Abstract
Salt sensitivity is associated with obesity, and increased cardiovascular morbidity and mortality. We investigated whether treatment of obesity and its associated metabolic abnormalities corrects salt sensitivity and restores impaired nitric oxide (NO) metabolism characteristic of salt sensitivity. Twenty, otherwise, healthy obese salt-sensitive subjects completed a 12-month program of caloric restriction, aerobic exercise and metformin. Two salt sensitivity tests were performed, that is at baseline and end of program. Lifestyle-metformin treatment decreased weight (9.8±0.3 kg), body mass index (3.9±0.2 kg/m2), waist (11.5±0.5 cm), systolic blood pressure (SBP) (8.6±0.4 mm Hg), diastolic blood pressure (DBP) (5.5±0.4 mm Hg), triglyceride (40±5 mg/dl), fasting (8.3±1 μIU/ml) and post-load (20±4 μIU/ml) insulin levels, and salt sensitivity. Going from a high-sodium (∼300 mmol) to a low-sodium diet (∼30 mmol of sodium/day) lowered SBP/DBP by 14.7±1.7/7.4±0.9 mm Hg at baseline and by 8.6±1.9/3.2±1.2 mm Hg after treatment (P<0.001). More importantly, blood pressure (BP) sensitivity to customary levels of dietary salt (∼150 mmol of sodium/day) was abolished by the lifestyle-metformin treatment. Differences in SBP/DBP between usual and low salt averaged 11±1/8±1 mm Hg before treatment, and 3±1/1±0.5 mm Hg after treatment (P<0.001). At baseline, NO-metabolite excretion was inhibited during high salt; this impairment was corrected by the lifestyle-metformin treatment. In conclusion, acquired correctable factors play an important role in the pathogenesis of salt sensitivity associated with obesity. Correction of salt sensitivity may account for the BP lowering induced by weight reduction. Restoration of the inability to increase or sustain NO production in response to high salt could account for the correction of salt sensitivity induced by the lifestyle-metformin treatment.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Campese VM . Salt sensitivity in hypertension: renal and cardiovascular implications. Hypertension 1994; 23: 531–550.
Franco V, Oparil S . Salt sensitivity, a determinant of blood pressure, cardiovascular disease and survival. J Am Coll Nutr 2006; 25: 247S–255S.
Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet 1997; 350: 1734–1737.
Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M . Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension 2001; 37 (Part 2): 429–432.
Bihorac A, Tezcan H, Ozener C, Oktay A, Akoglu E . Association between salt sensitivity and target organ damage in essential hypertension. Am J Hypertens 2000; 13: 864–872.
Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V et al. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989; 321: 580–585.
Sharma AM, Ruland K, Spies KP, Distler A . Salt sensitivity in young normotensive subjects is associated with a hyperinsulinemic response to oral glucose. J Hypertens 1991; 9: 329–335.
Zavaroni I, Coruzzi P, Bonini L, Mossini GL, Musiari L, Gasparini P . Association between salt sensitivity and insulin concentrations in patients with hypertension. Am J Hypertens 1995; 8: 855–858.
Fuenmayor N, Moreira E, Cubeddu LX . Salt sensitivity is associated with insulin resistance in essential hypertension. Am J Hypertens 1998; 11: 397–402.
Bigazzi R, Bianchi S, Baldari G, Campese VM . Clustering of cardiovascular risk factors in salt-sensitive patients with essential hypertension: role of insulin. Am J Hypertens 1996; 9: 24–32.
Uzu T, Kimura G, Yamauchi A, Kanasaki M, Isshiki K, Araki S et al. Enhanced sodium sensitivity and disturbed circadian rhythm of blood pressure in essential hypertension. Am J Hypertens 2006; 24: 1627–1632.
Cusi D, Barlassina C, Azzani T, Casari G, Citterio L, Devoto M et al. Polymorphisms of α-adducin and salt sensitivity in patients with essential hypertension. Lancet 1997; 349: 1353–1357.
Poch E, Gonzalez D, Giner V, Bragulat E, Coca A, de La Sierra A . Molecular basis of salt sensitivity in human hypertension. Evaluation of renin–angiotensin–aldosterone system gene polymorphisms. Hypertension 2001; 38: 1204–1209.
Hoffmann IS, Tavares-Mordwinkin R, Castejon AM, Alfieri AB, Cubeddu LX . Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics. J Human Hypertens 2005; 19: 233–240.
Beeks E, Kessels AG, Kroon AA, van der Klauw MM, de Leeuw PW . Genetic predisposition to salt-sensitivity: a systematic review. J Hypertens 2004; 22: 1243–1249.
Reaven GM, Lithell H, Landsberg L . Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. New Engl J Med 1996; 334: 374–381.
Rocchini AP . Obesity hypertension, salt sensitivity and insulin resistance. Nutr Metab Cardiovasc Dis 2000; 10: 287–294; review.
