Drugs

, Volume 28, Supplement 1, pp 120–142

Magnesium, Electrolyte Transport and Coronary Vascular Tone

  • Burton M. Altura
  • Bella T. Altura
Section 2: Mechanism and Physiological Significance of Electrolyte Disturbances

Summary

Coronary heart diseases (CHD) have high indices of mortality and morbidity. A number of CHD and myocardial ischaemic syndromes such as unstable angina pectoris, sudden death ischaemic heart disease, acute myocardial infarction and ventricular arrhythmias have been associated with losses of myocardial magnesium and potassium.

Mg++ ions are essential for regulation of Na+ and K+ transport across cell membranes, including those found in cardiac and vascular smooth muscle cells. Mg++ activates an Na+-K+-ATPase pump which in turn plays a major role in regulating Na+-K+ transport. Loss of cellular Mg++ results in loss of critically important phosphagens: MgATP and creatine phosphate. Thus, under conditions where cellular Mg++ is depleted (e.g. hypoxia, ischaemia, anoxia), the Na+-K+ pump and phosphagen stores will be compromised, leading to alterations in resting membrane potentials. Cellular Mg++ depletion has been found to result in concomitant depletion of K+ in a number of cells, including cardiac and vascular muscles. The consequences of these events are often production of cardiac arrhythmias. Myocardial and vascular injury lead to disturbances in electrolyte transport across cell membranes, whereby Na+ and Ca++ uptakes are enhanced and, just prior or concomitantly, Mg++ and K+ are lost. Such electrolyte disturbances often lead to necrotic foci.

Considerable evidence has accumulated to indicate that the extracellular concentracion of Mg++ is important in control of arterial tone and blood pressure via regulation of vascular membrane Mg++-Ca++ exchange sites. A reduction in the extracellular Mg++ concentracion can produce hypertension, coronary vasospasm and potentiation of vasoconstrictor agents by allowing excess entry of Ca++; concomitantly, the potency of vasodilator agents is reduced. Alterations in vascular membrane Mg++ result in arterial and nrteriolar membranes which are ‘leaky’, thus contributing to the cellular reduction in K+ and gain of Na+ and Ca+. Alterations in extracellular K+ or Na+ concentracions over physiological ranges, in the face of a Mg++ deficit, can exacerbate the coronary vasospasm noted with reduction in only extracellular Mg++. Since free Mg++ ions are necessary for maintaining Ca+ ions (both plasma membrane-bound and sarcoplasmic reticulum membrane-bound via Ca++ ATPases), intracellular free Mg++ would rise in conditions which result in cellular loss of Mg++, thereby exacerbating and contributing to elevation of blood pressure and coronary vasospasm. Data are also accumulating to suggest that Mg++ may control a Na+-Ca++ pump which is essential for maintenance of normal coronary vascular tone.

Overall, the available data suggest that Mg++ plays critical roles in maintenance of normal cardiac excitability and coronary vascular tone. Based on these and other findings reviewed herein, magnesium prophylaxis and intervention may be extremely useful in the prevention and treatment of CHD, sudden death ischaemic heart disease, hypertension and acute myocardial infarction.

Résumé

L’insuffisance coronarienne est grevée d’indices élevés de mortalité et de morbidité. Un certain nombre de formes cliniques d’insuffisance coronarienne et d’ischémie myocardique ont été mises en rapport avec un déficit en potassium et en magnésium. C’est le cas de l’angine de poitrine instable, de la mort subite par ischémie myocardique, de l’infarctus aigu du myocarde et des arythmies ventriculaires.

Les ions Mg++ sont essentiels au transport normal du Na+ et du K+ à travers la membrane cellulaire y compris celle du muscle cardiaque et celle du muscle vasculaire lisse. Le Mg++ active la Na+ -K+ -ATPase de la pompe membranaire laquelle régularise le transport Na+ -K+. Une perte de Mg + + cellulaire équivaut à une perte de phosphagènes dont le rôle est primordial à savoir le MgA TP et le phosphate de créatinine. Ainsi, dans les circonstances où existe une déplétion en Mg + + (i.e. l’hypoxie, l’ischémie, l’anoxie), le fonctionnement de la pompe Na+ -K+ et les réserves en phosphagènes sont compromises et il en résulte des altérations dans le potentiel membranaire de repos. La perte de Mg+ + entraîne une perte de K+ dans de nombreuses cellules y compris celles du coeur et du muscle vasculaire. La conséquence en est souvent le développement d’arythmies. Les altérations du myocarde et des vaisseaux coronaires conduit à des modifications du transport électrolytique à travers la membrane cellulaire où l’entrée de Na+ et de Ca+ sont facilités parallèlement à une perte de Mg+ + et K+. Ceci favorise la formation de foyers de nécrose.

