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(Hypertension. 2005;46:469.)
© 2005 American Heart Association, Inc.
Editorial Commentaries |
From the Nephrology Research and Training Center, Department of Medicine, University of Alabama at Birmingham.
Correspondence to David G. Warnock, MD, Room 647 THT, 1530 Third Ave S, UAB Station, Birmingham, AL 35294-0006. E-mail dwarnock{at}uab.edu
The epithelial sodium channel (ENaC) is a critically important final regulator of the balance between intake and excretion of dietary sodium,1 and along with the thiazide-sensitive NaCl cotransporter, constitutes the predominant sodium transport systems in the aldosterone-sensitive distal nephron.2 As proposed by Guyton,3 and confirmed by the unraveling of the activating ENaC mutations in Liddles syndrome,4 dysregulation of the final balance of sodium intake and excretion can result in chronic volume expansion, plasma renin suppression, and arterial hypertension.1 Blacks often have low-renin, salt-sensitive hypertension, which could be explained by some sort of persisting activation of ENaC, even in the face of relative excess dietary salt intake.5 The possibility that polymorphisms in the 3 ENaC subunits could contribute to this apparent activation of ENaC6 and the utility of amiloride as an ENaC blocker in black hypertension have been considered previously.7
In this issue of journal, Saha et al8 describe a systematic investigation of the effects of amiloride, spironolactone, and their use in combination in a short-term, randomized, placebo-controlled crossover study in blacks with established low-renin hypertension. As such, these studies represent important extension of the previous work of this group published in Hypertension.9 Both agents block the effects of aldosterone on the aldosterone-sensitive distal nephron, with amiloride directly interacting with ENaC and spironolactone affecting all aldosterone-sensitive systems, including ENaC and the thiazide-sensitive NaCl cotransporter.2 Of note, the 98 black subjects in this report were hypertensive despite treatment that included thiazides and calcium channel blockers. Amiloride and spironolactone significantly reduced systolic blood pressure, but only amiloride significantly reduced diastolic blood pressure with the modest doses used in this study (10 mg amiloride and 25 mg spironolactone). There was a significant additive effect of the combination of amiloride and aldosterone antagonist on diastolic and systolic blood pressures.
That the effects of spironolactone were broader than inhibition of ENaC was demonstrated by a significant reduction in endothelin-1 levels.8 This may well be an important finding because there is greater endothelin-1dependent vasoconstriction in black compared with white hypertensive subjects,10 as well as other vasodilatory responses to aldosterone antagonists in obesity,11 heart failure,12 and primary aldosteronism.13 Whether these effects of aldosterone antagonists are related to effects of aldosterone on the cardiovascular system is a question for further research.
The effects of amiloride and spironolactone on plasma aldosterone, plasma renin activity, and serum potassium levels should be emphasized. Amiloride, alone or in combination with spironolactone, caused a marked increase in the plasma aldosterone concentration, whereas there was only a mild increase in plasma aldosterone seen with spironolactone, and that likely was attributable to increases in serum potassium levels. The observation that amiloride and triamterene increase plasma aldosterone levels was noticed nearly 40 years ago.14,15 The more striking increase in plasma aldosterone with amiloride compared with spironolactone appears to be related to the increased plasma renin activity caused by amiloride that then promoted more aldosterone secretion. This effect of amiloride on plasma renin activity appears to be a short-term effect that is independent of any changes in extracellular volume,16 but the mechanism whereby amiloride stimulates plasma renin activity has not been defined. A direct effect of amiloride on the macula densa or the renin-containing granules of the afferent arteriole would be of interest but has not been explored.
As pointed out by Saha et al,8 the synergistic effects of amiloride and spironolactone may permit lower doses of each agent to be used in combination and therefore decrease the side effect profile of larger doses of either agent. Hyperkalemia is an important limiting side effect,17 especially if multiple inhibitors of the renin-angiotensin-aldosterone system are used.18 The possibility that amiloride may directly stimulate renin activation or release could open up new therapeutic possibilities because stimulation of renin activity increases aldosterone secretion, which enhances potassium secretion, whereas the direct effect of amiloride to block ENaC limits potassium secretion.18 It could useful to tease apart the effects of the amiloride analogues on renin activation to see if they could be distinguished from their direct effects on ENaC.
