(Hypertension. 1997;30:636.)
© 1997 American Heart Association, Inc.
Articles |
Plasma Triglycerides and Red Cell Ion Transport Alterations in Genetically Hypertensive Rats
From the Institute of Physiology, Academy of Sciences of the Czech Republic, Prague.
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Abstract |
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Abstract Ion transport abnormalities in essential hypertension are often associated with concomitant changes of lipid metabolism, but this information is missing in rats with genetic hypertension. We therefore studied the alterations of red cell Na+ and K+ transport and their relationship to blood pressure and plasma lipids (cholesterol and triglycerides) in Prague hereditary hypertriglyceridemic (HTG) rats, Lyon hypertensive (LH) rats, and HTGxLewis F2 hybrids. In both hypertensive models and F2 hybrids, red cell Na+ content (Na+i) was positively related to plasma triglycerides but not to plasma cholesterol levels. Na+i elevation was more pronounced in HTG than in LH rats, probably due to higher plasma triglycerides in the former strain. The two hypertensive strains differed in bumetanide-sensitive Na+ transport, which was augmented in HTG rats with low plasma cholesterol but suppressed in LH rats characterized by high cholesterol levels. In the two genetic models, there was a positive association of blood pressure with Na+ leak, and this was also confirmed by the cosegregation of these parameters in F2 hybrids. We conclude that the enhancement of Na+ leak represents the major ion transport abnormality in rats with genetic hypertension. The alterations in plasma lipids are important determinants of abnormal red cell ion transport in hypertensive models studied. Although the detailed mechanism of their participation in ion transport regulation is still not completely understood, triglyceride-dependent changes in membrane microviscosity seem to be responsible for the modulation of particular ion transport pathways.
Key Words: blood pressure • erythrocytes • Na+-K+ cotransport • Na+-K+ pump • plasma triglycerides • plasma cholesterol
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Introduction |
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Ion transport alterations in humans are often associated with abnormal lipid metabolism. This is also true for numerous ion transport defects seen in erythrocytes of essentially hypertensive patients. Such relationships can be best illustrated by the example of the Na+-Li+ countertransport, which is one of the most studied ion transport systems. The increased activity of the Na+-Li+ countertransport system in hyperlipidemic and/or hypertensive patients1 2 3 can be reduced by lipid-lowering therapy.4 5 The kinetic properties of this transport system are dependent on the lipid composition of the erythrocyte membrane.5 6 7 Dietary modification of membrane lipid composition often affects the kinetic properties of various Na+ transporting systems, including the Na+-K+ pump, Na+-K+-2Cl- cotransport, Na+ leak, and also partially Na+-Li+ countertransport.8 9 The activity of Na+-Li+ countertransport is not only inversely related to the membrane content of polyunsaturated fatty acids6 10 11 but also depends on the amount and distribution of cholesterol10 11 12 as well as on the content of particular classes and molecular species of phospholipids in the red cell membrane.7 10 13 14
Cholesterol-to-phospholipid (C:P) ratio is an important determinant of membrane fluidity. This is a reason for the association of elevated membrane microviscosity with altered kinetics of the Na+-Li+ countertransport system.15 16 It is important to note that both C:P ratio17 18 and membrane microviscosity17 19 20 are inversely related to plasma triglyceride levels. These relationships are the explanation for the frequently reported positive correlations of plasma triglycerides with the activity of the Na+-Li+ countertransport system,3 4 21 22 23 the Na+-K+-2Cl- cotransport system,22 24 25 the Na+-K+ pump,21 24 and Na+ leak.21 25 The influence of plasma triglycerides on the activity of the above red cell transport systems is usually more pronounced than that of plasma cholesterol, although HDL cholesterol (namely the HDL2 fraction) has a strong inverse relationship to these ion transport systems.21 24 25
In contrast to humans, there is only scarce information on the relationship between red cell ion transport and abnormalities of lipid metabolism, although multiple ion transport alterations were also disclosed in erythrocytes of spontaneously hypertensive rats (SHR) (for review see Reference 2626 ) and other rat strains with genetic hypertension.27 28 29 30
At present, there are several independently selected rat strains with genetic hypertension accompanied by abnormal lipid metabolism. In this study we tried to compare two of them: Lyon hypertensive (LH) rats and Prague hereditary hypertriglyceridemic (HTG) rats. Three Lyon inbred rat strains were originally selected from Sprague-Dawley rats for different blood pressure level,31 and they are characterized by changes in plasma cholesterol and triglycerides.32 On the other hand, HTG rats were originally selected from Wistar rats for elevated plasma triglycerides,33 and they were also found to be hypertensive.34 LH and HTG animals differ substantially in plasma cholesterol level, which is elevated in LH but reduced in HTG compared with respective controls.
The aim of the present study was to investigate the changes in red cell Na+ and K+ transport and their relationship to blood pressure and plasma lipids (triglycerides and cholesterol) in the above two hypertensive and dyslipidemic rat strains. Our attention was focused on in vivo red cell Na+ content (Na+i) and Na+ and K+ (Rb+) movements mediated by the Na+-K+ pump, Na+-K+-2Cl- cotransport, and passive membrane permeability (cation leaks) that represent major mechanisms responsible for erythrocyte Na+i level. Cation transport through the above pathways was therefore estimated under the conditions when intracellular and extracellular Na+ and K+ (Rb+) concentrations were close to in vivo values. Our study offers a unique possibility to compare ion transport alterations in the two strains of genetically hypertensive rats differing not only in their genetic origin but also in the abnormalities of lipid metabolism.
To verify the associations between ion transport alterations and lipid abnormalities that were disclosed by the comparison of hypertensive strains with their controls, we have prepared a set of HTGxLewis F2 hybrids in which we measured red cell ion transport and plasma lipids by the same techniques.
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Methods |
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Animals
Male inbred LH, Lyon normotensive (LN), and Lyon low-blood-pressure (LL) rats (n=10 of each strain, kindly provided by Prof M. Vincent and Prof J. Sassard, Faculty of Pharmacy, Université Claude Bernard, Lyon, France), as well as HTG rats and normotensive Wistar-derived Lewis rats (n=12 of each strain, Institute of Physiology AS CR, Prague), were used at the age of 3 months. Age-matched HTGxLewis F2 hybrids (n=65) were obtained from the cross of normotensive Lewis females with hypertensive HTG males. The experimental protocol and animal care were approved by the Ethical Committee (Institute of Physiology AS CR, Prague).
Two days before the experiment, plasma triglycerides, total cholesterol, and uric acid were determined by using commercially available kits (Lachema) in the blood obtained from the tail vessels of unfasted animals. On the day of experiment, blood pressure was measured under light ether anesthesia by a direct puncture of the carotid artery.
Ion Transport Measurements
Hematocrit and hemoglobin, as well as Na+ and
K+ contents in fresh erythrocytes, were determined in
heparinized blood withdrawn from the abdominal aorta. Cation transport
mediated by the Na+-K+ pump or the
Na+-K+-2Cl- cotransport system and
cation movements reflecting passive membrane permeability were studied
as described in detail elsewhere.35 Erythrocytes were
washed three times with saline medium (in mmol/L: NaCl 140,
glucose 5, phosphoric acid 2.5, MOPS 10, pH 7.4 at 37°C, 310 mOsm/L)
and incubated in the same medium containing 3.5 mmol/L RbCl
for 30 minutes at 37°C. Net Na+ movements and
unidirectional Rb+ (K+) fluxes were assessed at
intracellular Na+ and extracellular Rb+
(K+) concentrations that were close to those found in vivo.
Ouabain (5 mmol/L) and bumetanide (100
µmol/L) were used to inhibit the
Na+-K+ pump (ouabain-sensitive Na+
net extrusion and Rb+ [K+] uptake) and the
Na+-K+-2Cl- cotransport system
(bumetanide-sensitive [BS] Na+ net uptake and
Rb+ [K+] uptake). Cation leaks were defined
as residual fluxes resistant to both ouabain and bumetanide.
Red cell cation contents and transport rates were expressed per mean
cell hemoglobin content found in particular animals.
Statistical Analyses
Results were expressed as mean±SEM, and the statistical
differences were evaluated by one-way analysis of variance and
least significant difference test. Linear correlation analysis
was used to test the relationships among blood pressure, serum lipids,
and ion transport parameters.
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Results |
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Blood pressure, plasma triglycerides, and uric acid were significantly higher in both hypertensive strains (HTG and LH) compared with respective normotensive controls (Lewis and LN) (Fig 1). However, plasma total cholesterol was increased in LH rats only, whereas its level in HTG rats was reduced. In 3-month-old LL rats, plasma triglycerides were also elevated, and plasma cholesterol was almost as high as that of LH animals (Fig 1).
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Red cell Na+ content (Na+i) was significantly higher in both hypertensive strains than in corresponding normotensive animals (Fig 2). Na+i was also increased in erythrocytes of LL rats, which were characterized by a borderline blood pressure elevation and high plasma triglycerides. In spite of Na+i differences among the Lyon strains, there were no significant differences in the Na+-K+ pump activity. On the contrary, Na+-K+ pump activity in HTG and Lewis rats was proportional to their red cell Na+ content (Fig 2). The activity of BS Na+-K+ cotransport was clearly elevated in erythrocytes of HTG rats, but among Lyon strains it was highest in LL rats (Fig 3). In contrast to the two Lyon control strains (LN and LL rats), the operation of cotransport system(s) in erythrocytes of LH animals was characterized by very low BS net Na+ inward movement but almost normal BS Rb+ uptake. Bumetanide-resistant (BR) Na+ net uptake (Na+ leak) was moderately elevated in both hypertensive strains (Fig 3).
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It should be mentioned that plasma triglycerides were positively associated with blood pressure in all hypertensive models studied, the correlation being most significant in HTG rats (Table). Furthermore, certain red cell ion transport parameters correlated significantly with plasma triglycerides or blood pressure (Table). A positive correlation of Na+i with plasma triglycerides was observed not only in HTG rats but also in Lyon strains. In both hypertensive models, blood pressure was positively related to BR Na+ leak. Nevertheless, in HTG rats there was a borderline positive correlation of blood pressure with BS net Na+ uptake (r=.410, n=24, P<.05), whereas the reverse was true in Lyon strains (r=-0.372, n=30, P<.05). There were no significant relationships of any ion transport parameter to plasma cholesterol in either rat strain (data not shown).
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In HTGxLewis F2 hybrids, there was a highly significant association of plasma triglycerides with red cell Na+ content, together with a positive correlation between Na+ leak and blood pressure (Table). None of the red cell ion transport parameters cosegregated with plasma cholesterol level (data not shown).
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Discussion |
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The present study compared two rat models of genetic hypertension accompanied by dyslipidemia (Prague hypertriglyceridemic rats and Lyon strains). Both hypertensive strains (HTG and LH rats) were characterized by elevated plasma levels of triglycerides and uric acid, whereas plasma total cholesterol was increased in LH rats but decreased in HTG animals. Furthermore, the two strains resembled each other in mild to moderate elevations of red cell Na+ content and Na+ leak, but they differed in BS Na+ net uptake, which is mediated by the Na+-K+-2Cl- cotransport system. Its activity was augmented in HTG but reduced in LH rats. Two important associations were disclosed in both hypertensive strains: plasma triglycerides correlated positively with red cell Na+ content, and blood pressure was positively related to Na+ leak. It is important to note that both associations were confirmed by the cosegregation of these parameters in HTGxLewis F2 hybrids.
The present cosegregation of blood pressure with Na+ leak is in accordance with our earlier findings concerning the importance of Na+ leak in genetic hypertension. Similar cosegregation was demonstrated in Prague recombinant inbred strains (derived from SHRxBrown Norway F2 hybrids).36 In Dahl rats, Na+ leak was found to be especially enhanced in erythrocytes of young salt-loaded salt-sensitive animals, which developed the most severe salt hypertension.29 Na+ leak was reported to correlate positively with plasma triglycerides in essential hypertension.21 25 In our experiments, this relationship was significant in HTG rats but not in LH rats or HTGxLewis F2 hybrids.
There is an important question as to which mechanisms are responsible for the association of elevated plasma triglycerides with abnormal ion transport. The correlations between plasma triglycerides and the microviscosity of the membrane lipid core,17 19 as well as between membrane microviscosity and the activity of various erythrocyte Na+ transporting systems (Na+-K+ pump37 38 and Na+-Li+ countertransport15 16 ), were often demonstrated in humans. The changes of membrane microviscosity are usually caused by alterations in membrane lipid composition.39 Membrane C:P ratio, which is positively related to DPH anisotropy (reflecting the microviscosity of the membrane lipid core), correlates negatively with plasma triglycerides.17 18 The decreased C:P ratio in patients with elevated plasma triglycerides is mainly based on increased total phospholipid content of the erythrocyte membrane.18 The above findings support the idea that triglyceride-dependent ion transport alterations observed in our experiments might be due to some changes in membrane microviscosity. Our recent data obtained in both Lyon40 and HTG rats41 42 indeed indicate that triglyceride dependence of cell Ca2+ handling is closely related to membrane microviscosity. It should also be noted that there are quite opposite relationships of the microviscosity of particular membrane domains (outer membrane leaflet and membrane lipid core) not only to cytosolic free Ca2+ concentration40 but also to plasma triglycerides.41
Although we did not find any significant relationship of red cell ion transport parameters to plasma cholesterol level, different cholesterol metabolism in the two studied hypertensive strains offers an explanation for the major difference in the Na+-K+-2Cl- cotransport activity between LH and HTG rats. As mentioned above, BS Na+ net uptake was enhanced in HTG rats with low plasma cholesterol, whereas it was reduced in LH rats characterized by high plasma cholesterol level. It is well known that the activity of the Na+-K+-2Cl- cotransport system is inversely related to membrane cholesterol content. The reduction of Na+-K+ cotransport activity seen after the in vitro enrichment of erythrocyte membrane with cholesterol38 43 is in good agreement with the inverse correlation between Na+-K+ cotransport activity and membrane cholesterol content found in erythrocytes of healthy or diabetic men.10 44 Thus, a possible difference in membrane cholesterol content might be a plausible explanation for different BS Na+ net uptake in both hypertensive strains, under the assumption that the majority of BS Rb+ uptake in LH rats is mediated by the K+-Cl- cotransport system. Nevertheless, the role of the Na+-K+-2Cl- cotransport system in the pathogenesis of genetic hypertension in the rat remains obscure, because we have observed totally contrasting relationships of BS Na+ net uptake to blood pressure in the two hypertensive strains studied, ie, a positive correlation in HTG rats and a negative one in Lyon strains.
The tentative explanation for observed lipid-dependent ion transport abnormalities is that the alterations of plasma lipids and/or cell membrane lipid composition modulate the activity of various ion transport pathways via the changes in membrane microviscosity. The impaired balance of monovalent and divalent cations in cells involved in cardiovascular regulation can modify blood pressure. It is clear that future studies of ion transport alterations in rats with genetic hypertension and dyslipidemia will require a careful analysis of cell membrane lipid composition and the determination of membrane microviscosity in its particular domains, ie, outer leaflet and lipid core.
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Acknowledgments |
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This work was partially supported by research grants 306/93/0573 (Grant Agency of the Czech Republic) and 3509-3 (Ministry of Health of the Czech Republic). Lyon rat strains were kindly provided by Prof M. Vincent and Prof J. Sassard, Faculty of Pharmacy, Université Claude Bernard, Lyon, France.
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Footnotes |
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Reprint requests to Dr J. Zicha, Institute of Physiology, Academy of Sciences of the Czech Republic, Vide
ská 1083, Prague 4, CZ-142 20, Czech Republic. Received March 15, 1997; first decision April 17, 1997; accepted April 30, 1997.
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