Acute Sodium Loading in Dahl-S Rats: Alterations in Renal and Vascular Sodium Pump Inhibition Amidst Unaltered Cardiotonic Steroid Levels?

It has previously been reported that hypertension is the number one risk factor for mortality in developed regions of the world, as well as in some emerging areas.1 In a large percentage of the population with hypertension, the increased blood pressure is salt-induced and may result from insufficient urinary sodium excretion. In these individuals, the circulating levels of endogenous cardiotonic steroids (CTSs) that inhibit the Na, K-ATPase (NKA), such as marinobufagenin (MBG) or endogenous ouabain (EO), may be increased by sodium, and CTS may contribute to or mediate the elevation in blood pressure. In an article in this issue, Bagrov et al. compare the effects of acute sodium loading in a rat model of salt-induced hypertension, the Dahl salt-sensitive rat (Dahl-S), vs. the effects in a normotensive strain, the Sprague-Dawley rat (S-D).2 S-D was chosen as the control strain over the more frequently used Dahl salt-resistant rat (Dahl-R) because S-D more closely resembles salt-resistant, normotensive humans in the responses of circulating MBG to salt and because the renal NKA in Dahl-R is unusually resistant to MBG, compared with other rat strains. In renal tubular cells, the NKA normally acts to reabsorb sodium and thus NKA inhibition by CTS has a natriuretic (and thereby antihypertensive) effect. CTS can similarly inhibit the NKA in vascular smooth muscle (VSM), causing enhanced VSM contractility. In contrast to the effects of NKA inhibition in the renal tubules, inhibition of this enzyme in VSM tends to increase blood pressure. Bagrov et al. show that acute sodium loading increases plasma and urinary CTS to a similar extent in Dahl-S and S-D.2 Therefore, the different blood pressure responses to sodium loading between the two strains and other inter-strain differences (Dahl-S had greater changes in systolic blood pressure and sodium pump inhibition in the aorta than S-D, but reduced urinary sodium excretion and renal NKA inhibition) cannot be explained by exaggerated increases in CTS levels in Dahl-S. How then can one explain the conundrum that the CTS responses to acute sodium loading are equivalent in Dahl-S and S-D, yet the levels of NKA inhibition after sodium loading are different between the two strains and vary from one tissue to another (greater NKA inhibition in the aorta of Dahl-S vs. S-D, but less inhibition in the kidney)? This article offers a potential way to reconcile such seemingly incongruent findings: the authors show that the responses of plasma atrial natriuretic peptide (ANP) and urinary cGMP excretion to acute hypertonic saline were attenuated in Dahl-S vs. S-D.2 The authors have previously demonstrated that ANP produces alterations in NKA in the renal medulla via cGMP-dependent phosphorylation of NKA.3 This phosphorylation enhances the sensitivity of the renal sodium pump to inhibition by MBG (which would tend to increase urinary sodium excretion). In VSM, ANP appears to cause the opposite effect, resulting in dephosphorylation of NKA and desensitization of this enzyme to MBG.3 Thus, the difference between Dahl-S and S-D in the ANP response to sodium loading can account for the other differences that are presently seen between the two strains, including those in blood pressure, sodium pump activities in the kidney and aorta, urinary sodium and cGMP excretion. Most novel findings in turn give rise to new inquiries. Questions that might stem from the authors' study, in combination with previous studies, include: (i) How does ANP cause dephosphorylation/desensitization of NKA in one tissue and the opposite effects in another? (ii) What are the mechanisms that cause the attenuation of the ANP response in Dahl-S? (iii) Since brain CTS such as the endogenous ouabain (EO) appear to regulate circulating levels of MBG after acute sodium loading,4,5 what role, if any, does the brain EO play in the plasma MBG response in chronic salt-sensitive hypertension? (iv) Since plasma [ANP] may be profoundly influenced by brain regions that also contain EO,6 is the regulation of plasma [ANP] and [MBG] coordinated? Such findings and the ensuing questions should provide the impetus for future examinations of the mechanisms of CTS-mediated responses to salt in physiological and pathophysiological states. The author declared no conflict of interest. This work was supported by a Grant-in-aid from the Heart and Stroke Foundation of Ontario (NA-6324).

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