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Saudi Journal of Kidney Diseases and Transplantation
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Year : 1997  |  Volume : 8  |  Issue : 4  |  Page : 410-413
Salt Excretion and Hypertension in Experimental Animals

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How to cite this article:
Wardle E N. Salt Excretion and Hypertension in Experimental Animals. Saudi J Kidney Dis Transpl 1997;8:410-3

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Wardle E N. Salt Excretion and Hypertension in Experimental Animals. Saudi J Kidney Dis Transpl [serial online] 1997 [cited 2022 Aug 9];8:410-3. Available from: https://www.sjkdt.org/text.asp?1997/8/4/410/39339

   Essential Hypertension Top

Although we label a patient as having "essential hypertension" after excluding secondary causes like renal disease, we yet do not understand precisely what its etiological factors are. Since it is commonly familial, we can reasonably suspect genetic influences but so far these have not been clearly defined. Also, we do know that at least half of hypertensive patients are "salt­sensitive", meaning that dietary salt loading will elevate these person's blood pressures. In fact, black hypertensive patients in USA and normotensive subjects who are prone to develop familial hypertension, retain more of a salt load than corresponding white persons, implying that urinary excretion of salt is delayed in these individuals.

In 1963, the Borst [1] explained their reasons for thinking that in essential hypertension the arterial blood pressure rises in order to offset an inability of the apparently normal kidneys to excrete adequate salt. On account of his interest in a necessary salt losing hormone or agent, the studies have been reviewed at regular intervals by de Wardener [2] . The scenario is that owing to the inability of the kidneys of the subject with essential hypertension to excrete adequate salt, when the dietary salt intake is more than 50 mmoles per day, sodium excretion will be inadequate. Thus, there will be expansion of the extracellular fluid (ECF) and the BP will rise. More recently, it has been suggested that there must be release of a sodium transport inhibitor from the brain [3] and that, this is an ouabain like substance [4] . Firstly, this must be a sodium-potassium ATPase inhibitor within the kidneys, thereby accounting at least in part for their inability to excrete salt [5] . Secondly, this substance causes arteriolar vasoconstriction by elevating intracellular calcium in vascular smooth muscle [3],[5],[6] .

   Strains of 'that Rat' may Yield Vital Information Top

In order to gain more information on genetic factors, workers in this field have focussed on strains of rat with genetic hypertension. Recently, there have also been many studies using transgenic animals [7] , with the aim of defining the effects of an abnormal renin or angiotensinogen gene and so on. There is the spontaneously hypertensive rat (SHR), in which at three weeks of age, the pressure-natriuretic response is blunted followed by the subsequent development of hypertension. Their renal vascular resistance is elevated accompanied by an increased tone of the afferent arterioles and there is reduced renal medullary blood flow. The diameter of the pre-glomerular arterioles is 20-30% smaller in SHR than that of normotensive Wistar-Kyoto rats. At 24 weeks of age, SHR do not have raised glomerular capillary pressures, although that might occur in old age. However, unilateral nephrectomy of SHR does lead to increased glomerular capillary pressures followed by intra-glomerular release of growth factor TGF beta resulting in glomerulosclerosis. Then, there are the stroke prone spontaneously hypertensive rats (SHR­SP), that are a substrain of SHR. They develop hypertension when fed on high sodium diet, which can be ameliorated by potassium supplementation. These animals may have an anomalous angiotensin converting enzyme (ACE) gene. Certainly by 12 weeks of age, they have elevated urinary protein excretion. They then have increased glomerular expression of TGF beta that is angiotensin II induced, and so they develop early glomerulosclerosis [8] . They also show impaired endothelium dependent vasorelaxation implying poor nitric oxide production.

