Parathyroid Hormone (PTH)

1299

Beta-antagonist and secondary hyperparathyroidism in chronic renal failure

KATSUJI TAKEDA , EIJI KUSANO, YASUSHI ASANO and SAICHI HOSODA

Department of Cardiology and the Kidney Center , Jichi Medical School Minamikawachi , Tochigi 329-04, Japan

Key words: Parathyroid hormone, calcitonin , oxprenolol, metoprolol, chronic hemodialysis patients

Abstract We evaluated the acute response of parathyroid hormone (PTH) and calcitonin (CT) secretion to non-selective and beta-1 selective antagonists and studied the long-term effects of non-selective beta - antagonists on calcium metabolism in chronic hemodialysis patients . Administration of exprenolol (non-selective) and metoprolol (beta-1 selective) depressed thePTH secretion similarly. Long-term administration of non-selective beta-antagonists resulted in a significant decrease in PTH , CT and alk aline Th phosphatase levels without producing any changes in calcium and phosphate levels. ese results suggest that 1) beta-1 adrenergic receptors may play an imp ortant role in the regulation of PTH secretion, 2) the beta-adrenergic system may also play a role in the regulation of CT secretion, and 3) beta-antagonist therapy may be useful for the prevention of secondary hyperparathyroidism in chronic hemodialysis patients.

Introduction hemodialysis patients have not yet been ade- Parathyroid hormone (PTH) has been postu- quately characterized. In animals, the major effect of calcitonin lated as a potential toxic substance in uremia, and several investigators have suggested that (CT) is to reduce the osteoclast-mediated reab- retention of PTH and its fragments may be sorption of bone. In man, the physiologic responsible for many of the manifestations seen role of CT remains undefined. Many factors in uremia. Ionized calcium (Ca) and magnesium have been identified which augment CT secretion (Mg) are the major determinants of PTH sec- in experimental animals and humans; they in- retion. In vivo and in vitro studies clude Ca, gastrin, cholecystokinin and a variety have indicated that beta-adrenergic receptors of other gastrointestinal hormones . There may play an important role in the secretion of is evidence that beta-adrenergic receptors may PTH. Their pathophysiological role in secondary also be involved However, the beta- hyperparathyroidism is suggested by the observa- receptors mediating CT secretion remain to be tion made in retrospective and prospective characterized. Furthermore, the long-term studies, that chronic oral administration of the effects of beta-antagonists on CT secretion in beta-antagonist propranolol effectively lowers hemodialysis patients are still unknown . elevated PTH levels. However, the beta-adrenergic We evaluated the acute response of PTH and receptors mediating PTH secretion in chronic CT secretion to non-selectiveand beta-1 selective beta-antagonists and studied the long-term

Received December 28 , 1984 effects of non-selective beta-antagonists on Japanese Journal of Nephrology Vol . 27, No. 9, 1985 (77) Katsuji Takeda, et al 1300 secondary hyperparathyroidism in chronic hemo- Table 1. Clinical characteristics of the control and beta-antagonist treated patients dialysis patients. in the chronic study.

Patients and Methods

Prior informed consent was obtained from all subjects participating in the present study.

1. Acute study

Six patients (3 males, 3 females) receiving maintenance hemodialysis participated in this study. They had no asthma or cardiac failure, and the PR interval on ECG was less than 0.2 sec, so that use of beta-antagonists was not con- traindicated. Etiologically, their chronic renal failure was due to chronic glomerulonephritis (4 nephritis (26 patients), nephrosclerosis (2 patients), toxicemia of pregnancy (one patient) patients), polycystic kidney, diabetic nephro- and nephrosclerosis (one patient). The mean age pathy, systemic lupus nephritis, and toxicemia of the patients was 39.0 •} 12.0 (mean •}SD) of pregnancy (one patient each), and miscellane

years. They had undergone hemodialysis for a out causes (3 patients). Maintenance hemodialy mean of 11.0 •} 10.1 months. The serum creati sis was performed for 12-15 hours weekly using nine level was 13.2 •} 2.9 mg/dl. Three of the hollow fiber dialyzers(surface area, 0.8-1.5 m2).

