The role of ANG II in the regulation of ion reabsorption by the renal thick ascending limb is poorly understood. Here, we demonstrate that ANG II (10⁸ M in the bath) inhibits HCO₃ absorption by 40% in the isolated, perfused medullary thick ascending limb (MTAL) of the rat. The inhibition by ANG II was abolished by pretreatment with eicosatetraynoic acid (10 µM), a general inhibitor of arachidonic acid metabolism, or 17-octadecynoic acid (10 µM), a highly selective inhibitor of cytochrome P-450 pathways. Bath addition of 20-hydroxyeicosatetraenoic acid (20-HETE; 10⁸ M), the major P-450 metabolite in the MTAL, inhibited HCO₃ absorption, whereas pretreatment with 20-HETE prevented the inhibition by ANG II. The addition of 15-HETE (10⁸ M) to the bath had no effect on HCO₃ absorption. The inhibition of HCO₃ absorption by ANG II was reduced by >50% in the presence of the tyrosine kinase inhibitors genistein (7 µM) or herbimycin A (1 µM). We found no role for cAMP, protein kinase C, or NO in the inhibition by ANG II. However, addition of the exogenous NO donor S-nitroso-N-acetylpenicillamine (SNAP; 10 µM) or the NO synthase (NOS) substrate L-arginine (1 mM) to the bath stimulated HCO₃ absorption by 35%, suggesting that NO directly regulates MTAL HCO₃ absorption. Addition of 10¹¹ to 10¹⁰ M ANG II to the bath did not affect HCO₃ absorption. We conclude that ANG II inhibits HCO₃ absorption in the MTAL via a cytochrome P-450-dependent signaling pathway, most likely involving the production of 20-HETE. Tyrosine kinase pathways also appear to play a role in the ANG II-induced transport inhibition. The inhibition of HCO₃ absorption by ANG II in the MTAL may play a key role in the ability of the kidney to regulate sodium balance and extracellular fluid volume independently of acid-base balance.

20-hydroxyeicosatetraenoic acid; tyrosine kinases; nitric oxide; signal transduction; acid-base regulation

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