On possède des preuves solides de l’importance de la concentration en Mg+ + extracellulaire dans le contrôle du tonus artériel et de la pression sanguine par le biais de sites d’échanges Mg + + -Ca + + au niveau de la membrane vasculaire. Une diminution du Mg+ + extracellulaire peut être à l’origine d’une réaction hypertensive, d’un spasme coronaire et d’une synergie d’effet avec des substances vasoconstrictrices en favorisant une entrée massive de Ca+ +. Parallèlement, l’effet des vasodilatateurs est diminué. Des modifications du Mg+ + de la membrane vasculaire rendent ‘perméables’ les artères et artérioles ce qui contribue à l’appauvrissement cellulaire en K+ et à son enrichissement en Na+ et Ca+ +. Une élévation du K+ ou du Na+ extracellulaires au-dessus des concentrations physiologiques accompagnée d’un déficit en Mg+ + peut renforcer le spasme coronaire observé avec la seule diminution de Mg + + extracellulaire. Puisque le Mg + + libre est indispensable au maintien d’un Ca+ + normal (Ca+ + lié à la membrane cytoplasmique et au réticulum endoplasmique via les Ca+ + ATPases) le Mg+ + libre intracellulaire s’élèverait dans les situations où existe une perte cellulaire de Mg + + contribuant de ce fait à une élévation de la pression sanguine et à un renforcement du spasme coronarien. Il existe aussi des données qui tendent à prouver que le Mg + + peut exercer un contrôle sur la pompe Na + -Ca + + qui est essentielle au maintien d’une tonicité normale des vaisseaux coronaires.

Au total, les données disponibles suggèrent que le Mg+ + joue un rôle fondamental dans le maintien d’un niveau normal d’excitabilité myocardique et de tonicité coronaire. Elles conduisent à penser que l’utilisation prophylactique et curative du magnésium est d’une grande utilité pour la prévention et le traitement de l’insuffisance coronarienne, la mort subite par ischémie myocardique, l’hypertension, l’infarctus aigu du myocarde.

Zusammenfassung

Koronare Herzkrankheiten (KHK) besitzen eine hohe Mortalitüt und Morbiditüt. Eine A nzahl von KHK und ischümischen Myokardsyndromen wie instabile Angina pectoris, plötzlicher Herztod bei ischümischer Herzkrankheit, akuter Herzinfarkt und ventrikulüre Arrhythmien wurden mit Verlusten an myokardialem Magnesium und Kalium in Verbindung gebracht.

Mg++ -Ionen sind für die Regulation des Na+ - und K+ -Transports durch die Zellmembran einschlieβlich der von kardialen und vaskulüren glatten Muskelzellen erforderlich. Mg+ + aktiviert die Na+ -K+ -ATPase die ihrerseits eine bedeutende Rolle für die Regulation des Na+ -K+ -Transports spielt. Ein Verlust an zellulürem Mg+ + führt zu Verlusten der kritisch wichtigen Phosphagene MgATP und Kreatinphosphat. Unter den Bedingungen, die zu einer zellulären Mg+ + -Erschöpfung führen (z.B. Hypoxie, Ischümie, Anoxie) wird die Funktion der Na+ -K+ -Pumpe und der Phosphagenspeicher beeinträchtigt was zu Veränderungen der Ruhemembranpotentiale führt. Es wurde nachgewiesen, daβ eine zellulüre Mg+ + -Verarmung in einer Anzahl von Zellen, einschlieβlich der Herz- und Gefäβmuskeln, eine gleichzeitige Verarmung an K+ ergibt. Die Konsequenzen dieser Ereignisse ist häufig das Auftreten von Herzarrhythmien. Myokardiale und vaskulüre Schüdigungen führen zu Störungen im Elektrolyttransport durch die Zellmembran, wodurch die Aufnahme von Na+ undCa+ + verstärkt und unmittelbar vorher oder gleichzeitig Mg+ + undK+ verloren gehen. Solche Elektrolytstörungen führen oft zu nekrotischen Bezirken.

