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
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, amongst other, within the myocardial cells re of diuretics and beta-adrenergic objectives taken into considera sults in a depletion of intramyo blockers has been advocated not tion. However, the only major cardial K + and in increases in only as a means of normalizing advantage of fixed-dose combi intracellular Na + and free cyto blood pressure in a higher num nations of diuretics and beta-ad solic Ca2+ concentrations, this ber of patients than when either renergic blockers proven to day drug is used alone, but also in has been an increased antihyper cationic pattern predisposing to order to balance out various un tensive efficacy with respect to serious cardiac arrhythmias and desirable pharmacological ac either component used alone [6], sudden death [22, 52, 54]. A sim tions [8, 28]. since combinations effectively ilar ionic shift could occur within Common diuretics increase the control blood pressure in 70- vascular muscle during Mg2+ de urinary excretion of K + and may 85 % of unstratified cases suffer pletion leading to vasospasm, thus conduce to somatic deple ing from essential hypertension. principally in the coronary arter tion of the cation [19, 47]. Di The effects, if any, of these com ies [ 1]. A positive association has uretic drugs block the reabsorp binations upon the incidences of been found between low-Mg2+ tion of filtered Na + at the loop cardiac arrhythmias, sudden intake and the risk of developing of Henle (e.g. furosemide) or at death and myocardial infarction acute myocardial infarction [39] the early portion of the distal have not been adequately and sudden death [37]. Both K + tubule (e.g. thiazides and chlor studied. Meanwhile the contro and Mg2+ concentrations are de thalidone), thus augmenting the verted [40, 46] idea that diuretic creased in infarcted myocardium amount of Na + available for induced K + depletion is of cen and perinecrotic areas [ 11 ]. Pa reabsorption at the terminal por tral importance to the failure of tients with severe coronary heart tion of the distal convoluted tub diuretics to reduce the incidence disease, diagnosed by coronary ule, where it is exchanged for K + of important cardiac events in arteriography, have been found and H + which are excreted into hypertensive patients to the rates to have lower-plasma Mg2+ con the nephronal lumen. Diuretics found in normotensive individ centration than controls [41]. activate the renin-angiotensin-at- uals, as these drugs reduce the Magnesium, and to a less extent Magnesium-Bulletin 4/1985 123
K +, deficiency could be also in or metabolic disorders. Smokers photometer using caesium as di volved [49, 53] in the mechanism or alcoholics were not studied. luent. Cl- was measured with an of diuretic-induced decrease in A standardized diet containing IL 446 analyser using a mercuric glucose tolerance [ 17, 53] and in 200 to 220 mmol of Na + and ap diluent. Total C02 was deter the shift diuretics provoke in the proximately 4000 ml of water mined with the same instrument plasma lipid profile towards a was prescribed on treatment days by conversion of bicarbonate pattern associated with an in and during the 24 hours preced into C02 by acid treatment and crease in cardiovascular risk (a ing each of them (control days). measurement of pC02 by means rise in total and LDL- and Subjects received placebo, 5 mg of a glass pH electrode/C02 VLDL-cholesterol and a fall in clopamide, I 0 mg pindolol and a permeable chamber. Magnesium, HDL-cholesterol [20, 65]). This combination of 5 mg clopamide Ca2+ and Zn2+ were measured latter metabolic shift may be and I 0 mg pindolol (CLOP + by atomic absorption with a Var counteracted by the coadminis PIND), separately and in ran ian 1275 instrument. Inorganic tration of beta-adrenergic block dom order, on four different phosphate, creatinine, urate, ers [43]. From these facts it treatment days which were at B.U.N. and glucose were all de would appear that blunting of di least 7 days apart. Medications termined colorimetrically on a uretic-induced hypermagnesi were given at 0800 hour with Model 34 Beckman Trace 11 uresis could be highly beneficial 100 ml tap water. Volunteers spectrophotometer. Colorimetric in hypertensive patients. Since were confined to a metabolic reactions were used for the as plasma Mg2+ and renin concen ward on treatment days when says of total inorganic phosphate trations are inversely related [50] ingestion of alcohol and drinks (Clinical Sciences kit) and crea and since urinary Mg2+ excre containing caffeine was forbid tinine (Boehringer-Mannheim tion seems to be positively influ den. No other medications, in kit); enzymatic colorimetric reac enced by aldosterone in man [21, cluding simple analgesics or the tions were employed for the eval 42], both ACE-inhibitors and topical use of corticosteroids, uations of uric acid (Boehringer beta-adrenergic blockers could were allowed during the entire Mannheim Peridochrom kit), be regarded as likely to provide study period. B.U.N. and glucose (Beckman the counteraction desired. A Each urine specimen collected kits). study by this group has shown from 0 3, 3-6,6-9,9-12 and that captopril exerts a hypermag 12-24 hours after dosing on Mathematical methods nesiuretic effect per se [38]; con treatment days and pooled urine All experimental values are ex sequently, the choice of a suita collected during the. previous pressed as means ± S.E.M. The ble agent for combination ther 24 hours were