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ROMK Inhibitor Actions in the Nephron Probed with Diuretics

More than a billion people worldwide are afflicted with essential hypertension and diuretics are usually the first line of treatment. Diuretics acting on specific nephron segments to inhibit Na+ reabsorption have been used clinically for decades; however, drug interactions, tolerance, and derangements in serum K+ complicate their use to achieve target blood pressure. ROMK is an attractive new diuretic target, in part, because its inhibition is postulated to indirectly inhibit the bumetanide‐sensitive Na+‐K+‐2Cl− co‐transporter, NKCC2, and the amiloride‐sensitive epithelial Na+ channel, ENaC. ROMK inhibition is also postulated to prevent urinary K+ wasting caused by NKCC2 inhibition. The development of small‐molecule ROMK inhibitors has created opportunities for exploring the physiological responses to ROMK inhibition. The present study evaluated how ROMK inhibition alone or in combination with NKCC2, ENaC, or the hydrochlorothiazide (HCTZ) target NCC, alters fluid and electrolyte transport in the nephron. The ROMK inhibitor VU591 failed to induce diuresis when administered orally to rats. However, another inhibitor, termed Compound A, induced a robust natriuretic diuresis without kaliuresis. Compound A produced additive effects on urine output and Na+ excretion when combined with HCTZ, amiloride or benzamil but not when co‐administered with bumetanide, suggesting that the major diuretic target site is the thick ascending limb (TAL). Interestingly, Compound A inhibited the kaliuretic response to NKCC2 inhibition, an effect we attribute to inhibition of ROMK‐mediated K+ secretion in the TAL and CD. Compound A had no effect on heterologously expressed flow‐sensitive BK channels (Slo1/b1). In conclusion, Compound A represents an important new pharmacological tool for investigating the renal consequences of ROMK inhibition and therapeutic potential of ROMK as a diuretic target.