Die vorliegenden Befunde zeigen daβ die extrazelluläre Konzentration von Mg+ + für die Kontrolle des arteriellen Tonus und Blutdrucks via Regulation der vaskulären Mg+ + -Ca+ + -Membranaustauschstellen wichtig ist. Eine Senkung der extrazellulären Mg+ + -Konzentration kann eine Hypertonie, koronare Vasospasmen und eine Potenzierung der Wirkung von Vasokonstriktoren durch einen gesteigerten Einstrom von Ca + + hervorrufen; gleichzeitig wird die Wirksamkeit von Vasodilatatoren vermindert. Veränderungen des Mg + + in der Gefäβmembran führen zu ‘durchlässigen’ und arteriolären Membranen, und begünstigen dadurch die Abnahme des intrazellulären K+ und Zunahme von Na+ und Ca+ +. Liegen neben dem Mg + + -Mangel Veränderungen der extrazellulären K+ - und Na+ -Konzentrationen vor, die über den physiologischen Bereich hinausgehen, kann dies zu einer weiteren Verschlimmerung der koronaren Vasospasmen führen. Da freie Mg++ -Ionen zum Erhalt von Ca++ -Ionen notwendig sind (sowohl über die Plasmamembran-gebundenen als auch am sarkoplasmatischen Retikulum Membran-gebundenen Ca+ + -ATPasen), steigt das intrazellulüre freie Mg+ + unter Bedingungen, die zu einem Verlust von zellulärem Mg + + und dadurch zu Exazerbationen und Beteiligungen an der Erhöhung des Blutdrucks und koronarer Vasospasmen führen. Es hüufen sich auch Hin weise, die vermuten lassen, daβ Mg + + eine Na+ -Ca++ -Pumpe kontrolliert, die zurAufrechterhaltung eines normalen Koronargefäβtonus erforderlich ist.

Insgesamt lassen die verfügbaren Daten vermuten, daβ Mg + + eine kritische Rolle für die Aufrechterhaltung der normalen kardialen Erregbarkeit und des koronaren Gefüβtonus spielt. Aufgrund dieser und anderer hier besprochener Befunde kann die Magnesium-Prophylaxe und Intervention für die Verhinderung und Behandlung von KHK, plötzlichem Tod bei ischämischer Herzkrankheit, Hypertonie und akutem Myokardinfarkt, auβerordentlich nützlich sein.

Sommario

La cardiopatia ischemica comporta indici elevati di mortalità e morbilitä. Numerose sindromi, espressione di’una miocardiopatia ischemica; quali l’angina instabile, la morte cardiaca improvvisa da ischemia miocardica, l’infarto miocardico acuto e le aritmie ventricolari, sono state associate ad un impoverimento miocardico di magnesio e di potassio.

Gli ioni Mg++ sono essenziali per la regolazione del trasporto del Na+ e del K+ attraverso le membrane cellutari, ivi incluse quelle delle cellule cardiache e delle miocellule vascolari lisce. Il Mg++ attiva una pompa Na+ -K+ -ATPasi dipendente la quule a sua volta esercita un ruolo fondamentale nel regolare il trasporto Na+ -K+. Una riduzione del Mg+ + cellulare comporta una perdita di composti a base di fosfato note volmente importanti: Mg-A TP e creatinfosfato. Pertanto, in condizioni di deplezione del Mg++ cellulare (per es. ipossia, ischemia, anossia) la pompa Na+ -K+ e le riserve di fosfageni saranno compromesse, con la conseguente alterazione dei potenziali di membrana a riposo. Si è osservato che l’impoverimento cellulare di Mg+ + comporta una deplezione concomitante di K+ in molti tipi di cellule, fra cui quelle muscolari, cardiache e vascolari. Come conseguenza di questo fenomeno si sviluppano spesso delle aritmie cardiache. Un danno miocardico e vascolare determina alterazioni nel trasporto di elettroliti attraverso le membrane cellulari, ove viene incrementata la captazione di Na+ di Ca+ + e, immediatamente prima o concomitantemente, si ha una perdita di Mg+ + e di K+. Tali squilibri elettrolitici determinano spesso necrosi parcellari.

Si sono accumulait numerosi dati sperimentali a favore dell’importanza delle concentrazioni extracellulari di Mg + + nel controllo del tono arterioso e della pressione arteriosa tramite la regolazione dei punti di scambio Mg+ + -Ca+ + sulle membrane vascolari. Una riduzione delle concentrazioni extracellulari di Mg+ + può produrre ipertensione, spasmo vascolare coronarico e potenziamento dell’azione di sostanze vasocostrittrici, facili-tando un eccessivo ingresso di Ca+ +; contemporaneamente è ridotta la potenza di sostanze vasodilatatrici. Alterazioni dei livelli di Mg+ + nelle membrane vascolari determinano la formazione di membrane arteriose e arteriolari ‘leaky’ (a maggiore permeabilité), contribuendo pertanto alla riduzione del contenuto cellulare di K+ ed all’ingresso di Na+ e Ca+ +. Alterazioni, nei limiti fisiologici, delle concentrazioni extracellulari di K+ o di Na+, in presenza di un deficit di Mg++, possono esacerbare lo spasmo vascolare coronarico osservato con la riduzione dei livelli del solo Mg+ + extracellulare. Dal momento che sono necessari ioni Mg+ + liberi per conservare gli ioni Ca+ + (sia legati alla membrana plasmatica sia legati alla membrana del reticolo sarcoplasmatico tramite Ca+ + A TPasi), le concentrazioni di Mg+ + libero intracellulare sarebbero incrementate in condizioni che comportino una perdita cellulare di Mg+ +, esacerbando pertanto e contribuendo ad elevare la pressione arteriosa e l’incidenza di spasmo coronarico. Viene anche suggerito da un numero sempre crescente di dati sperimentali che il Mg+ + puà controllare una pompa Na+ -Ca+ + di essenziale importanza per mantenere il normale tono vascolare coronarico.