measured for con mean experimental values of the apy is confined at present to centrations of Cl-, Na +, K +, urinary volume and solutes, ac beta-adrenergic blockers. Ca2+, Mg2+, inorganic phos cumulated by the end of each The objectives of this study phate, Zn2+, creatinine and urate. post-dosing collecting period on were to assess how the acute ad On treatment days, blood was treatment days, M, as functions ministration of a combination of drawn by venipuncture just be of time, t, were fitted by a mathe a diuretic and a beta-adrenergic fore medication and from 5.5 to matical model [51]: blocker to normal subjects af 6.5 and 23.5 to 24.5 hours later 20M/log(100-M) exp[2.30 fects the urinary outputs of fluid, for measurement of serum con (t-t1)/(a + bt)], Mg2+, K +, Na+, and other sol centrations of Cl-, Na+, K+, where t1 is the time at which M utes, by comparison with the ad Ca2+, Mg2+, inorganic phos = 0.1 unit used for the fitting ministrations of placebo and of phate, creatinine, blood urea ni and a (time) and b (dimension the active components of the trogen (B. U. N.), urate, total less) are the zero ordinate value combination given separately. C02 and glucose. Blood was col and the slope parameters of the lected in plain glass tubes and regression of the linearised trans Subjects and methods serum was separated by centrifu formation of the function respec gation and frozen until chemical tively. The fitting procedure was Subjects and experimental design analysis. described previously [51]. Nine healthy male adult students Flows of urinary variables volunteered to participate in the Laboratory methods were defined as the derivative of study after a full explanation of All laboratory analyses were car M with respect to time [51]: its implications. All were aged ried out by technicians who were dM/dt = (a+bt1)/[(a+bt)2) between 18 and 24 and had ta unaware of the protocol. j(0.43/M) + (0.432/[(1 00 ken no other medication within Urinary and serum variable -M)log(100-M)]f]. the previous 2 months. None was concentrations were measured as This derivation is graphically obese nor had any history of follows: Na+ and K+ were eval exemplified in Fig. 1. Flows were renal, cardiovascular, hepatic uated with an IL 943 flame characterized by the times to 124 Magnesium-Bulletin 4/1985 peak flows of urinary variables techniques were detected in a ide alone (Table 11). When the after dosing, tm, since a nihil de few cases, all descriptive and in effects of pindolol 10 mg .were rivative of the latter function ferential methods used were compared to those of CLOP + with respect to time ( d2M/ dt2 = parametric. Correlation and re PIND, significant increases in 0) exists when flow is maximal, gression on linearised data and mean 24-h urinary outputs of and tm summarizes the parame the paired t-test were deployed. Cl-, Na + and fluid in response tric relationships between t 1, a All statistical tests were two to CLOP + PIND were detect and b in the analytical expres tailed and p = 0.05 was consid ed, whereas no significant differ sion for d2M/dt2. Mean time to ered the limit of significance. ences existed between outputs of peak flow of each urinary varia the other variables. Clopamide 5 mg induced significantly higher ble after dosing was calculated Results on a computer, from the corres mean 24-h urinary outputs of ponding flow function, through No significant differences were CI-, Na+, fluid, K+, Mg2+ and an iterative procedure. found between the mean 24-h ac Zn2+ than pindolol 10 mg, whilst Normality of frequency distri cumulated urinary outputs of no significant differences arose butions and homoscedasticity of fluid and solutes after placebo for Ca2+, inorganic phosphate, and those yielded on control sample variances were evaluated, creatinine and urate. Figure 2 days. The urinary outputs of Cl-, for all variables, through the chi shows the percentual changes in Na +,fluid, K +, Ca2+, Mg2+, in the mean 24-h urinary outputs of square test and the F ratio res organic phosphate, Zn2 +, cre pectively. Since only minor de Na +, K + and Mg2+ with respect atinine and urate accumulated at to corresponding outputs after partures from formal prerequi 3, 6, 9, 12 and 24 h after the in sites for parametric statistical- placebo. It appears clear that clo take of placebo, clopamide 5 mg, pamide 5 mg and CLOP + pindolol 10 mg and of CLOP + PIND exerted impressive natri PIND are shown in Table I. ~ 280 uretic effects of similar magni E tude whilst pindolol I 0 mg did E The significances of the differ o not affect mean 24-h urinary W+ ences between the mean 24-h uri r: 0,9999 Na + output. It is also evident ~ ~ 140 nary outputs after placebo and ...J p < 0,00001 that whereas clopamide 5 mg sig ::I> t1 = 0,0484 h after the active medications are :::Ea: nificantly increased kaliuresis ::I
5 mg are illustrated in Fig. 3. The tween the two ions and show a placebo and post-pindolol flows relationships between the time different pattern from that of the of Ca2+ and of Na + exhibited courses of the post-placebo and Mg2+ and Ca2+ flow relation different patterns for each of the post-clopamide flows were ships (Fig. 3). cations and were also at variance homomorphic for Mg2+ and Figure 4 reveals that the mean with reference to the Mg2+ and Ca2+, i.e. an initial increase in 24-h urinary flows of Mg2+ and K +-flow-relationship pattern. flows caused by clopamide was K + after placebo and pindolol The relationships between followed by a small decrease 10 mg were homomorphic; an post-placebo and post-CLOP + (undershoot) with respect to the initial phase where the post-pin PIND mean urinary flows of corresponding placebo response. dolol flows had higher values Mg2+, Ca2+, Na+ and K+ are In the case of Na + and K + the than their post-placebo counter depicted in Fig. 5. The Mg2+, relationships between the post parts was succeeded by a period Ca2+ and K + flows were homo placebo and post-clopamide where the reverse occurred. The morphic in the sense that a pri flows were heteromorphic be- relationships between the post- mary phase, when the post-
