PARATHYROID HORMONE-RELATED PROTEIN-DETECTION AND INTERACTION WITH NOAND CYCLIC-AMP IN THE RENOVASCULAR SYSTEM

The presence of parathyroid hormone-related protein (PTHrP) in human k idney vasculature and the signal transduction pathways stimulated duri ng PTHrP-induced vasodilation of the rabbit kidney were investigated. Immunostaining of human kidney revealed the abundant presence of PTHrP in media and intima of all microvessels as well as in macula densa. I n isolated perfused rabbit kidney preconstricted with noradrenaline, 1 0(-5) M Rp-cAMPS, a direct inhibitor of protein kinase A, produced com parable inhibition of 2.5 x 10(-7) M forskolin- and 10(-7) M PTHrP-ind uced vasorelaxations. Renal vasorelaxation and renal microvessel adeny lyl cyclase stimulation underwent comparable desensitization following exposure to PTHrP. Nitric oxide (NO)-synthase inhibition by L-NAME (1 0(-4) M), NO scavenging by an imidazolineoxyl N-oxide (10(-4) M) and g uanylyl cyclase inhibition by methylene blue (10(-4) M) decreased PTHr P-induced vasorelaxation by 27 to 53%, abolished bradykinin-induced va sorelaxation and did not affect forskolin-induced vasorelaxation. The effects of Rp-cAMPS and L-NAME were not additive on PTHrP-induced vaso relaxation. Damaging endothelium by treating the kidney with either an tifactor VIII-related antibody and complement, gossypol or detergent, did nor affect PTHrP- or forskolin-induced vasorelaxations but reduced bradykinin-induced vasorelaxation by 53 to 92%. Conversely, endotheli al damage did not alter the inhibitory action of L-NAME on PTHrP-induc ed vasorelaxation. In conclusion, PTHrP is present throughout the huma n renovascular tree and juxtaglomerular apparatus. Activation of both adenylyl cyclase/protein kinase A and NO-synthase/guanylyl cyclase pat hways are directly linked to the renodilatory action of PTHrP in a way that does not require an intact endothelium in the isolated rabbit ki dney.