Tolins JP, Shultz PJ . Endogenous nitric oxide determines sensitivity to the pressor effect of salt. Kidney Int 1994; 46: 230–236.
Cubeddu LX, Alfieri AB, Hoffmann IS, Jimenez E, Roa CM, Cubeddu R et al. Nitric oxide and salt sensitivity. Am J Hypertens 2000; 13: 970–973.
Wisse BE . The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 2004; 15: 2792–2800.
Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of the High Blood Cholesterol in Adults (ATP III). JAMA 2001; 285: 2486–2497.
Luft FC, Rankin LI, Bloch R, Weyman AE, Willis LR, Murray RH et al. Cardiovascular and humoral responses to extremes of sodium intake in normal black and white men. Circulation 1979; 60: 697–706.
Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 2003; 289: 1799–1804.
Vitale C, Mercuro G, Cornoldi A, Fini M, Volterrani M, Rosano GM . Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med 2005; 258: 250–256.
Ratner R, Goldberg R, Haffner S, Marcovina S, Orchard T, Fowler S . Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes Care 2005; 28: 888–894.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403.
Rocchini AP . Obesity hypertension. Am J Hypertens 2002; 15: 50S–52S; review.
Rocchini AP, Yang JQ, Gokee A . Hypertension and insulin resistance are not directly related in obese dogs. Hypertension 2004; 43: 1011–1016.
Eriksson MK, Westborg CJ, Eliasson MC . A randomized trial of lifestyle intervention in primary healthcare for the modification of cardiovascular risk factors. Scand J Public Health 2006; 34: 453–461.
Scaglione R, Scaglione R, Ganguzza A, Corrao S, Parrinello G, Merlino G et al. Central obesity and hypertension: pathophysiologic role of renal haemodynamics and function. Int J Obes Relat Metab Disord 1995; 19: 403–409.
Radin MJ, Holycross BJ, Hoepf TM, McCune SA . Increased salt sensitivity secondary to leptin resistance in SHHF rats is mediated by endothelin. Mol Cell Biochem 2003; 242: 57–63.
Chen PY, Sanders PW . L-arginine abrogates salt sensitivity hypertension in Dahl–Rapp rats. J Clin Invest 1991; 88: 1559–1567.
Kohan DE . The renal medullary endothelin system in control of sodium and water excretion and systemic blood pressure. Curr Opin Nephrol Hypertens 2006; 15: 34–40; review.
Majid DSA, Omoro SA, Chin S-Y, Navar LG . Intrarenal nitric oxide activity and pressure natriuresis in anesthetized dogs. Hypertension 1998; 32: 266–272.
Sharma AM, Schattenfroh S, Kribben A, Distler A . Reliability of salt sensitivity of salt sensitivity testing in normotensive subjects. Klin Wochenschr 1989; 67: 632–634.
Garcia AH, Plato CF, Stoos BA, Garvin JL . Nitric oxide-induced inhibition of transport by thick ascending limbs from Dahl salt-sensitive rats. Hypertension 1999; 34: 509–513.
Rodriguez-Plaza LG, Alfieri AB, Cubeddu LX . Urinary excretion of nitric oxide metabolites in runners, sedentary individuals and patients with coronary artery disease: effects of 42 km marathon, 15 km race and a cardiac rehabilitation program. J Cardiovasc Ris 1997; 4: 367–372.
Li Z, Rodriguez-Iturbe B, Ni Z, Shahkarami A, Sepassi L, Vaziri ND . Effect of hereditary obesity on renal expressions of NO synthase, caveolin-1, AKt, guanylate cyclase, and calmodulin. Kidney Int 2005; 68: 2766–2772.
Roberts CK, Vaziri ND, Sindhu RK, Barnard RJ . A high fat, refined-carbohydrate diet affects renal NO synthase protein expression and salt sensitivity. J Appl Physiol 2003; 94: 941–946.
Dumont AS, Hyndman ME, Dumont JR, Fedak PM, Kassell NF, Sutherland GR et al. Improvement of endothelial function in insulin-resistant carotid arteries treated with pravastatin. J Neurosurg 2001; 95: 466–471.
Alfieri AB, Malave A, Cubeddu LX . Nitric oxide synthases and cyclophosphamide-induced cystitis in rats. Naunyn Schmiedebergs Arch Pharmacol 200; 363: 353–357.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hoffmann, I., Alfieri, A. & Cubeddu, L. Effects of lifestyle changes and metformin on salt sensitivity and nitric oxide metabolism in obese salt-sensitive Hispanics. J Hum Hypertens 21, 571–578 (2007). https://doi.org/10.1038/sj.jhh.1002182
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.jhh.1002182
Keywords
This article is cited by
-
Determination of erythrocyte sodium sensitivity in man
Pflügers Archiv - European Journal of Physiology (2013)