Table 1: Accumulated excretions of urinary variables after administration of single doses of clopamide 5 mg, a combination of clopamide 5 mg and pindolol 10 mg (CLOP + PIND) and pindolol!O mg to nine healthy volunteers. Values as mean ± S.E.M.
Urinary Hours after dosing Medication variable 3* 6 9 12 24
Chloride Placebo* 35±8 66± 13 93± 17 126±21 190±31 (mmol) Clopamide 5 mg 64±9 142± 14 229±21 272±23 349±26 CLOP+ PIND 65±6 !52± 15 230±21 273±24 364±23 Pindolol 10 mg 26±4 63±9 97± ll 120± 12 174± 15 Sodium Placebo 25±6 52±10 75± 13 101± 16 154±23 (mmol) Clopamide 5 mg 56±7 119 ± 12 188±21 220±22 285±26 CLOP+ PIND 57±4 122± 13 186±20 224±24 307±24 Pindolol I 0 mg 17±3 43±8 73± 11 96± 13 148± 12 Fluid Placebo 0.48±0.09 1.10±0.12 1.55±0.15 2.00±0.15 3.11±0.18 (litre) Clopamide 5 mg 0.60±0.10 1.35 ± 0.11 2.26±0.13 2.76±0.13 3.90±0.10 CLOP+ PIND 0.78±0.07 1.72±0:16 2.51±0.23 2.98±0.21 4.00±0.19 PindolollO mg 0.57±0.09 1.35±0.10 1.93 ±0.13 2.42±0.12 3.25±0.10 Potassium Placebo 13.3 ± 1.7 26.4±2.3 32.9±2.7 41.8±3.1 61.3±5.0 (mmo1) Clopamide 5 mg 15.6±2.3 30.9±2.4 46.2±3.1 55.3±3.7 76.9±5.8 CLOP+ PIND 14.4 ± 1.8 25.5±2.8 34.4±3.4 39.9±4.3 54.9±4.3 Pindolol!O mg 11.4± 1.2 22.6±2.3 30.0±2.9 36.9±2.5 49.0±2.1 Calcium Placebo 0.56±0.07 1.08±0.11 1.69±0.17 2.22±0.25 4.80±0.53 (mmol) Clopamide 5 mg 0.91±0.11 1.74±0.22 2.61 ±0.37 3.12±0.46 4.94±0.73 CLOP+ PIND 0.93±0.16 1.88±0.26 2.49±0.33 2.86±0.38 4.21 ±0.66 Pindolol 10 mg 0.53±0.08 1.34±0.17 1.92±0.19 2.79±0.34 4.90±0.74 Magnesium Placebo 0.53±0.07 1.14±0.08 1.72±0.13 2.17±0.19 4.97±0.40 (mmol) Clopamide 5 mg 0.96±0.05 1.80±0.11 2.81 ±0.24 3.36±0.32 6.32±0.62 CLOP+ PIND 0.87±0.09 1.80±0.14 2.44±0.23 3.02±0.37 4.90±0.88 Pindo1ol!O mg 0.53±0.05 1.27±0.09 1.76 ± 0.20 2.40±0.30 4.25±0.54 Inorganic Placebo 5.1 ± 1.1 8.4± 1.3 13.0± 1.6 19.1 ± 1.8 42.8±3.5 phosphate Clopamide 5 mg 4.1±1.4 6.3 ± 1.6 12.3±2.2 16.5±2.6 36.9±4.0 (mmol) CLOP+ PIND 3.0±0.5 7.8± 1.7 13.4±2.1 20.4±3.1 41.1 ± 2.5 Pindolol!O mg 2.2±0.6 4.9±0.7 9.1 ± 1.2 15.9±2.3 35.6±2.9 Zinc Placebo 1.17±0.28 1.92±0.39 2.90±0.52 3.79±0.66 8.11 1.23 (llJllol) Clopamide 5 mg 1.80±0.28 3.04±0.39 4.92±0.70 5.98±0.89 10.16± 1.67 CLOP+ PIND 1.81 ±0.31 3.07±0.50 4.59±0.80 5.40± 1.01 8.56± 1.74 Pindolol I 0 mg 1.19±0.18 2.16±0.31 3.23±0.53 4.08±0.57 6.60±0.75 Creatinine Placebo 3.5±0.3 6.0±0.4 8.4±0.6 11.4±0.7 22.0± 1.5 (j.tmol) Clopamide 5 mg 3.4±0.3 5.7 ±0.5 9.0±0.7 11.3 ±0.8 20.6± 1.2 CLOP+ PIND 3.6±0.2 6.6±0.7 9.7±0.8 12.1 ± 1.0 22.0± 1.1 Pindo1ol 10 mg 2.8±0.2 5.5±0.4 8.3±0.6 11.2 ±0.7 20.4±0.9 Urate Placebo 1.18 ±0.24 1.95±0.23 2.78±0.28 3.72±0.39 6.35 ±0.59 (mmol) Clopamide 5 mg 0.93 ±0.11 1.58±0.18 2.72±0.30 3.35 ± 0.38 5.39±0.52 CLOP+ PIND 0.84±0.08 1.56±0.18 2.48±0.28 3.10±0.34 4.99±0.40 Pindolol I 0 mg 0.68±0.05 1.36±0.11 2.26±0.19 3.07±0.24 5.08±0.23
* Hour-3 placebo values were derived from seven cases. 126 Magnesium-Bulletin 4/1985
CLOP + PIND flow surpassed but was above the corresponding 24 hours after CLO:t;> + PIND, the post-placebo flow, was fol post-pindolol flow throughout and mean serum inorganic phos lowed by an' undershoot of the the 24-h period. phate was increased 6 hours after post-active-medication flow with Mean values of serum varia placebo. respect to that after placebo, At bles before and after dosing with variance, the post-CLOP + the four formulations are shown PIND mean urinary N a+ flow in Table IV. Statistically signifi Discussion was above its post-placebo coun cant falls in serum K + and eleva terpart throughout the 24-hour tions in serum urate level were Urinary outputs offluid and elec period. noted 6 and 24 hours after dos trolytes Figure 6 shows that the rela ing with CLOP + PIND and 24 The effect that clopamide 5 mg tionships between post-clopam hours after clopamide 5 mg and had in increasing the mean 24-h ide and post-CLOP + PIND pindolol I 0 m g. Mean serum K + urinary outputs of Cl-, N a+, mean urinary flows of Mg2+, concentration also rose signifi fluid, K + and Mg2+ with respect Ca2+ andK+ were homomorphic; cantly 24 hours after placebo. to placebo and the decreases it a first phase during which the B.U.N. fell 6 hours after all for induced in the outputs of cre post-CLOP + PIND flow sur mulations and rose 24 hours after atinine and urate could be ex passed the post-clopamide flow placebo and clopamide. Total pected on the basis of current was followed by a period when C02 was significantly increased knowledge about the actions of the reverse took place. Urinary 24 hours after clopamide. Serum diuretics with renal acceptors flow of Na + after CLOP + Ca2+ level was reduced 24 hours principally situated in the first PIND did not follow this pattern after placebo. Serum glucose rose portion of the distal convoluted
Table 11: Probabilities corresponding to dependent-t statistics evaluating the significance of the differences between any two mean 24-hour urinary variable outputs after administration of single doses of clopamide 5 mg, a combination of clopamide 5 mg and pindolol!O mg (CLOP+ PIND) and pindolol!O mg.
