Home Nephro News Low dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents.

Low dose L-NAME induces salt sensitivity associated with sustained increased blood volume and sodium-chloride cotransporter activity in rodents.

Credits to the Source Link Obum
Large image of abstract-image.

In animals treated with low-dose L-NAME, our results suggest that the initiation of salt-induced hypertension may be mediated by subnormal vasodilation in response to salt loading and not abnormally large increases in blood volume in response to salt loading. Our results further suggest that in the L-NAME-treated animals, the maintenance of hypertension with a high salt diet may require abnormally high renal tubular NCC activity and blood volume. The abnormally high level of NCC activity may be mediated by the effects of oxidative stress on the phosphorylation of NCC.

NO in the kidney could be derived from any isoform of NO synthase 22x22Mount, P.F. and Power, D.A. Nitric oxide in the kidney: Functions and regulation of synthesis. Acta Physiol (Oxf). 2006;
187: 433–446
Crossref | PubMed | Scopus (150)
| Google ScholarSee all References

Blood volume expansion was associated with increased blood pressure on day 1 of high salt intake in the L-NAME+HS group, but in the control group, the same blood volume expansion was not associated with an increase in blood pressure on day 1. This finding demonstrated that elevated blood volume is not sufficient for the initiation of hypertension. The results suggest that within the first 24 hours of salt loading, the L-NAME+HS animals failed to normally vasodilate and reduce systemic vascular resistance in response to salt loading and blood volume expansion. In contrast, the normal controls may have responded to the same degree of salt-induced volume expansion by vasodilating and reducing systemic vascular resistance, which prevents the salt-induced increases in blood volume from increasing blood pressure, which is consistent with previous studies5x5Beard, D.A. Assessing the Validity and Utility of the Guyton Model of Arterial Blood Pressure Control. Hypertension. 2018;
72: 1272–1273
Crossref | PubMed | Scopus (1)
| Google ScholarSee all References
,6x6Morris, R.C. Jr., Schmidlin, O., Sebastian, A., Tanaka, M., and Kurtz, T.W. Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension. Circulation. 2016;
133: 881–893
Crossref | PubMed | Scopus (46)
| Google ScholarSee all References
,7x7Kurtz, T.W., DiCarlo, S.E., Pravenec, M., Ježek, F., Šilar, J., Kofránek, J., and Morris, R.C. Jr. Testing Computer Models Predicting Human Responses to a High-Salt Diet. Hypertension. 2018;
72: 1407–1416
Crossref | PubMed | Scopus (4)
| Google ScholarSee all References
,8x8Evans, R.G. and Bie, P. Role of the kidney in the pathogenesis of hypertension : time for a neo-Guytonian paradigm or a paradigm shift ?. Am J Physiol Regul Integr Comp Physiol. 2016;
310: 217–229
Crossref | PubMed | Scopus (24)
| Google ScholarSee all References
,13x13Schmidlin, O., Sebastian, A.F., and Morris, R.C. Jr. What initiates the pressor effect of salt in salt-sensitive humans? Observations in normotensive blacks. Hypertension. 2007;
49: 1032–1039
Crossref | PubMed | Scopus (57)
| Google ScholarSee all References
,14x14Schmidlin, O., Forman, A., Leone, A. et al. Salt sensitivity in blacks: evidence that the initial pressor effect of NaCl involves inhibition of vasodilatation by asymmetrical dimethylarginine. Hypertension. 2011;
58: 380–385
Crossref | PubMed | Scopus (40)
| Google ScholarSee all References
,15x15Kurtz, T.W., DiCarlo, S.E., and Pravenec, M. The pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension. Curr OpinNephrol Hypertension. 2018;
27: 83–92
Crossref | PubMed | Scopus (6)
| Google ScholarSee all References
,16x16Kurtz, T.W., DiCarlo, S.E., Pravenec, M., and Morris, R.C. Changing views on the common physiologic abnormality that mediates salt sensitivity and initiation of salt-induced hypertension: Japanese research underpinning the vasodysfunction theory of salt sensitivity. Hypertens Res. 2019;
42: 6–18
Crossref | PubMed | Scopus (5)
| Google ScholarSee all References
,17x17Laffer, C.L., Scott, R.C., Titze, J.M. et al. Hemodynamics and Salt-and-Water Balance Link Sodium Storage and Vascular Dysfunction in Salt-Sensitive Subjects. Hypertension. 2016;
68: 195–203
Crossref | PubMed | Scopus (33)
| Google ScholarSee all References
. The decrease in blood volume was associated with an increase in urinary sodium excretion. This finding suggests that to maintain salt-sensitive hypertension, sodium retention and increases in blood volume are necessary. In the current study, we clarified the potential role of NCC in maintaining a high circulating volume after L-NAME treatment both in vivo and in vitro.

