Salt-Sensitivity of Blood Pressure: Is It Time to Customize the Antihypertensive Therapy?

Salt-Sensitivity of Blood Pressure: Is It Time to Customize the Antihypertensive Therapy? The salt-sensitivity of blood pressure (BP) refers to the interindividual difference in the BP response to a given change in salt intake. The majority of individuals have a decrease in BP with reduction in dietary salt intake, with a small proportion of subjects showing no response or even some increase in BP. In fact, the BP response to changes in salt intake behaves as a continuous variable with a simil-Gaussian distribution,1,2 not allowing to detect any distinct subpopulation.3 This notwithstanding, based on these responses, individuals are often defined either salt-sensitive or salt-resistant using particular maneuvers and “arbitrary” cut-offs.4 Noteworthy, salt- sensitivity of BP was associated with several cardio- metabolic risk factors, among which excess body weight, diabetes and metabolic syndrome,5,6 and even with a high rates of organ damage and cardiovascular events.7–9 Qi and collaborators,10 in an article recently published in this journal, reported the results of a network meta-analysis, which compared the efficacy of different classes of antihypertensive agents in adult patients with salt-sensitive hypertension and without concomitant diseases. The main findings indicated a greater BP effect of the calcium antagonist- diuretic (hydrochlorothiazide) combination, while the calcium antagonist-metformin association was most effective in obese patients. The results also showed that clonidine was more effective during low salt intake, although only one study explored the effect of this particular antihypertensive agent. A limitation of this study was given by the different methods used to evaluate the BP salt-sensitivity. Another limitation was the inclusion in the analysis of both randomized and nonrandomized controlled trials, the majority of which were based on the use of calcium antagonists. Finally, there was a large heterogeneity in the characteristics of the different studies with respect to length of follow-up, sample size, and different dosage and form of the antihypertensive agents under investigation. An interesting finding of the study was the apparent sodium-induced attenuation of BP lowering during high salt intake. This trend seems to be opposite to the positive relationship between salt intake and BP levels, and to the results of the beneficial effect of the reduction in salt intake on organ damage in patients with concomitant antihypertensive treatment.11,12 Indeed, this effect may be explained by a natriuretic effect of the treatment, not only of the diuretic, but also of the calcium antagonist13,14 and ACE-inhibitor15 administration. In particular, there were abnormal dihydropyridine binding sites on calcium channels13 and higher intracellular calcium levels in salt-sensitive hypertensive patients during high salt intake than low salt intake.14 On the other hand, other studies showed that the increased urinary sodium excretion after calcium antagonists administration was independent of salt-sensitivity of BP.16 Moreover, in a study on multiracial salt-sensitive subjects, the BP reduction was achieved both for an ACE-inhibitor and a calcium channel antagonist, and it was consistently greater on a low salt diet in all three races.17 Regarding the higher effect of the calcium antagonist and metformin association, this could be expected because of the clear evidence of the positive association between excess body weight and insulin resistance and its role on BP salt-sensitivity,18 and also for the favorable effect of metformin on insulin sensitivity and body weight.19 In line with the current era of therapy customization and in consideration of the high cardiovascular risk of the salt-sensitive individuals, this study highlights a primary topic. Of course, conceivably the first line of hypertension treatment in salt-sensitive individuals is to reduce dietary salt intake to less than 5 g per day, also in