Medication Urinary Medication variable Clopamide 5 mg + Placebo Pindolol!O mg pindolol I 0 mg
Chloride Clopamide 5 mg 0.0025* <0.0001* 0.5796 CLOP+ PIND <0.0001* <0.0001 * Pindolol I 0 mg 0.5902 Sodium Clopamide 5 mg <0.0001 * 0.0003* 0.4464 CLOP+ PIND <0.0001* <0.0001* Pindolol!O mg 0.7099 Fluid Clopamide 5 mg 0.0003* 0.0001 * 0.6002 CLOP+ PIND 0.0012* 0.0019* Pindolol I 0 mg 0.2240 Potassium Clopamide 5 mg 0.0291 * 0.0010* 0.0006* CLOP+ PIND 0.3617 0.1490 Pindolol I 0 mg 0.0629 Calcium Clopamide 5 mg 0.7911 0.9208 0.2979 CLOP+ PIND 0.3362 0.4306 Pindolol I 0 mg 0.8524 Magnesium Clopamide 5 mg 0.0091* 0.0080* 0.1249 CLOP+ PIND 0.9362 0.4215 Pin dolo! I 0 mg 0.1953 Inorganic Clopamide 5 mg 0.1194 0.7004 0.3323 phosphate CLOP+ PIND 0.4395 0.1265 Pindolol I 0 mg 0.0965 Zinc Clopamide 5 mg 0.0901 0.0124* 0.1567 CLOP+ PIND 0.7750 0.1827 Pindolol I 0 mg 0.2053 Creatinine Clopamide 5 mg 0.0256* 0.8123 0.2135 CLOP+ PIND 0.9679 0.2547 Pindolol!O mg 0.1325 Urate Clopamide 5 mg 0.0382* 0.5376 0.3294 CLOP+ PIND 0.0179* 0.7940 Pindolol I 0 mg 0.0639
* Significant. Magnesium-Bulletin 4/1985 127 tubule. Zinc urinary output rose taining effect expected of an also if the sample analysed were and inorganic phosphate urinary early distal tubular diuretic like larger. When directionally com output decreased after clopamide clopamide [5], since it usually pared with the outputs which fol administration, but these only becomes apparent after re lowed clopamide administration, changes were not statistically sig peated administration of the di the post-pindolol urinary outputs nificant with respect to placebo, uretic. showed opposite tendencies for although the probabilities of con Pindolol did not affect the Cl-, Na+, fluid, K+, Mg2+ and firmation of the null hypothesis mean 24-h urinary outputs of any Zn2+ (Table I); these contrary were borderline with those of re variable to a statistically signifi actions achieved statistical sig jection in each case (Table 11); cant degree, although the de nificance. the relationship between the creases in the outputs of K + and Beta-adrenergic blockers in small sample size and the arbi inorganic phosphate (Table I) duce K +-retention through an trary level of significance set after pindolol 10 mg with respect inhibition of renal renin release, could account for these findings. to post-placebo excretions were mainly due to beta-1-adrenergic The mean urinary Ca2+ output near the border of significance blockade in man [66], and secon after clopamide did not differ (Table 11), and would become dary decreases in angiotensin-II from that after placebo; this is significant upon an increase in formation and plasma aldoster not at variance with the Ca2+ -re- the alpha level set and possibly one concentration. The action of
n:9 0/o 4 IN 24-h URINARY OUTPUT -30 0 30 60 90 VERSUS PLACEBO
p < 0,001 jNS p< 0,001 p< 0,001 I p < 0,001 ------~ NS ------~
p p < 0,01 m111111111111Ill J I NS NS liiiiii1 NS NS ~~ CLOPAMIDE 5 mg ITII1J PINDOLOL 10 mg a umm = 111 Fig. 2: Percentage changes in the mean 24-h urinary outputs of Na +, K + and Mg2'+ after separate administration of single doses of clopamide 5 mg, a combination of clopamide 5 mg and pindolol 10 mg, and pindolol 10 mg per os to nine healthy volunteers. The probability values refer to comparisons between corresponding mean values. 128 Magnesium-Bulletin 4/1985 pindolol, which exhibits higher served in the present study when for this effect, by the beta-adre intrinsic sympathomimetic activ CLOP + PIND did not affect nergic blocker [27]. CLOP + ity (ISA) than most current beta the urinary K + output, despite of PIND acted on Cl-, Na + and adrenergic blockers [66], on the having significantly increased fluid outputs to the same extent RAA system has been the subject the renal urinary output of Na + as clopamide 5 mg (Table II). of much controversy, apparently and therefore the availability of The lack of any detrimental ef derived from different experi this cation at the late distal con fect of pindolol on natriuresis, mental designs and results. Con voluted tubule where Na+ is ex sistent reports exist, however, in when added to the diuretic, sug dicating that pindolol decreases changed for K + and H +. Pin gests that the beta-adrenergic the activity of the RAA system dolol I 0 mg per se did not de blocker did not promote further when it has previously been acti crease the mean 24-h urinary out N a+ excretion despite counter vated [2, 78], or when the coad put of Na + with respect to pla acting the diuretic-induced enh ministration of a diuretic tends cebo, which could mean plasma ancement of the RAA system; to enhance this activity [65]. A aldosterone concentration was this could be due to an haemo result of this interaction was ob- reduced, to the necessary extent dynamic effect of pindolol n:9 0,4 ... 0,48 . .. ..- ..- . -I -I + ·. + .r::. .. C'll .c:: C'll .: en- ('Q -0 . 0 :E e 0,2 ~0,24 > E >- a: - a: <( 3: <(3: z 0 ~0 -a: ..J £r..J :::1 u.. 0 ::IlL 0 0 12 24 0 12 24 HOURS HOURS . ·. 32 5,6 : ·.. ..- . ..-- -I I .r::. .r::. .. .· . + . . -0 ('Q 0 . .. z - . .. ~ E E 16 : .. 2,8 E . .. >! >a:- . . .. a:: <( ---PLACEBO ...... CLOPAMIDE 5 mg Fig. 3: Mean urinary Mg2+, Ca2+, Na + and K + flows after separate administration of placebo and of a single dose of clopamide 5 mg per os to nine healthy volunteers at time 0 (0800 h). The relationship between the post-placebo and post-clopamide flows of Mg2+ is homomorphic with respect to the relationship between the post-placebo and post-clopamide flows of Ca2+, i.e. each of these two relationships shows two analogous phases. The relationship between the post-placebo and post-clopamide flows of Na+ and that corresponding to K + exhibit different patterns with respect to each other and are also at variance with the flow-relationship pattern common to Mg2+ and Ca2 +. Magnesium-Bulletin 4/1985 129 (vasodilation) that would tend to the intrinsic sympathomimetic does not appear to be the princi cause retention of Na + via a re activity of pindolol. pal regulatory mechanism of the flex increase in plasma aldoster CLOP + PIND did not affect renal excretion of the cation, at one. This potential N a+ -retain the 24-h urinary output of Mg2+ least under physiological circum ing property of pindolol was not significantly when compared to stances. A dissimilitude in the exhibited by the drug alone, but placebo. The role of aldosterone relative importances of the RAA could have become overt when in the control of renal Mg2+ han system in the renal handlings of beta-adrenergic blockade coun dling has been the subject of K + and Mg2+, when the system teracted the enhanced activity of much debate, mainly on the basis is activated by a diuretic, is the RAA system induced by clo of animal experiments [42]. shown by the fact that the differ pamide 5 mg; the resultant fall in However, there is evidence that ences between the mean urinary the serum level of angiotensin 11, aldosterone increases renal Mg2+ outputs of K + after clopamide which has a permissive action on excretion and subsequently re 5 mg and after CLOP + PIND the effects of adrenergic stimula duces plasma Mg2+ concentra was highly significant statisti tion, would have counteracted tion in man [23], although this cally (Table 11), whereas the n:9 0,4 0,48 ,...