Resistance to the action of PTH is encountered in chronic renal failure (CRF). This was attributed to downregulation of PTH receptor due to the state of secondary hyperparathyroidism of CRF. The present study examined whether the amount of PTH-PTH-related peptide (PTH-PTHrP) mRNA in a traditional (kidney) and a nontraditional (liver) organs for PTH action was reduced in CRF. PTH-PTHrP mRNA was measured in kidney and liver obtained from normal rats, animals with CRF of 6 weeks’ duration, normocalcemic parathyroidectomized CFR rats and from CRF and normal rats treated with verapamil. The mRNA of receptor was quantitated with Northern blot analysis of kidney RNA and liver poly A+ RNA. The relative amounts of mRNA of the PTH-PTHrP receptor to that of β-actin in both kidney and liver of CRF rats were significantly (p < 0.01) lower than in normal animals. Parathyroidec-tomy of CRF rats was followed either by significant (p < 0.01) improvement (kidney) or normalization (liver) of the receptor mRNA. Treatment of CRF rats with verapamil also significantly (p < 0.01) improved the concentration of the receptor mRNA in the kidney. The data demonstrate that CRF is associated with downregulation of the PTH-PTHrP receptor mRNA in kidney and liver. This defect is partially or completely reversed by parathyroidectomy of the CRF rats or their treatment with verapamil. The decrease in the receptor mRNA would likely result in a decrease in PTH receptor synthesis and consequently PTH receptor numbers, and hence relative resistance to the action of PTH. It is proposed that, at least, one signal that mediates the reduction in the amount of the receptor mRNA is the PTH-induced rise in cytosolic calcium in CRF. Indeed, both parathyroidectomy of CRF rats or their treatment with verapamil is associated with normalization of cytosolic calcium and significant improvement in the expression of the receptor mR