patients were hypertensive, the others were The Ca concentration of the dialysate was normotensive. 6.5 mg/dl. Phosphate-binders were administered Oxprenolol (non-selective beta-antagonist) to maintain the predialysis P concentrations was administered intravenously (i.v.). The prim below 5.5 mg/dl. None of the patients had ing dose was 1 mg diluted in 20 ml of 5% glucose, taken vitamin-D analogs.The patients were divid and this was followed by continuous perfusion ed into a control group (18 patients) and a beta for 60 min at 1 ƒÊg/kg/min. Metoprolol (beta-1 antagonist treated group (17 patients).

selective) was administered according to the same protocol at a dose which produced the 1) Beta-antagonist group: These patients same degree of beta-antagonism: 1.2 mg as the received a non-selective beta-antagonist (pro

priming dose and 1.2 ƒÊg/kg/min for perfusion. pranolol, oxprenolol) for the treatment of Each of the 6 patients received each of the two hypertension and angina pectoris. The drug was drugs at 2-week intervals. The patients rested administered before or after the start of hemo

for 30 min before drug administration. Their dialysis therapy. The averagedose was 60 mg/day heart rate and blood pressure were measured (30-120 mg/day), and administration was con during the treatment period. At 0, 15, 30, and 60 tinued for 11 months (3-24 months). Two min after drug administration, blood was sampl- patients had a urine output of greater than 500 ed to measure the serum calcium (Ca), phos mg/day, and the others voided less than 200 mg/day. phate (P), magnesium (Mg), PTH, and CT levels. 2) Control group: Six of the 18 patients were Chronic study (Table 1) hypertensive. They were treated with agents other than beta-antagonist, i.e., methyldopa, Thirty-five patients on maintenance hemo hydralazine and Ca antagonists. Two patients dialysis were studied. Etiologically, their chronic had a urine output of greater than 500 mg/day, renal failure was due to chronic glomerulo- and the others voided less than 200 ml/day. Japanese Journal of Nephrology Vol. 27, No. 9, 1985 (78) Beta-antagonist and secondary hyperparathyroidism in chronic re nal failure 1301

Analytical methods

Serum calcium, phosphate, magnesium and alkaline phosphatase were measured with an autoanalyzer. PTH was measured by a radio- immunoassay technique using an N-terminal specific antibody in the acute study and a C- terminal antibody in the chronic study. The normal range of PTH levels using the N-terminal antibody is 230-620 pg/ml . The upper normal limit of PTH using the C-terminal antibody is 500 pg/ml. CT was measured by radioimmuno- assay, the upper limit of the normal level being 300 pg/ml.

Statistics Fig. 1. Percentage change in PTH concentration (mean •}SE) after administra-

Student's t test was used for probability tion of oxprenolol or metoprolol . * P<0 determinations employing the formula for equal .01, ** P<0.05, as compared to the basal values. or unequal variances , as indicated by the data.

Results

1) Acute study

a) Effect on PTH concentration The mean PTH concentration was 578 .3 •} 105.8 pg/ml (n=6) before the administration of

oxprenolol and 716.0 •} 246 .9 pg/ml (n=6) before the administration of metoprolol . As shown in (Fig. 1), oxprenolol induced a signifi-

cant decrease in the PTH concentration by 24 .5 •} 4.2% at 15 min, 25.0 •} 10 .9% at 30 min and