- + ,.- I C\1 ~ + .c a- C\lcu o ::E e 0,2 o E 0,24 > E a:- >a:- E 32 5,6 ,... ,... -I -I .c + .c cu-= 0 z 0 + E 16 ~ E 2,8 > E >E a:- a:- l <:= <:= I ~0 ~0 a:...J a:...J ::lLL 0 ::lLL 0 12 24 0 12 24 HOURS HOURS PLACEBO ---- PINDOLOL 10 mg Fig. 4: Mean urinary Mg2+, Ca2+, Na + and K + flows after separate administration of placebo and of a single dose of pin dolo! tO mg per os to nine healthy volunteers at time 0 (0800 h). The relationship between the post-placebo and post-pindolol flows of Mg2+ is homomorphic with respect to the relationship between the post-placebo and post-pindolol flows of K +, i.e. each of these two relationships shows two analogous phases. The relationship between the post-placebo and post-pindolol flows of Ca2+ and that corresponding to Na+ exhibit different patterns with respect to each other and are also at variance with the flow-relationship pattern common to Mg2+ and K+. 130 Magnesium-Bulletin 4/1985 corresponding difference m held in the case of all variables involving acidic thiazide-type di mean urinary Mg2+ output did after all formulations, the time uretics acting solely from within not attain statistical significance, courses of the mean flows, which the tubular lumen. although it approached it (Table were described in terms of the With respect to placebo, 11). In addition, despite the fact derivative of the fitted function CLOP + PIND had similar di that both differences lay outside with respect to time, constitute rectional effects to clopamide the significant range, the differ reliable descriptions. The times 5 mg on the tm values corres ence between the K + outputs to maximal flows after dosing, ponding to Cl-, Na +, Ca2+, after pindolol 10 mg and after tm, presented in Table Ill afford Mg2+, Zn2+ and creatinine (Ta CLOP + PIND had a lower a variable for the simplified over ble Ill). The differences between probability of rejection of the all description of the time cours the post-placebo and post-CLOP null hypothesis than its Mg2+ es of all the mean fluid and so + PIND tm values for Cl-, N a+ counterpart, which would also lute flows. and Zn2+ were lower than the support the postulate that aldos The directional effect of clop corresponding differences be terone is a more important regu amide on the mean urinary flows tween the post-placebo and lator of renal K+ than of renal of Cl-, N a+, Ca2 +, Mg2+ and post-clopamide 5 mg tm values Mg2+ excretion, at least when a Zn2+ consisted in an accel and higher than the differences common early distal convoluted eration, whereas the mean flows corresponding to Ca2+ and tubular diuretic is administered. of fluid, K +, inorganic phos Mg2+. CLOP + PIND accelerat The opposite, albeit statisti phate, creatinine and urate were ed the flows of creatinine, fluid cally non-significant, effects of practically unaffected (Table and K +, which had not been af clopamide 5 mg and pindolol Ill). These facts indicate that uri fected by clopamide 5 mg, and 10 mg on urinary Zn2+ output nary Cl- and Na + excretions delayed the inorganic phosphate with respect to placebo became were strongly linked, whereas flow with respect to placebo. statistically significant when the that of fluid could be more relat These changes are difficult to effects of the active drugs were ed to the changes in urine osmol analyse on the sole basis of the directly compared (Table 11). ality that certainly followed the tm values and are best under This fact, which would seem to administration of the diuretic. In stood by examining the entire indicate beta-adrenergic block this particular case, the excretion time courses of the flows. ade opposes renal Zn2+ excre of K + appears to be related to Figure 3 shows the mean uri tion, is difficult to interpret in that of Na + in a looser manner nary flows of Mg2+, Ca2+, Na + detail since knowledge of the than usual after the administra and K + during the 24-h periods renal handling of Zn2+ is tion of diuretics; this fact, which following the administrations of limited [61, 62]. confirms clopamide is pharma placebo and clopamide 5 mg. The facts clopamide and cologically different from the The diuretic caused initial in CLOP + PIND caused signifi thiazides [45, 72], is perhaps due creases in the mean flows of cant increases in the mean 24-h to that clopamide acts from both Mg2+ and Ca2+ with respect to urinary output of urate with res the tubular lumen and the milieu placebo, corresponding to aug pect to placebo, and that the cor interieur, whereas the thiazides mentations of the outputs of responding effect of pindolol only act from the tubular lu these cations. This phase ended was directionally similar and men [45]. at a point at which the mean nearly reached significance, The reductions in the tm values flows after clopamide turned to could be expected on the basis of of Na + and Mg2+ induced by fall below those of placebo until established knowledge that early clopamide with respect to place the completion of the 24-h post distal tubular diuretics and beta bo were 1.25 and 1.22 hours res dosing period. This decrease, adrenergic blockers diminish re pectively (Table Ill), a finding at which may be referred to as an nal urate excretion. variance with the most frequently undershoot of urinary flow since observed response to loop and it follows an initial increase in Urinary flows offluid and solutes early distal tubular diuretics, the output of an urinary variable The mathematical model used which is a widening of the gap caused by a formulation with res [51] fitted the outputs of urinary between tm values of Na + and pect to placebo, is also apparent variables accumulated as func Mg2+ after administration of the from the data in Table I. When tions of time in a highly satisfac drug. This result is consistent an undershoot is much below its tory manner (Table Ill). The val with the lack of any acute effect reference mean flow or is very idity of the application of the by clopamide 5 mg on the tm of prolonged, as occurred with Ca2 model and the accuracy with K +, indicating an association be N (Fig. 3), the outcome may be a which it describes the urinary ex tween the mechanisms that ac balance between overshoot and cretion of any natural or exogen count for Mg2+ and K + excre undershoot that almost equalises ous solute has been discussed tions after clopamide, which can the flows being compared during elsewhere [51]. Since the model not be inferred from any studies the 24-h period in question, thus Magnesium-Bulletin 4/1985 131 accounting for the lack of statist promotes renin secretion [69], one-mediated contribution to ically significant changes in the and subsequently elevates uri clopamide-induced hyperkali 24-h outputs of the variable con nary Mg2+ excretion. The homo uresis and hypermagnesiuresis is cerned. The undershoots could morphism of the relationships provided by the fact that the dif be determined by either a dimi between the post-placebo and ference between mean urinary nution of the source of the solute post-clopamide urinary Mg2+ K + flows after placebo and clop (decrease in its plasma concen and Ca2+ flows (both consist of amide was lower than that be tration) or by the activation of an overshoot and an undershoot tween the Na + flows. More evi regulatory mechanisms tending phases) would be principally ex dence on the importance of al to conserve the solute in ques plained by related underlying dosterone in urinary Mg2+ excre tion. In the case of Ca2+, the ini mechanisms affecting urinary tion might be afforded by similar tial increase in the flow and out Ca2+ and Mg2+ excretions. If ur experiments in which Na + in put of the variable in urine was inary Ca2+ output were reduced take were manipulated. accompanied by an increase in when clopamide is chronically The time courses of the mean plasma Ca2+ concentration, administered, as it happens with urinary flows of Mg2+, Ca2+, which in spite of being a non-sig the other early distal tubular di Na + and K + that followed the nificant change could be relevant uretics, plasma PTH would be administrations of placebo and in so far as there was a direction consequently decreased [68], pindolol 10 mg are compara ally opposite change (non-signi thus conducing to further urinary tively shown in Fig. 4. Beta-ad ficant decrease) in plasma Ca2+ Mg2+ losses by a reduction in 2 renergic blockers could affect the 6 hours after the administration PTH-dependent Mg + reabsorp active physio-biochemical of placebo with respect to the tion in the loop of Henle [52, 54]. mechanisms regulating the excre pre-dosing mean concentration The lower panel of Fig. 3 tions of Mg2+ and Ca2+ at the of the variable (Table IV). This shows that the mean urinary parathyroid gland and renal lev constancy in plasma Ca2+ con Na + flow after clopamide was els, by reducing the activity of centration after the diuretic higher than the mean post-pla adenylate cyclase, which is under might well have been the result cebo flow over the entire study the positive control of catechol of an elevation in serum parathy period of 24 hours, and that a amines, and therefore the forma roid hormone (PTH), secondary similar consideration holds, in tion of cyclic adenosine mono to the increase in calciuresis re practical terms, for the mean K + phosphate (cAMP) [52, 54]. corded from 0 to 3 and from 3 to flow. Since increases in Na + ex Beta-adrenergic blockers could 6 hours after dosing with clop cretion induced by diuretics en amide 5 mg, which could have tail a rise in the amount of the also affect the processes underly determined a fall in plasma Ca2+ electrolyte available for K + and ing urinary N a+ and K + excre concentration earlier than H + exchange in the last portion tions by influencing plasma al 6 hours after dosing thus raising of the distal tubule, the homo dosterone levels, since the re plasma PTH; the increase in morphism between urinary K + lease of renin by the kidney is plasma PTH could in turn have and N a+ flows after the adminis under the positive control of the caused an increase in Ca2+ and tration of clopamide and placebo sympathetic system at nephronal Mg2+ reabsorptions in the loop would indicate a related underly beta receptors and most aldoster of Henle with a corresponding ing mechanism of a different na one secretion is angiotensin-II decrease in the urinary excretions ture to that accounting for Mg2+ dependent. However, in the of Mg2+ and Ca2+ consistent and Ca2+ flows. The exchange particular case of pindolol, the with the undershoots observed. between N a+ and K + in the dis fact it possesses marked ISA pre The effect of PTH on the reab tal tubule is augmented by the cludes any clear analysis of the sorption of filtered Mg2+ at the secondary hyperaldosteronism flows shown in Fig. 4 because, in loop of Henle would not appear caused by the increase in urinary addition to uncertainty regarding to be as important as it is for N a+ output when a diuretic is the effects of ISA in this situa Ca2+, since the magnitude of the administered. Since this effect is tion, the blocking action of pin undershoot in mean urinary known to become physiologi dolol of the RAA system may Mg2+ flow after clopamide was cally important within a few only be unequivocally assumed lower than that of mean urinary hours of the commencement of to exist when the system is acti Ca2+ flow, to the extent that the the natriuretic action of a di vated concomitantly with the ad Mg2+ undershoot did not bal uretic and to extend for some ministration of pindolol. ance out the effect of the pre hours, it could also partly ex The responses of the mean uri vious increase in mean urinary plain the relatively unimpressive nary flows of Mg2+, Ca2+, N a+ flow on Mg2+ output, as oc undershoot in urinary Mg2+ flow and K + to the administrations of curred with respect to Ca2+. This following clopamide 5 mg. Fur placebo and CLOP + PIND are was perhaps due to the fact PTH ther evidence for an aldoster- shown in Fig. 5, where the flow 132 Magnesium-Bulletin 4/1985 relationships for Mg2+, Ca2+ pect to placebo following CLOP may not be explained in terms of and K + are clearly homo + PIND administration; thus, the plasma-Ca2+-, plasma-PTH morphic, whilst the urinary Na + the homomorphism between the related hypothesis explicited for flow relationship