Magnesium-Bulletin 4/1985 121 Blunting of diuretic-induced increases in urinary magnesium and potassiunt outputs by beta-adrenergic blockade in healthy subjects By A. J. Reyes, W. P. Leary and K. van der Byl Departamento de Investigaci6n Cardiovascular, Fundaci6n Procardias, and Universidad de la Republica, Montevideo, Uruguay and Department of Experimental and Clinical Pharmacology, University of Natal, Durban, South Africa Zusammenfassung puts of fluid and Na + with respect to pla­ pertension arterielle devraient etre inves­ Der Zweck dieser Studie Jag darin festzu­ cebo. CLOP significantly increased the tiguees par des etudes chroniques. mean 24-h urinary outputs of Mg2+ (%D. stellen, ob eine adrenerge ~-Blockade ei­ nen EinfluB auf die Diuretika-bedingte = 27, p<O,Ol) and K+ (%D. = 25, p < 0,05) with respect to placebo, whereas Hypermagnesiurie und Hyperkaliurie hat. CLOP PIND did not affect either out­ Sieben Tage tang wurde an neun ge­ + put significantly (%D. for Mg2+ = -I; Introduction sunden Versuchspersonen Plazebo, das %D. for K + 10). PIND did not affect Diuretikum Clopamid 5 mg (CLOP), der Evidence that essential hyperten­ any of the studied urinary outputs signifi­ sion constitutes an important adrenerge ~-Blocker Pindolol 10 mg cantly. (PIND) und eine Kombination von CLOP would have augmented the re­ cardiovascular risk factor has CLOP und PIND (CLOP + PIND) im nal production of renin and subsequently lead to the recommendation that randomisierten Doppelblind-Versuch ver­ raised plasma aldosterone concentration; it should be treated vigorously abreicht. Der Stoffwechsel der Personen PIND could have blunted these increa­ [44]. Clinical and epidemiologi­ wurde unter streng kontrollierten Bedin­ ses. Therefore, the diuretic-induced in­ gungen untersucht. crease of urinary Mg2+ output would cal results appear to support this CLOP und CLOP + PIND erhOhen have been, at least partly, due to secon­ approach [44]. However, in prac­ die Fliissigkeits- und Natrium-Ausschei­ dary hyperaldosteronism. The potential tical terms it is difficult to treat dung iiber den 24-Stunden-Urin signifi­ clinical application of the present fin­ all patients with elevated blood kant im Vergleich zur Plazebo-Gruppe. dings merit chronic studies in patients pressure specifically because of a CLOP erhOhte signifikant die Mehraus­ suffering from high blood pressure. scheidung von Mg2+ (%D.= 27, p<O,Ol) variety of problems, including und K + (%D. 25, p < 0,05) im 24-Stun­ Resume the high prevalence of hyperten­ den-Urin im Vergleich zur Plazebo-Grup­ Cette investigation eut par objetive !'eva­ sion in most modern societies, pe wiihrend CLOP + PIND keine der luation de l'effet du blocage beta-adre­ the fact that the disease is usually Ausscheidungen signifikant beeinflu13te nergique sur les accroissements des excre­ (% D. fiir Mg2+ - l; o/o D. fiir K + = tions urinaires de Mg2+ et de K + induits asymptomatic and therefore pa­ - 10). PIND beeinflul3te keine der rena­ par les diuretiques. tient~ are not prone to comply Ien Ausscheidungen signifikant. On administra, de fat;on double aveu­ with sophisticated therapeutic re­ CLOP konnte die renale Produktion gle, des doses uniques de placebo, du gimes, the variability of response von Renin erhohen, erhoht aber gleich­ diuretique clopamide S mg (CLOP), du to most therapies, the high inci­ zeitig die Plasmaaldosteron-Konzentra­ beta-bloquant adr(mergique pindolol tion. PIND konnte diese Erhohung abge­ I 0 mg (PIND) et de la combination de dence of significant undesirable schwlicht haben. Daher konnte der Diu­ CLOP et PIND (CLOP + PIND) a neuf side and toxic effects of avail­ retika-bedingte Anstieg der Mehraus­ volontaires normaux. Chaque dose fut able drugs and the expense of scheidung von Mg2+ iiber die Niere administree sept jours a part des autres, comprehensive diagnosis and se­ zumindest teilweise auf einen Hyperaldo­ de maniere randomise. Les sujets furent lective management. For these steronism us zuriickzufiihren sein. Die etudies chez une salle metabolique, sous moglichen Vorteile dieser Ergebnisse fiir des conditions strictement controlees. reasons a tendency exists to stan­ die Behandlung von Hypertonie-Patien­ La CLOP et la CLOP + PIND aug­ dardize antihypertensive therapy, ten miissen in Langzeit-Studien unter­ menterent significativement les moyen­ in a manner aimed at minimizing sucht werden. nes des debits urinaires de 24 heures de the risk/benefit ratio and the liquide et de Na+ par rapport au placebo. La CLOP augmenta significativement les costs involved. Initially, success moyennes des debits urinaires de Mg2+ in achieving these goals was Summary (D.% 27, p<O,Ol) et de K+ (D.