24.3 •} 7.3% at 60 min post-administration . At 15 and 30 min post-administration , the decrease in PTH induced by metoprolol was greater than

that induced by exprenolol . b) Effect on CT concentration The mean CT concentration was 115 .8•} 24.1 pg/ml (n=6) before the administration of Fig. 2. Percentage change in CT concentra-

oxprenolol and 107 .0 •} 18.5 pg/ml (n=6) before tion (mean •}SE) after administra- the administration of metoprolol; these tion of oxprenolol or metoprolol . values *P<0 were within the normal limits for CT .02, **p<0.05, as compared . As shown to the basal values. in (Fig. 2) , metoprolol induced a significant increase in the CT concentration by 35 .3 •} 20 ficant effect on the CT concentration at any of .6% at 15 min and by 39 .8 •} 33.5% at 30 min the 3 test points. post-administration, Oxprenolol exerted no signi - Both oxprenolol and metoprolol caused signi- Japanese Journal of Nephrology Vol. 27, No. 9, 1985 (79) Katsuji Takeda, et al 1302 ficant decreases of mean arterial pressure and regulating PTH secretion may be of the beta-2 heart rate during their administration. However, type. Coevoet et a1. demonstrated that in uremic patients, propranolol, a non-selective noticeable side effects of these agents, such as marked hypotension and bradycardia, were not beta-antagonist, acutely suppressed PTH secre- observed. tion and that metoprolol, a beta-1 selective antagonist, did not. They suggested that in these 2) Chronic study patients, PTH secretion is modulated by a specific beta-2 receptor. On the other hand, the in vitro studies of Kukreja et al. revealed that The mean values of PTH were 1850 •} 380 tazolol, a beta-1 selective adrenergic agonist, pg/ml in the control group and 860 •} 100 pg/ml significantly stimulated PTH secretion, whereas in patients receiving the beta-antagonists; these terbutaline, a beta-2 selective agonist, exerted no values were significantly different (p<0.01), as effect. In addition, the beta-1 selective antago- were the mean values of CT and alkaline phos- nist practolol inhibited isoproterenol- or tazolol- phatase (Table 2). There were no significant stimulated PTH secretion. In normal human differences in the serum Ca and P levels between subjects, injection of the non-selective beta- the two patient groups. agonist isoproterenol significantly increased the The serum levels of Ca, P and Mg were thus not significantly altered by oxprenolol or meto- serum PTH levels, whereas the beta-2 selective agonist terbutaline had no effect. These results prolol in the acute and chronic studies. suggest that the adrenergic receptor regulating Table 2. Comparison of laboratory data for PTH secretion may be of the beta-1 type. Our the control and beta-antagonist treat- data are in good agreement with the latter hypo- ed groups. thesis: the similar depression of PTH secretion by oxprenolol and metoprolol in our acute study suggests that beta-1 adrenergic receptors may play an important role in regulating the PTH secretion in chronic hemodialysis patients. Although the physiological role of CT is not yet clear, many factors have been identified which augment its secretion in animals and humans. These include calcium, gastrin, cholecystokinin and various other intestinal hormones. A relationship has also been demonstrated between the beta-adrenergic system and the secretion of CT. Isoprenaline, Discussion epinephrine, and sulbutanol stimulated CT Previous studies have demonstrated a role for secretion which was inhibited by propranolol the beta-adrenergic system in the control of in vitro in animalsi and humansi. In uremic patients, propranolol was shown to pre- PTH secretion. However, the beta-adrenergic vent the increase of CT secretion induced by receptors mediating PTH secretion remain to be alcohol injection. Coevoet et a1. also found characterized. Brown et al. reported hetero- that the CT secretion of uremic patients was geneity of the beta-receptor subtype (beta-1 or significantly decreased by propranolol, but not beta-2) in the parathyroid tissue of different by metoprolol. They concluded that CT secre- patients with hyperparathyroidism. Based on the tion may be modulated by beta-2 receptors in relative PTH response of isolated bovine para- such patients. However, our acute study demon- thyroid cells to beta-agonists (i.e., isoproterenol strated that CT secretion was decreased by > epinephrine > norepinephrine), Brown et neither oxprenolol nor metoprolol. This result al. concluded that the adrenergic receptors