In vivo experiments showed that HCTZ but not amiloride induced a strong natriuretic effect in the L-NAME plus HS group, which suggests that NCC, but not ENaC, may be responsible. This result is partly consistent with a previous study on nephron-specific disruption of NOS3 in mice, in which phosphorylated and total NCC, but not ENaC, were elevated in the KO mice after 4 hours of an acute 3.2% Na+ load 28x28Gao, Y., Stuart, D., Takahashi, T. et al. Nephron-Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion. J Am Heart Assoc. 2018;
7: e009236
Crossref | PubMed | Scopus (5)
| Google ScholarSee all References

L-NAME changes renal blood flow 30x30Dobrowolski, L. and Kuczeriszka, M. Role of atrial natriuretic peptide in mediating the blood pressure-independent natriuresis elicited by systemic inhibition of nitric oxide. Pflugers Arch. 2015;
10: 833–841
Crossref | Scopus (5)
| Google ScholarSee all References

The renal brush border has high ACE activity, which contributes to intrarenal angiotensin II formation in vivo, and local ACE in the kidney was reported to play a pivotal role in L-NAME-induced salt sensitivity 28x28Gao, Y., Stuart, D., Takahashi, T. et al. Nephron-Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion. J Am Heart Assoc. 2018;
7: e009236
Crossref | PubMed | Scopus (5)
| Google ScholarSee all References

TEMPO did not completely reduce the BP level back to the control level, thus suggesting that in addition to oxidative stress, other pathways might be involved in L-NAME-induced salt sensitivity. It has been shown that NKCC2 plays a role in the NO-related sodium balance 33x33Ramseyer, V.D., Ortiz, P.A. et al. Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs. Am J Physiol Renal Physiol. 2016;
310: 748–754
Crossref | PubMed | Scopus (1)
| Google ScholarSee all References

There are limitations in our study. The major limitation of the study is that we did not monitor cardiac output and vascular resistance during initiation or maintenance of salt-induced hypertension; therefore, we can only speculate on the hemodynamic mechanisms through which low-dose L-NAME treatment enables a high-salt diet to initiate and maintain hypertension. We did not directly examine NCC activity by measuring sodium transport but by pharmacological examination in response to HCTZ and amiloride. Although we could not change the local NO levels solely in the kidney using kidney-specific knockout of three subtypes of NOS, our model is closer to the clinical condition than other models. This study used a rodent model, and it is unclear if the results are applicable in humans; however, in human studies, it has been reported that NOS polymorphisms and decreased NOS activity are common in black or aging people who have a high prevalence of salt-sensitive hypertension 35x35Stephen, T., Chapman, A.B., and Schwartz, G.L. Effects of Endothelial Nitric Oxide Synthase, a-Adducin, and Other Candidate Gene Polymorphisms on Blood Pressure Response to Hydrochlorothiazide. AJH. 2003;
16: 834–839
Google ScholarSee all References
,36x36Elijovich, F., Weinberger, M.H., Anderson, C.A.M. et al. Salt Sensitivity of Blood Pressure A Scientific Statement From the American Heart Association. Hypertension. 2016;
68: 37–46
Crossref | Scopus (121)
| Google ScholarSee all References
,37x37Svetkey, L.P., McKeown, S.P., and Wilson, A.F. Heritability of salt sensitivity in black Americans. Hypertension. 1996;
28: 854–858
Crossref | PubMed | Scopus (83)
| Google ScholarSee all References
,38x38Sverdlov, A.L., Ngo, D.T., Chan, W.P., Chirkov, Y.Y., and Horowitz, J.D. Aging of the nitric oxide system: are we as old as our NO?. J Am Heart Assoc. 2014;
18: 3–7
Google ScholarSee all References
, and salt-sensitive humans release less NO during NO agonist administration than patients with salt-resistant essential hypertension 39x39Ghiadoni, L., Virdis, A., Taddei, S. et al. Defective nitric oxide pathway in salt-sensitive essential hypertensive patients. Am J Hypertens. 1997;
10: 20–25
Crossref
| Google ScholarSee all References

In conclusion, the initiation of salt sensitivity in normotensive rodents could be due to hyporeactivity of the vasculature, and maintaining blood pressure could results in a high circulating volume due to inappropriate NCC activity in the low-dose L-NAME model. L-NAME impairs natriuresis by activating NCC via the oxidative stress/pSPAK pathway and induces blood volume expansion, finally leading to established salt-sensitive hypertension.

Source Link

Related Posts

Leave a Comment

This website uses cookies to improve your experience. We will assume you are ok with this, but you can opt-out if you wish. Accept Read More

%d bloggers like this: