Abnormal magnesium metabolism in two rat models of genetic hypertension' I. C. WEL~"BBNB D. K . AGWAWAL Dep~~tnaents of Biomedical Sciences, Division of Biochemistryy and of Medicine, Crekghton University School of Medicine, Orzaaha IVB 68178, U.S.A. Received July 22, 1991
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by Depository Services Program on 01/12/15 For personal use only.
WELJS,I. C., and AGWAWAL, B.K. 1992. Abnormal magnesium metabolism in two rat models of genetic hypertension. Can. b. Phy siol. Pharmacsl. 70: 1225 - 1229. Magnesium concentrations in erythrocyte ghosts and arterial tissue of male, spontaneously hypertensive rats (SHR) were significantly less than in these tissues of male normotensive controls (Wistar-Kyoto; WKY) of the same age, which were also fed rat chow and tap water. The magnesium concentration in SHR erythrocyte ghosts was increased to the control value by incubating SHR erythrocytes with WKY blood plasma; SHR plasma did not affect the magnesium concentration in WKY erythrocyte ghosts. The magnesium concentrations in erythrocyte ghosts, aortas, and mesenteric arteries from female saltsensitive (SS/JR) and salt-resistant (SR/JR) Dahl-derived rats, both maintained ad libitum on laboratory rat chow and either tap water or 0.9% NaCl, were not different but were significantly less than those of Sprague-Dawley rats considered as controls. While the ingestion of 8.9% NaCl had no effect on the magnesium concentrations measured in these animals, it caused the salt-sensitive rats to become severely hypertensive. It is evident from these observations that the decreased binding of magnesium to the plasma membrane of cells may be an inheritable metabolic defect that may be associated with the development of hypertension. However, in those instances of hypertension in which this defect occurs, it appears to be a contributing cause of the hypertension; by itself the defect is not a cause of hypertension. Key words: essential hypertension, magnesium. SHR rats, salt-sensitive rats (SS/JR).
WELW,I. C., et AGRAWAL, D. K. 1992. Abnormal magnesium metabolism in two rat models of genetic hypertension. Can. 9. Physiol. Phamacol. 70 : 1225 - 1229. Les concentrations de magnksium des fanthanes d9Crythrocyteset du tissu artkriel de rats spontankment hypertensifs (RSH) males ont 6tk significativement plus faibles que ceB1es de rats tkmoins normotendus males (WKY) dae m$me Pge, ayant une dikte composCe de nourriture pour rat et d'eau du robinet. On a augment6 la concentration de magnCsium des fantbmes d'6rythrocytes des RSH au niveau de celle des tCmoins, en incubant les Crythrocytes des WSH avec du plasma sanguin de WKY; toutefois, le plasma des RSH n'a pas influencC la concentration de magnesium dans les fantdmes d'kqthrocytes des WKY. Dans les fanthanes d'krythrocytes, les aortes et les artkres mCsentkriques de rats de type Dahl femelles rksistants au sel (RS/JR) et de rats femelles sensibles au sel (SS/JR), soumis cad lib a une dikte contenant de la nourriture de laboratoire et de 19eaudu robinet ou du NaClO,9%, les concentrations de magnCsium n'ont pas diffCrC, mais ont CtC significativement plus faibles que celles des rats Sprague-Dawley tCmins. Bien que l'absorption de NaCl 0,9% n'ait pas eu d'effet sur les concentrations Be magnksium de ces anirnaux, elle a rendu les rats sensibles au sel trks hypertensifs. D'aprks ces observations, il appert que la fixation rCduite de magnCsium B la membrane plasmatique des cellules pourrziit Stre une anomalie mCtabolique hCrCditaire et pourrait kitre associ6e au dkveloppement de l'hypertension. Toutefois, il semble que cette anomalie we suit qu9un facteur accompagnant l'hypertension et n'en est pas la cause en soi. Mots elks : hypertension essentielle, magnCsium, rats spontankment hypertensifs, rats sensibles au sel (SS/JR). [Traduit par la rCdaction]
'