Lewis K. Dahl produced from the Sprague­ Dawley line two strains of rats that were either susceptible (S) or resistant (R) to the hypertensive effects of a high salt (8% Nacl) diet. On a high salt intake, the S rats soon developed low renin hypertension. Conversely, the R rats remained normotensive in spite of a high salt intake [9] . The S rats showed poor production of epoxygenase metabolites when loaded with salt and a deficiency of the monooxygenase metabolite 20 hydroxy-eicosatetraenoic acid (HETE), which is an inhibitor of loop chloride reabsorption [10] . Even more strikingly, there was a deficiency of nitric oxide in the medullary vessels of the S rats which explains the poor excretion of salt and water. In normal rats, a high salt diet will augment nitric oxide production and augment cortical and medullary tissue levels of cGMP. If L-arginine is provided early during salt exposure of the S rats, their abnormal pressure-natriuresis curve can be corrected. The S rats seem to have a genetic defect affecting the nitric oxide synthetase of their vascular smooth muscle cells [11] . The critical alleles seem to be near the gene for atrial natriuretic peptide receptor [12] .

The Milan hypertensive rat strain (MHS) has been used in many kidney cross­transplantation studies to demonstrate that hypertension is determined by a defect in the kidney. Recently, it has been shown that there is increased membrane Na+ - K+ ATPase activity related to an abnormality of the gene for adducin [13] , which is a membrane­skeleton protein that effects coupling to several transmembrane proteins. Normal adducin inhibits actin dynamics, but a double mutated adducin results in a higher level of filamentous actin within tubular cells. In some way, this affects the Na+- K+ ATPase ion channels.

Various transgenic rats or mice have been created, so as to be able to study the effects of distinct genes. When a human renin gene or the angiotensinogen gene is put into mice separately, they have no effect on blood pressure. However, if renin and the angiotensinogen genes are introduced together, the mice develop hypertension due to angiotensin II effects on the vascular smooth muscle cells of arterioles. Transgenic mice over-expressing the Na+- H+ion exchanger, develop sodium retention and thus hypertension, which is dependant on sodium intake [14] . Conversely, delivery of human tissue kallikrein into SHR reduces their blood pressure [15] .

Increased activity of tubular Na/H + exchangers and a reduction of urinary kallikrein are features of the genetic hypertensive strains of rat. Many studies have demonstrated that the activity of the Na/H "'exchanger NHE-1 is increased in a subset of patients with essential hypertension. This could be due to intracellular calcium acting on a Ca­-calmodulin site of the NHE-1 enzyme.

Hypertension due to Vascular Reactivity as in SHR When examining the biochemical pharmacology of the kidneys of the various rat strains, one has to bear in mind that raised renal vascular resistance is determined by the factors listed in [Table - 1].

Vascular smooth muscle of SHR shows increased reactivity, and there is increased tubulo-glomerular feedback in spite of the raised blood pressure. Both erythrocytes and smooth muscle of SHR show increased Na+­-K+ ATPase activity. Renal tubular Na+- K + ATPase activity is enhanced and that accounts for sodium retention at an early stage.

The angiotensin 1 (ATI) receptors on the renal vascuiature of SHR respond to angiotensin II with exaggerated vasoconstriction. Also, there is increased thromboxane biosynthesis in these rats [16] . Thromboxane is an intermediary for the action of angiotensin II.

In general, plasma and renal noradrenaline levels are higher in SHR than normotensive rats. There are increased renal alpha 1 and alpha 2 adrenoceptors in SHR at the pre­hypertensive stage (3-7 weeks) and even at the 22 week established hypertension stage [17] . Any activation of these receptors mitigates against good salt and water excretion. It is also known that vasorelaxation through the beta­adrenoceptors is impaired in SHR [17] . In all, one suspects that the cyclic AMP system is defective in SHR, and there is experimental evidence that accords with this [18] . In SHR, the cAMP down-regulatory control might not be responding to kinins, E-prostaglandins or dopamine. In fact, we do know that high salt intake down-regulates tissue kallikrein, the precursor of kinins, in SHR [19] as well as Dahl-SS rats. Also, there probably are subtle defects in the generation of nitric oxide in SHR [20] .

   Enzyme Determined Anomalies of Salt Balance Top

The renal monooxygenase and microsomal p450 arachidonic acid epoxygenase pathways [21] [Figure - 1] explain some aspects of renal salt handling in rats that could explain the occurrence of hypertension.

