EFFECT OF 5-METHOXYTRYPTAMINE ON SERUM CALCIUM AND PHOSPHATE IN RATS

¹ Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina

Injection of 5-methoxytryptamine HCl (5-MT) in a single s.c. dose caused a rapid (within 30 minutes) and prolonged (at least 2-3 hours) hypocalcemia and hyperphosphatemia in rats. The hyperphosphatemic response required at least 5 mg/kg of 5-MT whereas the hypocalcemic response required only 0.2 mg/kg. With pargyline it was possible to dissociate these two responses. Although concurrent administration of pargyline (35 mg/kg i.p.) and 5-MT abolished the hypocalcemia found after 5-MT alone, it strikingly enhanced the 5-MT-induced hyperphosphatemia. Thus the results indicate that production of hyperphosphatemia is not responsible for the fall in serum calcium induced by 5-MT. 5-MT produced hypocalcemia and hyperphosphatemia both in thyroidectomized and parathyroidectomized rats, indicating that these effects were not mediated either by the thyroid or by the parathyroid glands. The effects of 5-MT on serum calcium and phosphate were still evident in acutely nephrectomized rats, indicating that these effects were not mediated by the kidney. Studies using rats labeled with ⁴⁵Ca showed that 5-MT increased the specific activity of plasma calcium (counts per minute per milligram of calcium) by producing a fall in total calcium but not in ⁴⁵Ca. The results with ⁴⁵Ca and the observation that 5-MT counteracted the serum calciumraising effect of parathyroid hormone given to acutely thyroparathyroidectomized rats suggest that 5-MT inhibits calcium mobilization from bone. The hyperphosphatemia must be the result of an action of 5-MT on sites other than bone. Results of structure-activity suggest that the methylation of serotonin at position 5 of the indole nucleus and the presence of a free amino group at position 3 (as represented by 5-MT) are required for the hypocalcemic effect; the amino group may need to be metabolized further since pargyline abolished the hypocalcemic action. The free amino group at position 3 and the concomitant presence of either a hydroxyl or a methoxyl group at position 5 as found in serotonin and 5-MT, respectively, appear to be essential for the production of hyperphosphatemia.