% = 25, limited by the drugs available. p < 0,05) par relation au placebo, autant The advent of thiazides, some The objective of this study was to assess que la CLOP + PIND ne modifia pas le whether beta-adrenergic blockade influ­ debit urinaire d'aucun des deux electroly­ three decades ago, constituted ences diuretic-induced hypermagnesi­ tes (D.% = l pour le Mg2+ et D.% = such an important turning~point uresis and hyperkaliuresis. - 10 pour le K +). in this respect that diuretics still Single doses of placebo, of the diuretic Le PIND pourrait avoir bloque !'eleva­ remain a cornerstone in the treat­ clopamide 5 mg (CLOP), of the beta-ad­ tion que la CLOP induit sur la produc­ ment of hypertension [18] and renergic blocker pindolol 10 mg (PIND) tion renale de renine, et par consequence and of a combination of CLOP and le PIND pourrait avoir diminue la con­ preserve their place as the most PIND (CLOP + PIND) were adminis­ centration plasmatique d'aldosterone. commonly prescribed group of tered 7 days apart, double-blind and in Les accroissements des debits urinaires drugs for this purpose worldwide random order, to nine healthy volunteers. de Mg2+ et de K+ induits par la CLOP [55, 77]. Subjects were studied in a metabolic seraient dus, au moins partialement, a ward under strictly controlled conditions. l'aldosteronisme secondaire provoque par It took some years for the un­ CLOP and CLOP + PIND significant­ ce diuretique. Les avantages potentielles desirable features of diuretics to ly increased the mean 24-h urinary out- de ces donnes pour le traitment de l'hy- become apparent, and to be in- 122 Magnesium-Bulletin 4/1985 vestigated in a systematic man­ dosterone (RAA) system [ 10, 12, incidences of cardiac insuffi­ ner. A policy directed at solving 19] through the decrease in blood ciency, renal failure and cerebro­ the problems these undesirable volume and the subsequent in­ vascular accidents [14, 76], has effects pose is still under de­ crease of beta-1 sympathetic acti­ been loosing ground to the con­ velopment and, at the same time, vation they induce [16, 70, 73], cept that diuretic-induced hyper­ new problems are being identi­ and through the decrease in Na + magnesiuresis [3, 4, 27, 36, 52, fied as medicine progresses and concentration in the milieu inte­ 54, 56, 75] and resulting somatic the scope and sensitivity of in­ rieur they provoke; thus, the uri­ Mg2+ depletion [26, 29, 30] are strumental analysis increase. nary excretion of K + is elevated at least as important in the over­ The introduction of beta-adre­ since aldosterone augments the all determination of the men­ nergic blockers provided an al­ exchange between Na + and K + tioned side effects and in the de­ ternative first choice for the drug plus H + that takes place in the crease in intracellular K + pro­ treatment of essential hyperten­ late distal tubule [ 12]. voked by diuretics [76]. This sion, according to some schools Somatic K + depletion, secon­ view, which is based upon clini­ [8, 16, 35]. However, these drugs dary to the increase in renal K + cal and experimental evidence are less efficacious than diuretics excretion induced by diuretics, [14, 67, 76], has been the subject in terms of the percentage of has been widely incriminated as of several recent reviews [52, 54, cases in which they can normal­ a critical determinant of cardiac 59, 64]. ize blood-pressure values when arrhythmias [18, 77], myocardial Somatic Mg2 + depletion may the unstratified population of pa­ infarction and sudden death occur in many patients during tients with essential hypertension which occur in diuretic-con­ prolonged diuretic therapy, parti­ is considered. Nevertheless, trolled hypertensives. Beta-adre­ cularly when other factors coex­ beta-adrenergic blockers increase nergic blockers, which at vari­ ist, nearly all of which are similar the antihypertensive action of di­ ance with diuretics have been la­ to those promoting K + defi­ uretics and are consequently of­ beled as "cardioprotective" [7], ciency [52, 54]. Most types of di­ ten added to diuretic regimens in counteract diuretic-induced hy­ uretics, including the mercurial, order to achieve optimal control perkaliuresis when they are coad­ the loop (furosemide-like), the of blood pressure in as many pa­ ministered via the decrease they early distal tubular (thiazide-like, tients as 82% [24]. Since beta-ad­ cause in plasma renin activity, be them uric-acid retainers or renergic blockers possess phar­ provided the dose relationship not) and the xantines induce hy­ macological properties that af­ between the drugs is correct, as permagnesiuresis in normal and fect several systemic variables in occurs in most fixed-dose combi­ diseased man. The subsequent an opposite direction to diuret­ nations which have been devel­ decrease in Mg2+ concentration ics, the conjoint administration oped with this,