The enzymes, monooxygenases and the epoxygenases are part of the cytochrome p450 microsomal enzyme systems found in the proximal tubules of the kidneys in particular, but also in other parts of the tubules as well as the mesangial cells. As shown in [Figure - 2], they utilize arachidonic acid to produce a variety of products, many of which affect ion channels. Herein probably lies their connection with hypertension. It has been discovered that the increased renal vascular resistance of SHR is supported by increased synthesis of the potent renal vasoconstrictor 20-HETE [22] . Furthermore, 19/20 HETE could account for the increased renal tubular Na+ - K+ ATPase activity that leads to retention of sodium in the early stage of hypertension in SHR. Treatment of SHR with stannous chloride to block the cytochrome p450 family 4A enzyme, stops formation of 20 HETE and then hypertension does not develop [23] .

In normotensive normal rats, salt loading induces the kidney epoxygenases and their products to regulate salt excretion by the tubules [24] . In fact, when rats on a high salt diet are treated with the epoxygenase inhibitor cotrimazole, there is then a rise of blood pressure. The metabolite 5,6 EET [Figure - 2] is a powerful inhibitor of sodium reabsorption in the distal nephron [25] . It is found that after uninephrectomy there is induction of renal epoxygenase in the remaining kidney that accompanies the hyperfiltration required to achieve salt and water excretion [26] . So without doubt, the renal epoxygenase products induced by salt intake will prevent sodium retention, volume expansion and systemic hypertension.

   Deductions Concerning Human Hypertension Top

Do these finding mean that there are men with hypertension in whom the epoxygenase system is defective? We do know that Dahl-S rats that are given salt fail to induce their renal epoxygenases. We also know that salt sensitive humans are characterized by their low urinary kallikrein excretion [27] . The need now is to know how the kallikreinkinin, the nitric oxide and the epoxygenase systems are related [28] . Is it all genetic or, are there biochemical interactions?