Despite the current enthusiasm for pharmacogenomic approaches and rigorous mathematical descriptions of polygenetic traits such as hypertension, the need for empiric approaches to complex biologic systems remains,19 and the carefully performed studies by Saha et al8 provide important insights into the possible role of dysregulation of ENaC in the pathogenesis of low renin hypertension in blacks.
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2. Meneton P, Loffing J, Warnock DG. Sodium and potassium handling by the aldosterone-sensitive distal nephron: the pivotal role of the distal and connecting tubule. Am J Physiol Renal Physiol. 2005; 287: F593F601.
3. Guyton AC, Coleman TG, Cowley AV Jr, Scheel KW, Manning RD Jr, Norman RA Jr. Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med. 1972; 52: 584594.[CrossRef][Medline] [Order article via Infotrieve]
4. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR Jr, Ulick S, Milora RV, Findling JW, Canessa CM, Rossier BC, Liifton RP. Liddles syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994; 79: 407414.[CrossRef][Medline] [Order article via Infotrieve]
5. Warnock DG. Low-renin and nonmodulating essential hypertension. Hypertension. 1999; 34: 395397.
6. Baker EH, Dong YB, Sagnella GA, Rothwell M, Onipinla AK, Markandu ND, Cappuccio FP, Cook DG, Persu A, Corvol P, Jeunemaitre X, Carter ND, MacGregor GA. Association of hypertension with T594M mutation in beta subunit of epithelial sodium channels in black people resident in London. Lancet. 1998; 351: 13881392.[CrossRef][Medline] [Order article via Infotrieve]
7. Baker EH, Duggal A, Dong Y, Ireson NJ, Wood M, Markandu ND, MacGregor GA. Amiloride, a specific drug for hypertension in black people with T594M variant? Hypertension. 2002; 40: 317.
8. Saha C, Eckert GJ, Ambrosius WT, Chun T-Y, Wagner MA, Zhao Q, Pratt JH. Improvement in blood pressure with inhibition of the epithelial sodium channel in blacks with hypertension. Hypertension. 2005; 46: 481487.
9. Pratt JH, Ambrosius WT, Agarwal R, Eckert GJ, Newman S. Racial difference in the activity of the amiloride-sensitive epithelial sodium channel. Hypertension. 2002; 40: 903908.
10. Campia U, Cardillo C, Panza JA. Ethnic differences in the vasoconstrictor activity of endogenous endothelin-1 in hypertensive patients. Circulation. 2004; 109: 31913195.
11. Cardillo C, Campia U, Iantorno M, Panza JA. Enhanced vascular activity of endogenous endothelin-1 in obese hypertensive patients. Hypertension. 2004; 43: 3640.
12. Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation. 2000; 101: 594597.
13. Nishizaka MK, Zaman MA, Green SA, Renfroe KY, Calhoun DA. Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation. 2004; 109: 28572861.
14. Bull MB, Laragh JH. Amiloride. A potassium-sparing natriuretic agent. Circulation. 1968; 37: 4553.
15. Keim HJ, Drayer JI, Thurston H, Laragh JH. Triamterene-induced changes in aldosterone and renin values in essential hypertension. Evidence of a role for aldosterone in preventing blood pressure reduction. Arch Intern Med. 1976; 136: 645648.
16. Endemann D, Marienhagen J, Stubanus M, Luger RJ, Fischereder M, Riegger GA, Kramer BK. Volume independent stimulation of renin secretion by a single dose of amiloride in man. Arzneimittelforschung. 2002; 52: 677683.[Medline] [Order article via Infotrieve]
17. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004; 351: 543551.
18. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004; 351: 585592.
19. Page GP, George V, Go RC, Page PZ, Allison DB. "Are we there yet?" Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits. Am J Hum Genet. 2003; 73: 711719.[CrossRef][Medline] [Order article via Infotrieve]
Related Article:
Hypertension 2005 46: 481-487.
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