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does not support the existence of a relationship Acknowledgement between the beta-adrenergic system and CT This study was supported in party by a grant from secretion in chronic hemodialysis patients. the Japanese Kindney Foundation Jinkenkyu-kai. Since the beta-adrenergic antagonist reduced the plasma PTH contenctrations on short-term Reprint requests to: administration, we also assessed its long-term Dr. Yasushi Asano: effects on the Ca metabolism in chronic hemo- Kidney Center dialysis patients. The group used for com- Jichi Medical School parative purposes consisted of chronic hemo- Minamikawachi, dialysis patients who did not receive a beta- Tochigi, Japan adrenergic antagonist. The two groups were identical with respect to age, duration of the References disease, period of hemodialysis, and serum creatinine. There were no significant differences 1) Massry S.G., Goldstein D.A.: The search for in the serum calcium and phosphate levels. The uremic toxin(s) "X" "X"=PTH. Clin. Nephrol . 11 : PTH and alkaline phosphatase levels were signifi- 181-189, 1979. 2) Slatopolsky E., Martin K., Hruska K.: Parathyroid cantly lower in the patients receiving beta- hormone metabolism and its potential as a uremic antagonist. These results are in agreement with toxin. Am. J. Physiol. 239, Fl-F12, 1980. those of Caro et a1., suggesting that administ- 3) Aurbach G.D., Brown E.M., Marz S.G.: Receptors ration of a non-selective beta-antagonist is and cyclic nucleotides in secretion and action of clinically useful for the prevention of secondary parathyroid hormone. Calcif Tissue Res. (Suppl.) 22 : 117-126, 1977. hyperparathyroidism in chronic hemodialysis 4) Williams G.A., Hargis G.K., Bowser EN., Henderson patients. W.J., Martinez N.J.: Evidence for a role of adeno The CT levels are usually elevated in chronic sine 3, 5..monophosphate in parathyroid hormone hemodialysis patients. This may be due to release. Endocrinology 92 : 687-691, 1973 . increased CT secretion, delayed degradation, or 5) Brown EM., Hurwitz S., Aurbach G.D.: Beta adrenergic stimulation of cyclic AMP content and both. However, the long-term effects of beta- parathyroid hormone release from isolated bovine antagonists on the serum CT levels remain parathyroid cells. Endocrinology 100 : 1696-1702, unknown. Our study shows that the CT levels 1977. are significantly lower in patients receiving beta- 6) Fischer J.A., Blum J.W., Binswanger U.: Acute antagonists. parathyroid hormone response to epinephrine in vivo. J Clin. Invest. 52 : 2434-2440, 1973. The mechanisms by which beta-antagonists 7) Kukreja S.C;, Johnson P.A,, Ayala G., Banerjee regulate CT release are not yet clear, although P., Bowser EN., Hargis G.K., Williams G.A.: Role of several possibilities may be postulated. One is calcium and beta-adrenergic system in control of that decreased PTH levels can be compensated parathyroid hormone secretion. Proc. Soc. Exp. Biol. Med. 151 : 326-328, 1976 for by a simultaneous decrease in serum CT. . 8) Kukreja S.C., Hargis G.K., Bowser E.N., Henderson Another is that CT secretion may be directly W.J., Fisherman E.W., Williams G.A.: Role of suppressed by the beta-antagonists. In view of adrenergic stimuli in parathyroid hormone sec the evidence for a role of CT in renal osteodys- retion in man. J. Clin. Endocrinol. Metab. 40 : 478-481 trophy, however, the possible adverse effects 1978. of beta-antagonists on renal osteodystrophy 9) Coevoet B., Desplan C., Sebert J.L., Macdassi R., Andrejak M., Gheerbrant J.D., Tolani M., Calmette should always be borne in mind. C., Moukhtar MS., Founier A.: Effect of propra We suggest that beta-antagonists are clinically nolol and metoprolol on parathyroid hormone useful for the prevention of secondary hyper- and calcitonin secretions in uremic patients. Br. Med. parathyroidism in chronic hemodialysis patients J.280 : 1344-1346, 1980. and that these drugs may be the drugs of choice 10) Farrington K., Hamzeh J., Varghese Z., Moorhead J.F.: Effect of oral propranolol on parathyroid for the treatment of hypertension in these hormone secretion in chronic renal failure. Br. patients. Med. J. 281 : 1320, 1980.

