Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension
Open accessAbstract
Prevailing theory holds that abnormally large increases in renal salt retention and cardiac output are early pathophysiologic events mediating initiation of most instances of salt-induced hypertension. This theory has come under increasing scrutiny because it is based on studies that lack measurements of sodium balance and cardiac output obtained during initiation of salt-loading in proper normal controls, i.e., salt-resistant subjects with normal blood pressure. Here we make the case for a “vasodysfunction” theory for initiation of salt-induced hypertension: In response to an increase in salt intake, a subnormal decrease in total peripheral resistance that involves a subnormal decrease in renal vascular resistance, in the absence of abnormally large increases in sodium retention and cardiac output, is the hemodynamic abnormality that usually mediates initiation of salt-induced increases in blood pressure (BP). It is the failure to normally decrease vascular resistance in response to salt loading that enables a normal increase of cardiac output to initiate the salt-induced increase in blood pressure. This theory is based on the results of properly controlled studies which consistently demonstrate that in salt-sensitive subjects, salt-loading initiates increased BP through a hemodynamic mechanism that: 1) does not usually involve early increases in sodium retention and cardiac output greater than those which occur with salt-loading in normal controls, and 2) usually involves an early failure to decrease vascular resistance to the same extent as that observed during salt-loading in normal controls. Multiple mechanisms including disturbances in nitric oxide and sympathetic nervous system activity likely underlie this subnormal vasodilatory response to salt that usually precedes and initiates salt-induced hypertension.
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Neither Guyton and his colleagues nor most other researchers investigating salt sensitivity abnormalities published studies measuring sodium balance, cardiac output, and systemic vascular resistance during salt loading in healthy people or animals.
“Also surprisingly,18, 19, 26 neither Guyton and his colleagues, nor most other investigators searching for abnormalities mediating salt sensitivity, published studies of sodium balance, cardiac output, and systemic vascular resistance responses to salt-loading in normal humans or animals.”
From Testing Computer Models Predicting Human Responses to a High-Salt Diet: Implications for Understanding Mechanisms of Salt-Sensitive Hypertension (2018) · cites this paper as [18]
In “The Lack of Appropriate Normal Controls in Studies of Salt-Induced Increases in Blood Pressure” (page unavailable), the paper says studies cited for the volume-loading theory did not compare salt-sensitive subjects with normal controls on sodium balance, cardiac output, and systemic vascular resistance during salt loading. That supports the concern about missing normal-control comparisons, but it does not establish that Guyton and his colleagues, or most other investigators, published no studies measuring those responses in normal humans or animals. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn salt-sensitive individuals, the rises in sodium balance and cardiac output after acute salt loading are no larger than those seen in salt-resistant healthy controls.
“While increases in sodium balance and cardiac output occur in response to acute salt loading, the increases that occur in salt sensitive subjects are not greater than those that occur in salt resistant normal controls.18, 19, 26”
From Testing Computer Models Predicting Human Responses to a High-Salt Diet: Implications for Understanding Mechanisms of Salt-Sensitive Hypertension (2018) · cites this paper as [18]
In “The Natriuretic and Hemodynamic Responses of Salt-Sensitive Subjects to Increases in Salt Intake” (page not provided), the paper says sodium retention and cardiac-output increases in salt-sensitive subjects are usually no greater than in normal controls. The claim omits “usually” and states the comparison categorically for salt-sensitive individuals, while the paper’s direct comparison focuses on normotensive salt-sensitive humans. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAccording to the vasodysfunction theory of salt sensitivity, salt loading makes normal subjects substantially lower their systemic vascular resistance, which offsets the potential pressor effect of increased cardiac output, while salt-sensitive subjects do not do this.
“These observations are also consistent with the vasodysfunction theory of salt sensitivity18, 19 which holds that in response to salt loading, normal subjects undergo substantial decreases in systemic vascular resistance that offset potential pressor effects of salt-induced increases in cardiac output whereas salt sensitive subjects do not.”
From Testing Computer Models Predicting Human Responses to a High-Salt Diet: Implications for Understanding Mechanisms of Salt-Sensitive Hypertension (2018) · cites this paper as [18]
In light of the current studies and previous animal and human experiments, the use of these models by Guyton and colleagues to reorient understanding of hypertension causes appears to have been overreaching.
“However, in light of the results of the current studies with the 1972 Guyton model and its derivatives, together with those of previous experimental studies in animals47–50 and humans,15, 18, 51, 52 the use of the models by Guyton and colleagues to “reorient understanding” of the causes of hypertension appears to have been overreaching.”
From Testing Computer Models Predicting Human Responses to a High-Salt Diet: Implications for Understanding Mechanisms of Salt-Sensitive Hypertension (2018) · cites this paper as [18]
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References 138 · Cited by 123
Research works printed but not linked: 2
- [62]Guyton AC Circulatory Physiology III: Arterial Pressure and Hypertension 1980 Philadelphia W.B. Saunders
- [65]Guyton AC Hall JE Coleman TG Manning RD Norman RA Jr Laragh JH Brenner BM The Dominant Role of the Kidneys in Long-Term Arterial Pressure Regulation in Normal and Hypertensive States Hypertension: Pathophysiology, Diagnosis, and Management 1995 1 2 New York Raven Press, Ltd 1311 1326
- Authors
- Morris, R. C., Schmidlin, O., Sebastian, A., Tanaka, M., & Kurtz, T. W.
- Affiliations
- University of California, San Francisco (US)
- From the Departments of Medicine (R.C.M., O.S., A.S., M.T.) and Laboratory Medicine (T.W.K.), University of California, San Francisco.
- ORCID
- Kurtz, Theodore W.
- Venue
- Circulation
- Published
- 2016-03
- Volume
- 133
- Issue
- 9
- Pages
- 881-893
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC4778403
- OpenAlex
- W2314336385
- Semantic Scholar
- 5a4be7f1446a5dc44e4cf8ae86eff8bf68e7d815
- Cited by
- 123
- References
- 138
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 10 · 2023: 8 · 2022: 11 · 2021: 14 · 2020: 13 · 2019: 10 · 2018: 16 · 2017: 15 · 2016: 11
- FWCI
- 18.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5m01rr000079-42)
- National Heart, Lung, and Blood Institute (R01HL064230, R01-HL64230)
- National Center for Research Resources (M0 RR-00079, M01-RR000079)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- salt-induced hypertension, renal vascular resistance, systemic vascular resistance, sodium retention, cardiac output, salt loading, salt-sensitive hypertension, nitric oxide, sympathetic activity
- MeSH terms
- Animals, Hemodynamics, Humans, Hypertension, Kidney, Kidney Diseases, Vasodilation, Sodium Chloride, Dietary
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