   References Top

1.Borst JGG, Borst de Gues A. Hypertension explained by Starling's theory of circulatory homeostasis. Lancet 1963;l:677-82.  Back to cited text no. 1    
2.de Wardener HE. The primary role of the kidney and salt intake in the aetiology of essential hypertension: Part 1. Clin Sci 1990;79:193-200.  Back to cited text no. 2  [PUBMED]  
3.de Wardener HE. Sodium transport inhibitors and hypertension. J Hypertens Suppl 1996;14(5):S9-18.  Back to cited text no. 3    
4.Gonick HC, Kramer HJ, Paul W, Lu E. Circulating inhibitor of sodium­potassium activated adenosine triphosphatase after expansion of extracellular fluid volume in rats. Clin Sci Mol Med 1977;53:329-34.  Back to cited text no. 4  [PUBMED]  
5.Kurashina T, Kirchner KA, Granger JP, Patel AR. Chronic sodium-potassium ATPase inhibition with ouabain impairs renal haemodynamics and pressure natriuresis in the rat. Clin Sci Colch 1996;91:497- 502.  Back to cited text no. 5  [PUBMED]  
6.de Wardener HE, MacGregor GA. Dahl's hypoth esis that a saluretic substance may be responsiblefor a sustained rise in arterial blood pressure: its possible role in essential hypertension. Kidney Int 1980;18:l-9.  Back to cited text no. 6    
7.Mullins JJ, Mullins LJ. Transgenes, hypotheses and hypertension. Hypertension 1994;23:428-30.  Back to cited text no. 7  [PUBMED]  
8.Nakamura T, Obata J, Kuroyanagi R, et al. Involvement of angiotensin II in glomerulosclerosis of stroke-prone spontaneously hypertensive rats. Kidney Int Suppl 1996;55:S109-12.  Back to cited text no. 8  [PUBMED]  
9.Rapp JP. Dahl salt susceptible and salt resistant rats. A review. Hypertension 1982;4:753-63.  Back to cited text no. 9    
10.Zou AP, Drummond HA, Roman RJ. Role of 20- HETE in elevating loop chloride reabsorption in Dahl SS/Jr rats. Hypertension 1996;27:631-5.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Sanders PW. Salt sensitive hypertension: lessons from animal models. Am J Kidney Dis 1996;28:775-82.  Back to cited text no. 11  [PUBMED]  
12.Deng Y, Rapp JP. Consegregation of blood pressure with angiotensin converting enzyme and arterial natriuretic peptide receptor genes using Dahl salt sensitive rats. Nat Genet 1992;l:267-72.  Back to cited text no. 12    
13.Tripodi G, Valtorta F, Toricelli L, et al. Hypertension associated point mutations in the adducing alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest 1996;97:2815-22.  Back to cited text no. 13    
14.Kuro-o M, Hanaoka K, Hiroi Y, et al. Salt sensitive hypertension in transgenic mice over-expressing Na + - proton exchanger. Circ Res 1995;76:148-53.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Wang C, Chao L, Chao J. Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats. J Clin Invest 1995;95:1710-16.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Shibouta Y, Terashita ZI, Inada Y, Nishikawa K, Kikuchi S. Enhanced thromboxane A2 biosynthesis in the kidney of spontaneous hypertensive rats during development of hypertension. Eur J Pharmacol 1981;70:247-56.  Back to cited text no. 16  [PUBMED]  
17.Takata Y, Kato H. Adrenoceptors in SHR: alterations in binding characteristics and intracellular signal transduction pathways. Life Sci 1996;58:91-106.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Ruan X, Arendshorst WJ. Role of protein kinase C in angiotensin II induced renal vasoconstriction in genetically hypertensive rats. Am J Physiol 1996;270:F945-52.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Wang C, Chao C, Chen LM, Chao L, Chao J. High-salt diet upregulates kininogen and down regulates tissue kallikrein expression in Dahl-S and SHR rats. Am J Physiol 1996;271:F824-30.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Singh. A, Sventek P, Lariviere R, Thibault G, Schiffrin EL. Inducible nitric oxide synthase in vascular smooth muscle cells from prehypertensive spontaneous hypertensive rats. Am J Hypertens 1996;9:867-77.  Back to cited text no. 20    
21.Laniado-Schwartzman M, Abraham NG. The renal cytochrome P-450 arachidonic acid system. Pediatr Nephrol 1992;6:490-8.  Back to cited text no. 21  [PUBMED]  
22.Makita K, Falck JR, Capdevila JH. Cytochrome P450, the arachidonic acid cascade, and hypertension: new vistas for an old enzyme system. Faseb J 1996;10:1456-63.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]
23.Sacerdoti D, Escalante B, Abraham NG, McGiff JC, Levere RD, Schwartzman ML. Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats. Science 1989;243:388-90.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Makita K, Takahashi K, Karara A, Jacobson HR, Falck JR, Capdevila JH. Experimental and/or genetically controlled alterations of the renal microsomal cytochrome P450 epoxygenase induce hypertension in rats fed a high salt diet. J Clin Invest 1994;94:2414-20.  Back to cited text no. 24  [PUBMED]  [FULLTEXT]
25.Sakairi Y, Jacobson HR, Noland TD, Capdevila JH, Falck JR, Breyer M. 5,6­EET inhibits ion transport in collecting duct by stimulating endogenous prostaglandin synthesis. Am J Physiol 1995;268:F931-9.  Back to cited text no. 25    
26.Takahashi K, Harris RC, Capdevila JH, et al. Induction of renal arachldonate cytochrome P-450 epoxygenase after uninephrectomy: counterregulation of hyperfiltration. J Am Soc Nephrol 1993;3(8):1496-500.  Back to cited text no. 26    
27.Ferri C, Bellini C, Carlomagno A, Perrone A, Santucci A. Urinary kallikrein and salt sensitivity in essential hypertensive males. Kidney Int 1994;46:780-8.  Back to cited text no. 27  [PUBMED]  
28.Woolfson RG, de Wardener HE. Primary renal abnormalities in hereditary hypertension. Kidney Int 1996;50:717-31.  Back to cited text no. 28  [PUBMED]  

Correspondence Address:
E Nigel Wardle
21, Common Road, North Leigh, Oxford OX8 6RD, England
United Kingdom
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