consideration that in most countries worldwide the habitual average sodium intake largely exceeds the recommended adequate intake determined on the basis of scientific evidence.20 However, since the mechanisms responsible for the salt-sensitive of BP are not completely established, there is no specific treatment forsalt-sensitive patients yet. Given these results, it would be hazardous to try to reach any definitive conclusion. High-quality investigations are needed regarding the effect of different classes and dosage of antihypertensive therapy, in terms of changes in BP, organ damage, and risk of cardiovascular events, in relation to salt-sensitivity. To this end, the adoption of appropriate and standardized tests for the assessment of BP salt-sensitivity is recommended when designing future studies. FUNDING The study was not supported by external funding. DISCLOSURE The author declared no conflict of interest. REFERENCES 1. Weinberger MH , Miller JZ , Luft FC , Grim CE , Fineberg NS . Definitions and characteristics of sodium sensitivity and blood pressure resistance . Hypertension 1986 ; 8 : II127 – II134 . Google Scholar CrossRef Search ADS PubMed 2. Sullivan JM . Salt sensitivity. Definition, conception, methodology, and long-term issues . Hypertension 1991 ; 17 : I61 – I68 . Google Scholar CrossRef Search ADS PubMed 3. He J , Gu D , Chen J , Jaquish CE , Rao DC , Hixson JE , Chen JC , Duan X , Huang JF , Chen CS , Kelly TN , Bazzano LA , Whelton PK ; GenSalt Collaborative Research Group . Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study . J Hypertens 2009 ; 27 : 48 – 54 . Google Scholar CrossRef Search ADS PubMed 4. Weinberger MH , Stegner JE , Fineberg NS . A comparison of two tests for the assessment of blood pressure responses to sodium . Am J Hypertens 1993 ; 6 : 179 – 184 . Google Scholar CrossRef Search ADS PubMed 5. Galletti F , Strazzullo P , Ferrara I , Annuzzi G , Rivellese AA , Gatto S , Mancini M . NaCl sensitivity of essential hypertensive patients is related to insulin resistance . J Hypertens 1997b ; 15 : 1485 – 1491 . Google Scholar CrossRef Search ADS 6. Strazzullo P , Barbato A , Galletti F , Barba G , Siani A , Iacone R , D’Elia L , Russo O , Versiero M , Farinaro E , Cappuccio FP . Abnormalities of renal sodium handling in the metabolic syndrome. Results of the Olivetti Heart Study . J Hypertens 2006 ; 24 : 1633 – 1639 . Google Scholar CrossRef Search ADS PubMed 7. 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 . Google Scholar CrossRef Search ADS PubMed 8. Morimoto A , Uzu T , Fujii T , Nishimura M , Kuroda S , Nakamura S , Inenaga T , Kimura G . Sodium sensitivity and cardiovascular events in patients with essential hypertension . Lancet 1997 ; 350 : 1734 – 1737 . Google Scholar CrossRef Search ADS PubMed 9. Weinberger MH , Fineberg NS , Fineberg SE , Weinberger M . Salt sensitivity, pulse pressure, and death in normal and hypertensive humans . Hypertension 2001 ; 37 : 429 – 432 . Google Scholar CrossRef Search ADS PubMed 10. Qi H , Liu Z , Cao H , Sun W , Peng W , Liu B , Dong S , Xiang Y , Zhang L . Comparative efficacy of antihypertensive agents in salt-sensitive hypertensive patients: a network meta-analysis . Am J Hypertens 2018 ; https://doi.org/10.1093/ajh/hpy027 . 11. D’Elia L , Galletti F , La Fata E , Sabino P , Strazzullo P . Effect of dietary sodium restriction on arterial stiffness: systematic review and meta-analysis of the randomized controlled trials . J Hypertens 2018 ; 36 : 734 – 743 . Google Scholar CrossRef Search ADS PubMed 12. D’Elia L , Rossi G , Schiano di Cola M , Savino I , Galletti F , Strazzullo P . Meta-Analysis of the effect of dietary sodium restriction with or without concomitant renin-angiotensin-aldosterone system-inhibiting treatment on albuminuria . Clin J Am Soc Nephrol 2015 ; 10 : 1542 – 1552 . Google Scholar CrossRef Search ADS PubMed 13. Galletti F , Rutledge A , Triggle DJ . Dietary sodium intake: influence on calcium channels and urinary calcium excretion in spontaneously hypertensive rats . Biochem Pharmacol 1991 ; 41 : 