprim to patch pipette solution at the resting membrane potential (-V pipette = 0 mV). Further decreases in mean time open were observed as -V pipette was reduced (that is, apical membrane hyperpolarization) to -40mV (mean time open=217 ± 85 msec) and to -80mV (mean time open=69 ± 13 msec). In vivo , trimethoprim caused a > 50% reduction in potassium (K + ) excretion due primarily to a fall in the [K + ] in the lumen of the terminal CCD. This effect of trimethoprim was markedly attenuated in an alkaline urine induced by acetazolamide. We conclude that it is the charged, protonated species of trimethoprim which blocks epithelial Na + channels. Increasing urinary pH decreases the concentration of the charged species of trimethoprim and minimizes its antikaliuretic effect. |
| Databáze: | OpenAIRE |
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