Chronic Inhibition of Renal Outer Medullary Potassium Channel Not Only Prevented but Also Reversed Development of Hypertension and End-Organ Damage in Dahl Salt-Sensitive Rats

Abstract

R enal outer medullary potassium channel (ROMK) is encoded by the KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) gene and expressed in the apical membranes of thick ascending limb of Henle and cortical collecting duct cells; ROMK mediates potassium recycling and facilitates sodium reabsorption through Na− cotransporter in the thick ascending limb of Henle and potassium secretion in cortical collecting duct.1-3 Thus, ROMK plays a critical role in the regulation of renal sodium reabsorption and the body's potassium homeostasis. Human genetic studies indicated that loss-of-function mutations in ROMK cause type II Bartter syndrome, 4-6 featuring polyuria, polydipsia, salt wasting, hypokalemia, alkalosis, hypercalciuria, low blood pressures, elevated plasma renin and aldosterone, and excess production of renal prostaglandins. ROMK heterozygous mutations in humans protect from the development of hypertension.7 ROMK-deficient mice exhibit a Bartter syndrome type II-like phenotype. 8,9 Heterozygous disruption of ROMK in rats is associated with reduced blood pressure and less severe renal injury.10 Furthermore, acute pharmacological intervention with a small molecule ROMK inhibitor (ROMKi) compound A evoked diuresis and natriuresis in rats and dogs, 11 which establishes the concept that ROMK inhibition represents a novel diuretic mechanism. We, therefore, hypothesize that chronic ROMK inhibition by selective small molecules would induce natriuresis and diuresis and, thereby, lower blood pressure and protect from end-organ damage in hypertensive subjects. To this end, we examined the effects of a selective and potent ROMKi B, recently synthesized by Merck & Co, Inc, 12 on systemic hemodynamics, renal function and structure, vascular function, and cardiac structure and compared the effects with those of hydrochlorothiazide (HCTZ) in 2 separate Abstract-The renal outer medullary potassium (ROMK) channel mediates potassium recycling and facilitates sodium reabsorption through the Na + /K + /2Cl − cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Evidence from the phenotype of humans and rodents with functional ROMK deficiency supports the contention that selective ROMK inhibitors (ROMKi) will represent a novel diuretic with potential of therapeutic benefit for hypertension. ROMKi have recently been synthesized by Merck & Co, Inc. The present studies were designed to examine the effects of ROMKi B on systemic hemodynamics, renal function and structure, and vascular function in Dahl salt-sensitive rats. Four experimental groups-control, high-salt diet alone; ROMKi B 3 mg·kg −1 ·d −1 ; ROMKi B 10 mg·kg −1 ·d −1 ; and hydrochlorothiazide 25 mg·kg −1 ·d −1 -were included in prophylactic (from week 1 to week 9 on high-salt diet) and therapeutic studies (from week 5 to week 9 on high-salt diet), respectively. ROMKi B produced sustained blood pressure reduction and improved renal and vascular function and histological alterations induced by a high-salt diet. ROMKi B was...

Thick Ascending Limb Sodium Transport in the Pathogenesis of Hypertension

“…This attenuation was more evident when rats were fed an 8% compared with a 4% salt diet (777). A role for thick ascending limb ROMK is also supported by data that show a ROMK inhibitor, ROMKi B, was able to prevent and reverse the rise in blood pressure in S/Jr fed a high-salt diet (776). Together these data all support the necessity of functional ROMK for the development of the hypertensive phenotype in S rats.…”

Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992

“…These responses are different from those induced by inhibitors of the renal outer medullary K 1 channel [ROMK (or Kir1.1)], another emerging diuretic target in the Kir channel family (Denton et al, 2013). We and others have shown that ROMK inhibition evokes diuresis and natriuresis without causing K 1 wasting (Garcia et al, 2014;Kharade et al, 2016;Zhou et al, 2017). The K 1 -sparing effect appears to result predominantly from the inhibition of K 1 secretion in the TAL with a relatively minor effect on distal K 1 secretion (Kharade et al, 2016).…”

Pore Polarity and Charge Determine Differential Block of Kir1.1 and Kir7.1 Potassium Channels by Small-Molecule Inhibitor VU590

“…2014; Zhou et al, 2017) indicate that Kir1.1 represents a viable molecular target for a novel class of diuretics for treating hypertension (Denton et al, 2013). The first publicly disclosed small-molecule inhibitor of Kir1.1, termed VU590, was discovered at Vanderbilt University in a high-throughput screen of approximately 225,000 compounds from the NIH Molecular Libraries Small-Molecule Repository.…”