893 – 896 . Google Scholar CrossRef Search ADS PubMed 14. Oshima T , Matsuura H , Matsumoto K , Kido K , Kajiyama G . Role of cellular calcium in salt sensitivity of patients with essential hypertension . Hypertension 1988 ; 11 : 703 – 707 . Google Scholar CrossRef Search ADS PubMed 15. Walker WG , Whelton PK , Saito H , Russell RP , Hermann J . Relation between blood pressure and renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium in 574 ambulatory subjects . Hypertension 1979 ; 1 : 287 – 291 . Google Scholar CrossRef Search ADS PubMed 16. Galletti F , Strazzullo P , Barba G , Ferrara I , Iacone R , Stinga F , Mancini M . Antihypertensive and renal effects of acute and chronic therapy with a dihydropyridine Ca-antagonist in patients with different salt sensitivity . J Cardiovasc Pharmacol 1996 ; 27 : 578 – 582 . Google Scholar CrossRef Search ADS PubMed 17. Weir MR , Chrysant SG , McCarron DA , Canossa-Terris M , Cohen JD , Gunter PA , Lewin AJ , Mennella RF , Kirkegaard LW , Hamilton JH , Weinberger MH , Weder AB . Influence of race and dietary salt on the antihypertensive efficacy of an angiotensin-converting enzyme inhibitor or a calcium channel antagonist in salt-sensitive hypertensives . Hypertension 1998 ; 31 : 1088 – 1096 . Google Scholar CrossRef Search ADS PubMed 18. Galletti F , Strazzullo P . The blood pressure-salt sensitivity paradigm: pathophysiologically sound yet of no practical value . Nephrol Dial Transplant 2016 ; 31 : 1386 – 1391 . Google Scholar CrossRef Search ADS PubMed 19. Dunn CJ , Peters DH . Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus . Drugs 1995 ; 49 : 721 – 749 . Google Scholar CrossRef Search ADS PubMed 20. World Health Organization . Guideline: Sodium Intake for Adults and Children . WHO Document Production Services : Geneva, Switzerland , 2012 . © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

Salt-Sensitivity of Blood Pressure: Is It Time to Customize the Antihypertensive Therapy?

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Publisher
Oxford University Press
Copyright
© American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
0895-7061
eISSN
1941-7225
D.O.I.
10.1093/ajh/hpy056
Publisher site
See Article on Publisher Site

Abstract

The salt-sensitivity of blood pressure (BP) refers to the interindividual difference in the BP response to a given change in salt intake. The majority of individuals have a decrease in BP with reduction in dietary salt intake, with a small proportion of subjects showing no response or even some increase in BP. In fact, the BP response to changes in salt intake behaves as a continuous variable with a simil-Gaussian distribution,1,2 not allowing to detect any distinct subpopulation.3 This notwithstanding, based on these responses, individuals are often defined either salt-sensitive or salt-resistant using particular maneuvers and “arbitrary” cut-offs.4 Noteworthy, salt- sensitivity of BP was associated with several cardio- metabolic risk factors, among which excess body weight, diabetes and metabolic syndrome,5,6 and even with a high rates of organ damage and cardiovascular events.7–9 Qi and collaborators,10 in an article recently published in this journal, reported the results of a network meta-analysis, which compared the efficacy of different classes of antihypertensive agents in adult patients with salt-sensitive hypertension and without concomitant diseases. The main findings indicated a greater BP effect of the calcium antagonist- diuretic (hydrochlorothiazide) combination, while the calcium antagonist-metformin association was most effective in obese patients. The results also showed that clonidine was more effective during low salt intake, although only one study explored the effect of this particular antihypertensive agent. A limitation of this study was given by the different methods used to evaluate the BP salt-sensitivity. Another limitation was the inclusion in the analysis of both randomized and nonrandomized controlled trials, the majority of which were based on the use of calcium