Introduction Magnesium depletion, owing to dietary deficiency or to disease, can produce hypertension in both experimental animals (Altura et ksl. 1984) and humans (Hall and Joffe 19'73), a result that is, however, not invariable (Shils 1969). This hypertension is reversed by magnesium repletion. Magnesium dso appears to be somehow associated with certain, but probably not all, cases of human essential hypertension (Mattingly et a/. 1991). However, in these instances the elevated blood pressure is not the result sf magnesium deficiency, since it is not reduced by the administration of nutritionally sufficient amounts s f magnesium. The crucial defect common in these two occurrences of magnesium-associated hypertension in humans appears to be, as exemplified by the erythrocyte membrane, the decreased binding sf magnesium to the plasma membrane of cells. 'Presented in part at the annual meeting of the Federation of American Societies for Experimental Biology, April 1990, in Washington, D.C. 'Author for correspondence at the following address: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, U.S.A. Printed in Canada / Imprim6 au Canada
Presumably this defect results in the decreased intracellular concentration s f magnesium ion observed in the erythrocytes s f a group s f patients with essential hypertension (Resnick et al. 1984). Such a defect undoubtedly occurs in the magnesium-depleted state as a direct consequence of the insufficiency of available magnesium, but in the essential hypertension cases examined, this defect may be classified as being metabolic, since it apparently results from the deficiency of a plasma factor that promotes the binding of magnesium to plasma membranes (Mattingly et al. B 99 1). The sequence s f events that results from the deficiency of magnesium in the cell membrane and that in certain instances may be associated with hypertension, is conjectural. Available evidence strongly supports the conclusion, however, that the structure of the plasma membrane is altered (Paolisss et a&. 198'7) and that its apparent permeability to the four major biologically significant cations, i.e., Na' , K + , CaN , and Mga , is modii-led so h a t the intracellular concentrations of K+ and Mg2+ may decrease while those of Na+ and CaN may increase (Shils 1969). Such abnormal concentrations of these ions in the smooth muscle cell are associated with increased muscle tone (Altura and Altura 1984) and therefore increased peripheral resistance in h e blood vascular system, which in
CAN. J . PHYSIBL. PHARMACBL. VOL. 70, 1992
TABLE1. Analyses of SHR and WKY rat tissues WKY
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by Depository Services Program on 01/12/15 For personal use only.
SHR
Blood pressure (mmHg)$ Mg concentration (pg/0.50 mg protein) Erythrocyte ghosts Aom Tertiary mesenteric artery Vas deferens
Mean f §EM
n
Mean f SEM
161 k7.0
5
128k2.6
5
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by Depository Services Program on 01/12/15 For personal use only.
WELJS,I. C., and AGWAWAL, B.K. 1992. Abnormal magnesium metabolism in two rat models of genetic hypertension. Can. b. Phy siol. Pharmacsl. 70: 1225 - 1229. Magnesium concentrations in erythrocyte ghosts and arterial tissue of male, spontaneously hypertensive rats (SHR) were significantly less than in these tissues of male normotensive controls (Wistar-Kyoto; WKY) of the same age, which were also fed rat chow and tap water. The magnesium concentration in SHR erythrocyte ghosts was increased to the control value by incubating SHR erythrocytes with WKY blood plasma; SHR plasma did not affect the magnesium concentration in WKY erythrocyte ghosts. The magnesium concentrations in erythrocyte ghosts, aortas, and mesenteric arteries from female saltsensitive (SS/JR) and salt-resistant (SR/JR) Dahl-derived rats, both maintained ad libitum on laboratory rat chow and either tap water or 0.9% NaCl, were not different but were significantly less than those of Sprague-Dawley rats considered as controls. While the ingestion of 8.9% NaCl had no effect on the magnesium concentrations measured in these animals, it caused the salt-sensitive rats to become severely hypertensive. It is evident from these observations that the decreased binding of magnesium to the plasma membrane of cells may be an inheritable metabolic defect that may be associated with the development of hypertension. However, in those instances of hypertension in which this defect occurs, it appears to be a contributing cause of the hypertension; by itself the defect is not a cause of hypertension. Key words: essential hypertension, magnesium. SHR rats, salt-sensitive rats (SS/JR).
