DESENSITIZATION OF VASCULAR TISSUE TO PARATHYROID-HORMONE AND PARATHYROID HORMONE-RELATED PROTEIN

Although PTH and PTH-related protein (PTHrP) are vasodilators, prolong ed exposure to elevated levels of PTH is often associated with hyperte nsion. We investigated the effects of prolonged incubation with PTH or PTHrP on arterial segments and cultured vascular smooth muscle cells (VSMC). PTH or PTHrP transiently relaxed precontracted arterial segmen ts within 10 min. Additional PTH or PTHrP added after 40-min exposure to these peptides had little effect on vascular tone, whereas forskoli n, isoproterenol, isobutylmethylxanthine, or acetylcholine were still potent. In fura 2-loaded VSMC, 5-min incubation with PTH or PTHrP atte nuated angiotensin II (Ang II)-induced calcium mobilization, an effect that was reduced by preincubation of VSMC with PTH for 1.5 h. Similar ly, 1.5-h preincubation with PTH or PTHrP decreased the cAMP response to these peptides but not to forskolin or NaF. Ang II potentiated the cAMP response to PTH and PTHrP but was also subject to desensitization . Nle(8,18)Tyr(34) bovine PTH(3-34) amide did not desensitize Vascular tissue to PTH or PTHrP. Our results suggest that homologous desensiti zation to PTH or PTHrP in vascular tissue requires receptor stimulatio n, occurs proximal to G stimulatory protein, and impairs attenuation o f calcium mobilization by PTH or PTHrP. This may be a mechanism by whi ch vasodilator effects of these peptides are decreased with prolonged elevation of PTH levels.