antagonists. Finally, there was a large heterogeneity in the characteristics of the different studies with respect to length of follow-up, sample size, and different dosage and form of the antihypertensive agents under investigation. An interesting finding of the study was the apparent sodium-induced attenuation of BP lowering during high salt intake. This trend seems to be opposite to the positive relationship between salt intake and BP levels, and to the results of the beneficial effect of the reduction in salt intake on organ damage in patients with concomitant antihypertensive treatment.11,12 Indeed, this effect may be explained by a natriuretic effect of the treatment, not only of the diuretic, but also of the calcium antagonist13,14 and ACE-inhibitor15 administration. In particular, there were abnormal dihydropyridine binding sites on calcium channels13 and higher intracellular calcium levels in salt-sensitive hypertensive patients during high salt intake than low salt intake.14 On the other hand, other studies showed that the increased urinary sodium excretion after calcium antagonists administration was independent of salt-sensitivity of BP.16 Moreover, in a study on multiracial salt-sensitive subjects, the BP reduction was achieved both for an ACE-inhibitor and a calcium channel antagonist, and it was consistently greater on a low salt diet in all three races.17 Regarding the higher effect of the calcium antagonist and metformin association, this could be expected because of the clear evidence of the positive association between excess body weight and insulin resistance and its role on BP salt-sensitivity,18 and also for the favorable effect of metformin on insulin sensitivity and body weight.19 In line with the current era of therapy customization and in consideration of the high cardiovascular risk of the salt-sensitive individuals, this study highlights a primary topic. Of course, conceivably the first line of hypertension treatment in salt-sensitive individuals is to reduce dietary salt intake to less than 5 g per day, also in consideration that in most countries worldwide the habitual average sodium intake largely exceeds the recommended adequate intake determined on the basis of scientific evidence.20 However, since the mechanisms responsible for the salt-sensitive of BP are not completely established, there is no specific treatment forsalt-sensitive patients yet. Given these results, it would be hazardous to try to reach any definitive conclusion. High-quality investigations are needed regarding the effect of different classes and dosage of antihypertensive therapy, in terms of changes in BP, organ damage, and risk of cardiovascular events, in relation to salt-sensitivity. To this end, the adoption of appropriate and standardized tests for the assessment of BP salt-sensitivity is recommended when designing future studies. FUNDING The study was not supported by external funding. DISCLOSURE The author declared no conflict of interest. REFERENCES 1. Weinberger MH , Miller JZ , Luft FC , Grim CE , Fineberg NS . Definitions and characteristics of sodium sensitivity and blood pressure resistance . Hypertension 1986 ; 8 : II127 – II134 . Google Scholar CrossRef Search ADS PubMed 2. Sullivan JM . Salt sensitivity. Definition, conception, methodology, and long-term issues . Hypertension 1991 ; 17 : I61 – I68 . Google Scholar CrossRef Search ADS PubMed 3. He J , Gu D , Chen J , Jaquish CE , Rao DC , Hixson JE , Chen JC , Duan X , Huang JF , Chen CS , Kelly TN , Bazzano LA , Whelton PK ; GenSalt Collaborative Research Group . Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study . J Hypertens 2009 ; 27 : 48 – 54 . Google Scholar CrossRef Search ADS PubMed 4. Weinberger MH , Stegner JE , Fineberg NS . A comparison of two tests for the assessment of blood pressure responses to sodium . Am J Hypertens 1993 ; 6 : 179 – 184 . Google Scholar CrossRef Search ADS PubMed 5. Galletti F , Strazzullo P , Ferrara I , Annuzzi G , Rivellese AA , Gatto S , Mancini M . NaCl sensitivity of essential hypertensive patients is related to insulin resistance . J Hypertens 1997b ; 15 : 1485 – 1491 . Google Scholar CrossRef Search ADS 6. Strazzullo P , Barbato A , Galletti F , Barba G , Siani A , Iacone R , D’Elia L , Russo O , Versiero M , Farinaro E , Cappuccio FP . Abnormalities of renal sodium handling in the metabolic syndrome. Results of the Olivetti Heart Study . J Hypertens 2006 ; 24 : 1633 – 1639 . Google Scholar CrossRef Search ADS PubMed 7. 