WELW,I. C., et AGRAWAL, D. K. 1992. Abnormal magnesium metabolism in two rat models of genetic hypertension. Can. 9. Physiol. Phamacol. 70 : 1225 - 1229. Les concentrations de magnksium des fanthanes d9Crythrocyteset du tissu artkriel de rats spontankment hypertensifs (RSH) males ont 6tk significativement plus faibles que ceB1es de rats tkmoins normotendus males (WKY) dae m$me Pge, ayant une dikte composCe de nourriture pour rat et d'eau du robinet. On a augment6 la concentration de magnCsium des fantbmes d'6rythrocytes des RSH au niveau de celle des tCmoins, en incubant les Crythrocytes des WSH avec du plasma sanguin de WKY; toutefois, le plasma des RSH n'a pas influencC la concentration de magnesium dans les fantdmes d'kqthrocytes des WKY. Dans les fanthanes d'krythrocytes, les aortes et les artkres mCsentkriques de rats de type Dahl femelles rksistants au sel (RS/JR) et de rats femelles sensibles au sel (SS/JR), soumis cad lib a une dikte contenant de la nourriture de laboratoire et de 19eaudu robinet ou du NaClO,9%, les concentrations de magnCsium n'ont pas diffCrC, mais ont CtC significativement plus faibles que celles des rats Sprague-Dawley tCmins. Bien que l'absorption de NaCl 0,9% n'ait pas eu d'effet sur les concentrations Be magnksium de ces anirnaux, elle a rendu les rats sensibles au sel trks hypertensifs. D'aprks ces observations, il appert que la fixation rCduite de magnCsium B la membrane plasmatique des cellules pourrziit Stre une anomalie mCtabolique hCrCditaire et pourrait kitre associ6e au dkveloppement de l'hypertension. Toutefois, il semble que cette anomalie we suit qu9un facteur accompagnant l'hypertension et n'en est pas la cause en soi. Mots elks : hypertension essentielle, magnCsium, rats spontankment hypertensifs, rats sensibles au sel (SS/JR). [Traduit par la rCdaction]
'
Introduction Magnesium depletion, owing to dietary deficiency or to disease, can produce hypertension in both experimental animals (Altura et ksl. 1984) and humans (Hall and Joffe 19'73), a result that is, however, not invariable (Shils 1969). This hypertension is reversed by magnesium repletion. Magnesium dso appears to be somehow associated with certain, but probably not all, cases of human essential hypertension (Mattingly et a/. 1991). However, in these instances the elevated blood pressure is not the result sf magnesium deficiency, since it is not reduced by the administration of nutritionally sufficient amounts s f magnesium. The crucial defect common in these two occurrences of magnesium-associated hypertension in humans appears to be, as exemplified by the erythrocyte membrane, the decreased binding sf magnesium to the plasma membrane of cells. 'Presented in part at the annual meeting of the Federation of American Societies for Experimental Biology, April 1990, in Washington, D.C. 'Author for correspondence at the following address: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, U.S.A. Printed in Canada / Imprim6 au Canada
Presumably this defect results in the decreased intracellular concentration s f magnesium ion observed in the erythrocytes s f a group s f patients with essential hypertension (Resnick et al. 1984). Such a defect undoubtedly occurs in the magnesium-depleted state as a direct consequence of the insufficiency of available magnesium, but in the essential hypertension cases examined, this defect may be classified as being metabolic, since it apparently results from the deficiency of a plasma factor that promotes the binding of magnesium to plasma membranes (Mattingly et al. B 99 1). The sequence s f events that results from the deficiency of magnesium in the cell membrane and that in certain instances may be associated with hypertension, is conjectural. Available evidence strongly supports the conclusion, however, that the structure of the plasma membrane is altered (Paolisss et a&. 198'7) and that its apparent permeability to the four major biologically significant cations, i.e., Na' , K + , CaN , and Mga , is modii-led so h a t the intracellular concentrations of K+ and Mg2+ may decrease while those of Na+ and CaN may increase (Shils 1969). Such abnormal concentrations of these ions in the smooth muscle cell are associated with increased muscle tone (Altura and Altura 1984) and therefore increased peripheral resistance in h e blood vascular system, which in
CAN. J . PHYSIBL. PHARMACBL. VOL. 70, 1992
TABLE1. Analyses of SHR and WKY rat tissues WKY
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by Depository Services Program on 01/12/15 For personal use only.
SHR
Blood pressure (mmHg)$ Mg concentration (pg/0.50 mg protein) Erythrocyte ghosts Aom Tertiary mesenteric artery Vas deferens
Mean f §EM
n
Mean f SEM
161 k7.0
5
128k2.6
5