is an outlier. In post-CLOP + PIND and post the homomorphism of the rela the cases of Mg2+, Ca2+ and placebo flows of Mg2+ and K + tionships between the post-pla K +, an initial increase in mean would be similarly explained by cebo and post-clopamide 5 mg urinary flow after CLOP + the fact that the participation of mean urinary flows of these ca PIND with respect to placebo aldosterone in the regulation of tions. The reason for this impos was followed by an undershoot. renal K + and Mg2+ flows be sibility resides in the lack of sta The blunting of aldosterone production by pindolol would came more evident when the tistically significant effect of account for the marked under RAA system was activated by CLOP+ PIND on urinary Ca2+ shoot of urinary Mg2+ flow fol clopamide and simultaneously excretion during the first 3 hours lowing CLOP + PIND with res inhibited by pindolol. The homo after dosing with CLOP + pect to placebo. Similarly, a pin morphism of the relationship be PIND (Table 1), that could have dolol-induced decrease in aldos tween the post-placebo and accounted for a change in terone would account for the post-CLOP + PIND mean uri plasma PTH concentration, and undershoot in K + flow with res- nary flows of Mg2+ and Ca2+ also in that the release of PTH n:9 0,4 0,48 ,.... ,.... -I - I + .c + .c N N . e»o CO 0 \ ::! E (.) 0,2 ~0,24 >~ > a: a:- 32 5,6 ,....- ....- I ~ .c ·"· +CO -0 I + 0 \ ~ E z E 16 I ' 2,8 >~ I > E a: ' a:- Table Ill: Statistical features and parameter values of the linear transformations of the functions M(t). CLOP + PIND = combi nation of clopamide 5 mg and pin dolo! IQ mg. Original Correla ordinate Time to Signif Slope of tion of value of peak ex Urinary Unit used in icance linear Medication linear tl linear- cretion variable calculations ofr (hour) ized M(t) ized M(t) ized M(t) p b tm r a (hour) (hour) Chloride mmol x l Q Placebo Q.9994 Table IV: Serum variables before (hour 0) and after administration of single doses of placebo, clopamide 5 mg, a combination of clopamide 5 mg and pindolol I 0 mg (CLOP + PIND), and pin dolo! l 0 mg to nine healthy volunteers. Values as mean ± S.E.M. Serum Hours after dosing Medication variable 0 6 24 Chloride Placebo 107.0± 1.0 105.7 ± 1.4 106.6± 1.2 (mmol.L-1) Clopamide 5 mg 102.9± 1.3 102.6± 1.7 101.8± 1.7 CLOP+ PIND 105.2±0.9 106.0±0.6 102.4± 1.7 PindolollO mg 104.1 ±0.5 105.3 1.0 103.2± l.l Sodium Placebo 140.7±0.7 140.2±0.5 140.8±0.3 (mmol.L- 1) Clopamide 5 mg 140.3±0.9 139.0±0.9 139.4±0.9 CLOP+ PIND 141.0±0.9 140.4±0.9 141.0± l.l PindolollO mg 140.9±0.8 141.7±0.9 141.7±0.9 Potassium Placebo 4.08±0.07 4.11 ± 0.11 4.41±0.12* (mmol.L- 1) Clopamide 5 mg 4.14±0.08 4.07±0.12 3.90±0.05* CLOP+ PIND 4.24±0.07 3.82 ± 0.07**** 3.79±0.09**** Pindolol 10 mg 4.31 ±0.10 4.11 ±0.07 3.90±0.08*** Calcium Placebo 2.69±0.05 2.63±0.06 2.54±0.06** (mmol.L-1) Clopamide 5 mg 2.54±0.10 2.63±0.06 2.54±0.09 CLOP+ PIND 2.63±0.08 2.69±0.08 2.70±0.07 Pindolol l 0 mg 2.58±0.08 2.54±0.o7 2.57±0.06 Magnesium Placebo 0.81 ±0.01 0.82±0.02 0.83±0.02 (mmol.L- 1) Clopamide 5 mg 0.85±0.02 0.83±0.02 0.83±0.02 CLOP+ PIND 0.84±0.02 0.83±0.02 0.81 ±0.02 Pindololl 0 mg 0.88±0,03 0.85±0.02 0.85±0.02 Inorganic Placebo 1.43 ±O.ll 1.43 ± 0.05•** 1.36±0.06 phosphate Clopamide 5 mg 1.18±0.11 1.28 ±0.14 1.34±0.09 (mmol.L-1) CLOP+ PIND 1.31±0.14 1.30±0.10 1.34±0.10 Pindolol 10 mg 1.21 ± 0.12 1.37±0.09 1.27±0.08 Creatinine Placebo 83.6± 10.9 97.2±3.5 92.7±3.5 (J.Lmol.L- 1) Clopamide 5 mg 102.7±3.5 103.8±4.0 106.2±5.2 CLOP+ PIND 102.5±2.5 104.3±4.5 101.4± 2.5 PindolollO mg 98.5±4.0 101.0±4.6 99.6±2.9 Blood urea Placebo 4.9±0.2 4.4±0.3* 5.7±0.2** nitrogen Clopamide 5 mg 5.0±0.3 4.1 ±0.2* 6.1 ±0.3*** (mmol.L- 1) CLOP+ PIND 5.0±0.3 3.9±0.3*** 5.5±0.4 Pindololl 0 mg 4.7±0.3 3.8±0.3** 4.8±0.3 Urate Placebo 0.36±0.02 0.35±0.02 0.37±0.02 (mmol.L- 1) Clopamide 5 mg 0.35±0.02 0.36±0.02 0.40±0.02**** CLOP+ PIND 0.36±0.02 0.37 ±0.02** 0.40±0.02**** PindolollO mg 0.35±0.02 0.35±0.02 0.38±0.02**** Total C02 Placebo 26.9± 1.0 26.2± 1.0 27.2± 1.0 (mmol.L-1) Clopamide 5 mg 25.6±0.6 26.0±0.7 27.1 ±0.7** CLOP+ PIND 24.3± 1.8 25.1 ±0.8 25.8±0.7 Pindolol l 0 mg 24.8± 1.0 24.7± 1.0 25.2±0.3 Glucose Placebo 5.5±0.3 5.6±0.3 5.3±0.1 (mmol.L-1 Clopamide 5 mg 5.2±0.1 5.4±0.4 5.4±0.2 CLOP+ PIND 5.3±0.1 6.1 ±0.4 5.8±0.1* Pindolol I 0 mg 5.1 ±0.2 6.4±0.6 5.4±0.1 •Data from four patients. Significances of the differences with respect to hour-0 mean values: *p < 0.05; **p<0.02; ***p< 0.01; ****p<0.001. Magnesium-Bulletin 4/1985 135 loop of Henle it is also handled to cardiac arrhythmias) and myo diovascular risk factor [63], in in the distal convoluted tubule, cardial infarction [52, 54]. In ad particular for sudden death in as proven by the fact amiloride dition, the deficiencies of these patients with ischaemic heart dis has been found to promote its re cations may interact with the ef ease, is beyond debate [71]. tention from preurine [33]. In fects of stress in a positive feed Mental stress in hypertensives in consequence, the possibility that back manner [9, 15, 74], and per creases heart rate, augments car aldosterone plays a role in the haps also reduce the chronic ef diac output, causes vasoconstric renal regulation of Ca2+ deserves fect of diuretics to some extent further basic research. tion and diminishes the electrical [13, 60], since Mg2+ exhibits va stability of the heart. Magnesium Clinical relevance of the findings sodilatatory properties in man deficiency also appears to be a The potential risks of diuretic under certain circumstances [25] mediator in the unfavourable al therapy secondary to Mg2+ and and a negative correlation be terations of carbohydrate metab K + depletions include the de tween plasma Mg2+ and blood olism and of the plasma lipid velopment of cardiac arrhyth pressure has been found [48]. profile induced by diuretics [20, mias, sudden death (mainly due The importance of stress as a car- 49,53]. 0,4 .··· 0,48 ., ...... - + .. ... N ~. r.:· . (:' ·, ., ·. .. \. «~o J! f .,·· ... 0 Eo 24 <··. 0,2 E ' if <··. .f ·, .,·-... ·. >_ ·: ·,·•• I . ·-.. a: 1: ., .. . '· ·.. ...... 32 5,6 Y"- ·...... - .....- . \ ·. I I .c: .c: I . ·. + i \ ·.. «< 0 + 0 z .. \ E 16 ::.::: E 2,8 ~ \ . > E > E a: a:- t ., . <( c::c;: i ' .,.. .. z ~0 I a:...J ·- ...... ·· ... .:..: : :..:.· ... 