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 hyper- parathyroidism 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 concentra- tion (mean •}SE) after administra- tion of oxprenolol or metoprolol Student's t test was used for probability . * 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.