In sintesi i dati disponibili suggeriscono che il Mg + + svolge un ruolo critico nel mantenere una normale eccitabilitü cardiaca ed un normale tono vascolare coronarico. Sulla base di questi e di altri dati qui esaminati, la profilassi e la terapia con magnesio possono risultare estremamente utili nella prevenzione e nel trattamento della cardiopatia ischemica, della morte improvvisa da miocardiopatia ischemica, dell’ipertensione e dell’infarto miocardico acuto.

Resumen

Las cardiopatías coronarias (CC) tienen un elevado indice de morbimortalidad. Cierto numéro de cuadros de CC y de sindrome isquémico miocàrdico, tales como angor inestable, cardiopatía isquémica con muerte sübita, infarto agudo de miocardio y las arritmias ventriculares, se han asociado a pérdidas de potasio y magnesio miocárdicos.

Los iones Mg++ son esenciales para el transporte de Na+ y K+ a través de las membranas celulares, incluyendo las de las células musculares cardiacas y del müsculo liso. El Mg+ + activa una bomba Na+ -K+ -ATPasa que, asuvez, desempeña un papel fundamental en la regulación del transporte de Na+ y K+. La pérdida de Mg + + intracelular tiene como consecuencia la pérdida de fosfágenos críicamente importantes: el MgA TP y el fosfato de creatina. Por ello, en condiciones en las que el Mg++ es déficiente (p.ej., hipoxia, isquemia, anoxia), la bomba Na + -K+ y los depósitos de compuestos de fosfato se verán alterados, con las alteraciones consiguientes en el potential de la membrana en reposo. Se ha observado que en determinado número de células, entre otras las de los músculos cardiaco y vasculares, la pérdida de Mg + + intracelular se acompaña de una depletión concomitante de K+. Con frecuencia, las consecuencias de estos acontecimientos es la productión de arritmias cardiacas. Las lesiones miocárdicas y vasculares dan lugar a alteraciones del transporte electrolítico a través de las membranas celulares, de modo que la captación de Na+ y Ca++ aumentan y, justo antes de que esto ocurra, o simultáneamente con ello, se pierden Mg+ + y K+. Tales alteraciones electrolíticas tienen como consecuencia frecuente la aparición de focos necróticos.

Hay gran cantidad de datos que vienen a señalar la importancia de la concentración extracelular de Mg + + en el control del tono arterial y la tensión arterial mediante la regulatión de los puntos de intercambio Mg+ + -Ca++ de la membrana vascular. Una reducción de la concentración extracelular de Mg++ puede producir hipertensión, vasospasmo coronario y potenciación de los agentes vasoconstrictores, al posibilitar una mayor entrada de Ca+ +; concomitantemente, lapotencia de los vasodilatadores se ve reducida. Las alteraciones en el Mg+ + de las membranas vasculares da lugar a membranas arteriales y arteriolares ‘con fugas’, to que contribuye a la depletion celular de K+ y la mayor acumulación de Na+ y Ca + +. Las modificaciones más alla de limites fisiológicos de las concentracions extracelulares de K+ o Na+ en presencia de un déficit de Mg+ + pueden exacerbar el espasmo coronario que se observa cuando la reductión sólo afecta al Mg + + extracelular. Dado que los iones libres de Mg+ + son necesarios para conservar los de Ca+ + a concentracion estable (tanto el unido a la membrana plasmática, como a la del retículo sarcoplásmico, mediante las Ca+ + -ATPasas), el Mg+ + libre intracelular aumentaria en las situaciones que producen pérdida celular de Mg+ +, exacerbando y contribuyendo asi a la elevatión de la tensión arterial y al vasospasmo coronario. Se están reuniendo asimismo datos que sugieren que quizd el Mg + + controle una bomba de Na+-Ca+ + esencial para la conservación del tono vascular coronario normal.