0 :JU.. 0 ·- 0 12 24 0 12 24 HOURS HOURS ...... ····· CLOPAMIDE 5 mg -·-·-·-cLOPAMIDE 5 mgU PINDOLOL 10 mg Fig. 6: Mean urinary Mg2+, Ca2+, Na+ and K + flows after the separate administration of single doses of clopamide 5 mg and of a combination of clopamide 5 mg and pindolol 10 mg {CLOP + PIND) per os to nine healthy volunteers at time 0 {0800 h). The relationships between the post-clopamide and post-(CLOP + PIND) flows are homomorphic for Mg2+, Ca2+ and K +, i.e. each of these three relationships shows two analogous phases. The relationship between the post-placebo and post-(CLOP + PIND) flows of Na+ exhibits an heteromorphic pattern with respect to the flow-relationship pattern common to Mg2 +, Ca2+ and K +. 136 Magnesium-Bulletin 4/1985 The counteraction of clopam captopril and hydrochlorothia plication. The dose relationship ide-induced hypermagnesiuresis zide plus sotalol combinations between the components of a and hyperkaliuresis by pindolol, studied. Low-risk formulations drug combination may not be when both drugs were adminis include captopril, pindolol, and ideal, with the result that hyper tered in a fixed relationship of 5 three diuretic combinations, hy magnesiuresis occurs even in and 10 mg respectively, consti drochlorothiazide 12.5 mg and acute experiments similar to the tutes the most favourable finding acebutolol 200 mg, hydrochlo present [35], or that additive ef in a series of studies in which the rothiazide 50 mg and amiloride fects of small, statistically non effects of various diuretics, pin 5 mg and clopamide 5 mg and significant, increases in daily dolo!, captopril, and combina pindolol 10 mg, the latter exhi Mg2+ or K + outputs become ap tions of hydrochlorothiazide with biting the lowest risk except for parent following prolonged dos acebutolol, amiloride, captopril, pindolol alone. ing with the formulation in ques or sotalol were studied in accord The present findings, and tion. An example of this is given ance with a similar protocol. Ta those derived from similar 24-h by the recent finding that the ble V shows the percentual changes with respect to control studies in healthy individuals, do acute administration of hydro in mean urinary Na+, K+ and not prove that somatic balance chlorothiazide 50 mg and amilo Mg2+ outputs recorded in the of Mg2+ and K + will be neces ride 5 mg caused a statistically studies in question. If the per sarily unaffected by prolonged non significant increase in mean centual changes in mean 24-h ur administration of formulations 24-h urinary Mg2+ output [32], inary K + and Mg2+ outputs fol that do not exhibit magnesiuretic but it caused a statistically signi lowing each formulation are and kaliuretic actions in acute ficant and clinically relevant fall added, an arbitrary indicator of studies like the present. Disease of plasma Mg2 + in hypertensive the potential risk entailed by related, drug-related or other pro patients after 20 weeks therapy therapy with each formulation is cesses coincidental with therapy [33]. The same combination has obtained (Table V). An increased may give place to differences be also been found to significantly risk is associated with the mono tween the results obtained in decrease plasma K + concentra component diuretic formulations acute experiments and those ob tion after a mean treatment and the hydrochlorothiazide plus served in long-term clinical ap- period of 19.5 weeks [47]. Table V: . Percentage changes in the mean 24-hour urinary outputs of Na +, K + and Mg2 + with respect to control values, after the administration of single doses of various antihypertensive formulations to healthy volunteers. Number of Drug and dose o/oL>K+ + %L>Na+ %L>K+ %L>Mg2+ Reference subjects (mg) o/oL> Mg2+ 13 CaptoprillOO mg 3.3 - 4.8 17.6b 12.8 [38] 9 Chlorthalidone I 00 mg 165.4< 69.6b 87.0b 156.6 [58] 9 Clopamide 5 mg 85.lc 25.4• 27.2b 52.6 [this publication] 13 Hydrochlorothiazide 25 mg 33.1< 20.5 73.4< 93.9 [38] 9 Hydrochlorothiazide 50 mg 63.0b 21.9• 43.8• 65.7 [31] 19 Hydrochlorothiazide 50 mg 6l.()c 29.9• 24.5• 54.4 [32] 9 Pindolol10 mg 3.9 -20.1 -14.5 - 34.6 [this publication] 13 Xipamide 5 mg 46.5b 40.6b 27.5b 68.1 [57] 13 Xipamide 10 mg 120.2c 55.4b 50.1< 105.5 [57] 13 Xipamide 20 mg 110.8< 79.5< 40.4c 119.9 [57] 9 Clopamide 5 mg 99.4' 10.4 - 1.4 11.8 [this and pindolol 10 mg publication] 10 Hydrochlorothiazide 12.5 mg 27.1• 12.2 4.3 16.5 [34] and acebutolol200 mg 13 Hydrochlorothiazide 50 mg 70.lc - 5.8 8.2 2.4 [32] and amiloride 5 mg 13 Hydrochlorothiazide 25 mg 74.8c 19.0a 45.1 c 64.1 [38] and captoprill 00 mg 12 Hydrochlorothiazide 50 mg 65.4c 47.8' 19.6• 67.4 [35] and sotalo\320 mg Significances of the differences between corresponding mean values after medication and during control: a p < 0.05; bp< 0.01; c p Various environmental and [5] Bloch, R., Steinner, C., Welsch, M .. [19] Griffing, G. T., Sindler, B. H., Aurec personal physiological and path Schwartz, J.: L'effet hypocalciurique chia, S. A., Melby, J. C.: The effects de !'hydrochlorothiazide, de la of hydrochlorothiazide on the re ological factors which tend to de chlorthalidone, de l'indapamide et nin-aldosterone system. Metabolism crease both somatic Mg2+ and de l'acide tienilique. Therapie 36 32 (1983) 197-201. K + may lead to deficiency of (1981) 567-574. [20] Gueux, E., Rayssiguier, Y., Piot, M. any of the cations per se, aggra [6] Brunner, H.:The antihypertensive ef C., Alcindor, L.: Reduction of fect of beta-blockers. In: Schweitzer, plasma lecithin-cholesterol acyl vate drug-induced losses or act W. (ed.): Beta-blockers - present transferase activity by acute magne together with drug therapy to status and future prospects. Hans sium deficiency in the rat. J. Nutr. produce the deficiencies. 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(1981) 67-72. diuretics is liable to cause deple (eds.): Frontiers in hypertension re [23] Horton, R., Bigheri, E. G.: Effect of tion of this cation, leading to re search. Springer-Verlag, New York/ aldosterone on the metabolism of Heidelberg/Berlin 1981, 423-435. magnesium. J. Clin. Endocrinol. latively minor effects such as [9] Classen, H.-G.: Stress reactions Metab. 22 (1972) 1187-1192. dysosmia and dysgeusia, to modified by magnesium status. [24] Iyun, A. 0., Akinsola, A.: Clinical sexual impotence, which may be Magnesium-Bull. 3 (1981) 148-154. experience with Viskaldix, a combi of significant degree, and to a re [10] Cody, R. J., Laragh, J. H., Case, nation of pindolol and clopamide. tardation in wound-healing [61, D. B., Atlas, S. A.: Renin system ac Curr. Ther. Res. 36 (1984) 490-497. tivity as a determinant of response [25] Ji, B. H., Erne, P., Kiowski, W., 62]. If the latter applied to the to treatment in hypertension and Biihler, F. 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