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 . Google Scholar CrossRef Search ADS PubMed 8. Morimoto A , Uzu T , Fujii T , Nishimura M , Kuroda S , Nakamura S , Inenaga T , Kimura G . Sodium sensitivity and cardiovascular events in patients with essential hypertension . Lancet 1997 ; 350 : 1734 – 1737 . Google Scholar CrossRef Search ADS PubMed 9. Weinberger MH , Fineberg NS , Fineberg SE , Weinberger M . Salt sensitivity, pulse pressure, and death in normal and hypertensive humans . Hypertension 2001 ; 37 : 429 – 432 . Google Scholar CrossRef Search ADS PubMed 10. Qi H , Liu Z , Cao H , Sun W , Peng W , Liu B , Dong S , Xiang Y , Zhang L . Comparative efficacy of antihypertensive agents in salt-sensitive hypertensive patients: a network meta-analysis . Am J Hypertens 2018 ; https://doi.org/10.1093/ajh/hpy027 . 11. D’Elia L , Galletti F , La Fata E , Sabino P , Strazzullo P . Effect of dietary sodium restriction on arterial stiffness: systematic review and meta-analysis of the randomized controlled trials . J Hypertens 2018 ; 36 : 734 – 743 . Google Scholar CrossRef Search ADS PubMed 12. D’Elia L , Rossi G , Schiano di Cola M , Savino I , Galletti F , Strazzullo P . Meta-Analysis of the effect of dietary sodium restriction with or without concomitant renin-angiotensin-aldosterone system-inhibiting treatment on albuminuria . Clin J Am Soc Nephrol 2015 ; 10 : 1542 – 1552 . Google Scholar CrossRef Search ADS PubMed 13. Galletti F , Rutledge A , Triggle DJ . Dietary sodium intake: influence on calcium channels and urinary calcium excretion in spontaneously hypertensive rats . Biochem Pharmacol 1991 ; 41 : 893 – 896 . Google Scholar CrossRef Search ADS PubMed 14. Oshima T , Matsuura H , Matsumoto K , Kido K , Kajiyama G . Role of cellular calcium in salt sensitivity of patients with essential hypertension . Hypertension 1988 ; 11 : 703 – 707 . Google Scholar CrossRef Search ADS PubMed 15. Walker WG , Whelton PK , Saito H , Russell RP , Hermann J . Relation between blood pressure and renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium in 574 ambulatory subjects . Hypertension 1979 ; 1 : 287 – 291 . Google Scholar CrossRef Search ADS PubMed 16. Galletti F , Strazzullo P , Barba G , Ferrara I , Iacone R , Stinga F , Mancini M . Antihypertensive and renal effects of acute and chronic therapy with a dihydropyridine Ca-antagonist in patients with different salt sensitivity . J Cardiovasc Pharmacol 1996 ; 27 : 578 – 582 . Google Scholar CrossRef Search ADS PubMed 17. Weir MR , Chrysant SG , McCarron DA , Canossa-Terris M , Cohen JD , Gunter PA , Lewin AJ , Mennella RF , Kirkegaard LW , Hamilton JH , Weinberger MH , Weder AB . Influence of race and dietary salt on the antihypertensive efficacy of an angiotensin-converting enzyme inhibitor or a calcium channel antagonist in salt-sensitive hypertensives . Hypertension 1998 ; 31 : 1088 – 1096 . Google Scholar CrossRef Search ADS PubMed 18. Galletti F , Strazzullo P . The blood pressure-salt sensitivity paradigm: pathophysiologically sound yet of no practical value . Nephrol Dial Transplant 2016 ; 31 : 1386 – 1391 . Google Scholar CrossRef Search ADS PubMed 19. Dunn CJ , Peters DH . Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus . Drugs 1995 ; 49 : 721 – 749 . Google Scholar CrossRef Search ADS PubMed 20. World Health Organization . Guideline: Sodium Intake for Adults and Children . WHO Document Production Services : Geneva, Switzerland , 2012 . © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

American Journal of HypertensionOxford University Press

Published: Apr 10, 2018

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