En resumen, los datos de que se dispone sugieren que el Mg + + desempeña papeles fundamentales en la conservación de la excitabilidad cardiaca y tono coronario normales. Sobre la base de estos y otros hallazgos que se revisan a continuacíon, la profilaxis e intervención sobre el magnesio qui’a sea extraordinariamente util para la prevención y tratamiento de las CC, cardiopatía isquémica con muerte súbita, hipertensión e infarto agudo de miocardio.

Resumo

As doenças coronárias (DC) apresentam um alto índice de mortalidade e de morbidez. Uma série de DC s e de síndromes isquêmicas do miocardio, tais como a angina pectoris instável, as doenças cardiacas isquêmicas que conduzem à morte súbita, o enfarte agudo do miocárdio e as arritmias ventriculares, foram associadas a perdas de magnésio e de potàssio por parte do miocárdio.

Os íons de Mg+ + são essenciais para a regulação do transporte de Na+ e de K+ através da membrana das células, incluindo as que se encontram nas células dos músculos lisos vasculares e cardíacos. O Mg + + ativa a bomba Na+ -K+ -ATPase, que por sua vez desempenha um importante papel na regulação do transporte de Na + -K+. A perda de Mg+ + do interior das células resulta na perda de fosfatos críticamente importantes: o MgATP e o fosfato de creatinina. Assim sendo, as condições em que se verifica depleção de Mg+ + no interior das células (por exemplo, hipoxia, isquemia, anoxia) comprometem a bomba Na+-K+ e as provisoes de fosfagênio, conduzindo a alterações nos potenciais das membranas em descanso. Descobriu-se que uma depleção de Mg++ no interior das células resulta numa concomitante depleção de K+ numa série de células, incluindo as células dos músculos cardíacos e vasculares. Uma das consequências disso, muitas vezes, é a produção de arritmias cardíacas. Os danos ao miocárdio e vasculares conduzem a distúrbios no transporte de eletrólitos através da membrana das células, pelo qual a absorção de Na+ e de Ca+ + é acentuada, verificando-se também, logo antes ou simultâneamente, perdas de Mg+ + e de K+. Estes distúrbios eletrolíticos conduzem muitas vezes a focos necróticos.

J’ se acumulou evidência considerável indicativa de que a concentração de Mg+ + no exterior das células é importante no controle do tônus arterial e na pressão sanguínea, por meio da regulação dos locais de intercâmbio de Mg + + -Ca + + nas membranas vasculares. Uma redução na concentração de Mg ++ no exterior das células pode produzir hipertensão, espasmos dos vasos coronários e potencialização de agentes vasoconstritores, ao permitir a entrada excessiva de Ca+ +; simultâneamente, é reduzida a potência dos agentes vasodilatadores. As alterações na concentração de Mg+ + nas membranas vasculares resultam em membranas arteriais e arteriolares com ‘vazamentos’, contribuindo assim para a redução de K+ no interior das células e para um aumento de Na + e de Ca+ +. As alterações na concentração de K+ ou de Na+ no exterior das células, dentro dos limites fisiológicos, e diante de um déficit de Mg+ +, podem exacerbar os espasmos dos vasos coronários observados com redução apenas na concentração de Mg++ no exterior das células. Visto que os íons livres de Mg + + são necessários para a manutenção dos ions de Ca++ (tanto os ligados à membrana do plasma como os ligados à membrana da retícula sarcoplásmica, por meio das Ca+ + ATPases), o Mg+ + livre no interior das células aumentaria em condições que resultam em perdas celulares de Mg+ +, desse modo exacerbando e contribuindo para a elevação da pressão sanguínea e dos espasmos dos vasos coronários. Há também dados acumulados sugerindo que o Mg+ + pode controlar a bomba Na+-Ca+ +, que é essencial para a manutenção de um tônus vascular coronário normal.

De maneira global, os dados disponíveis sugerem que o Mg + + desempenha papéis críticos na manutenção da excitabilidade cardíaca normal e do tônus dos vasos coronários. Com base nestas e em outras descobertas aqui analisadas, a profilaxia e a intervenção com magnésio podem ser extremamente úteis na prevenção e no tratamento de DCs, doenças cardiacas isquêmicas conduzindo a morte súbita, hipertensão e enfarte agudo do miocárdio.

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Copyright information

© ADIS Press Limited 1984

Authors and Affiliations

  • Burton M. Altura
    • 1
  • Bella T. Altura
    • 1
  1. 1.Department of Physiology, SUNY-Downstate Medical CenterState University of New YorkBrooklynUSA

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