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11) Besarb A., Caro J.F., Ihle B.U., Eurke J.F., Calcif. Tissue Res. (Suppl.) 22 : 137-141, 1977. Glennon J.A., Fischer J.A.: Suppression of secondary 19) Brown E.M., Gardner D.G., Windeck R.A., Hurwitz hyperparathyroidism by propranolol in renal failure S., Brennan M.F., Aurbach G.D.: ƒÀ-Adrenergically patients. Nephron 27 : 127-133, 1981. stimulated adenosine 3-, 5--monophosphate ac 12) Aliapoulios A., Goldhaber P., Munson P.: Thyro cumulation in and parathyroid hormone release calcitonin inhibition of bone resorption induced by from dispersed human parathyroid cells. J. Clin. parathyroid hormone in tissue culture. Science 151 : Endocrinol. Metab. 49 : 618-626, 1979. 330-331, 1966. 20) Kukreja S.C., Ayala G.A., Banerjee P., Bowser E. 13) Deftos L.J., Powell D., Parthemore J.G., Potts N., Hargis G.K., Williams G.A.: Characterization of J.T.: Secretion of calcitonin in hypocalcemic states the ƒÀ-adrenergic receptors mediating secretion of

in man. J. Clin. Invest. 52 : 3109-3144, 1973. parathyroid hormone. Horm. Metab. Res. 12 : 334- 14) Cooper C.W., Schwesinger W.H., Mahgoub A.M., 338, 1980. Ontjes D.A.: Thyrocalcitonin: Stimulation of secre 21) Kanis J.A., Adams N.D., Cecchettin M., Luizetto tion by pentagastrin. Science 172 : 1238-1240, G., Heynen G.: Ethanol induced secretion of calci 1971. tonin in chronic renal failure. Clin. Endocrinol. 10 : 15) Care A.D., Bates R.F.L., Gitelmen H.J.: Evidence 155-161, 1979. for a role of cyclic AMP in the release of calcitonin. 22) Caro J.F., Besarb A., Burke J.F., Glennon J.A.: A

Ann. N Y. Acad. Sci. 185 : 317-326, 1971. possible role for propranolol in the treatment of 16) Care A.D., Bruce J.B., Boelkins J., Kenny A.D., renal osteodystrophy. Lancet 2 : 451-453, 1978. Conaway H., Anast C.S.: Role of pancreozymin- 23) Silva O.L., Becker K.L., Shlhoub R.J., Snider R.H., cholecystokinin and structurally related compounds Bivins L.E., Moore C.F.: Calcitonin levels in chronic as calcitonin secretogogues. Endocrinology 89 : renal disease. Nephron 19 : 12-18, 1977. 262-271, 1971. 24) Kanis J.A., Earnshaw M., Heynen G., Ledingham 17) Hsu W.H., Cooper C.W.: Hypercalcemic effect of J.G.G., Oliver DO., Russell R.G.G., Woods C.G., catecholamines and its prevention by thyrocalcitonin. Franchimont P., Gasper S.: Changes in histologic Calcif. Tissue Res. 19 : 125-137, 1975. and biochemical indexes of bone turnover after 18) Heynen G., Cecchettin M., Kanis J., Franchimont bilateral nephrectomy in patients on hemodialysis: P.: The effect of beta-blockade on ethanol induced Evidence for a possible role of endogenous calcito secretion of calcitonin in chronic renal failure. nin.N. Engl. J. Med. 296 : 1073-1079, 1977.

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